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Zhang L, Liu T, Chen M, Gao S, Staley CA, Yang L, Zhu L. Dual inhibition of oxidative phosphorylation and glycolysis using a hyaluronic acid nanoparticle NOX inhibitor enhanced response to radiotherapy in colorectal cancer. Biomaterials 2025; 323:123437. [PMID: 40449083 DOI: 10.1016/j.biomaterials.2025.123437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Revised: 05/04/2025] [Accepted: 05/25/2025] [Indexed: 06/02/2025]
Abstract
Metabolic reprogramming characterized by mitochondrial dysfunction and increased glycolysis is associated with aggressive tumor biology and poor therapeutic response. The interplays among NADPH oxidase (NOX)-mediated reactive oxygen species, regulation of glycolysis and oxidative phosphorylation (OXPHOS) in cancer cells suggest an opportunity to develop a new cancer therapy. We found that treatment with a hyaluronic acid nanoparticle encapsulated with GKT831 (HANP/GKT831), a NOX1/4 inhibitor, markedly inhibited the proliferation and invasion of cancer cells. Treated tumor cells had reduced levels of mitochondrial ROS, glycolysis, and OXPHOS. The combination of HANP/GKT831 with radiation reduced colony formation and invasion of tumor cells. The combination therapy markedly inhibited the levels of molecules in glycolysis, OXPHOS, and DNA repairing pathways in tumor cells. Systemic administrations of HANP/GKT831 combined with radiotherapy significantly inhibited tumor growth by 84.7 % in a mouse colorectal tumor model. Tumors treated with HANP/GKT831 and radiation had increased DNA damage and apoptotic cell death. Furthermore, the combined therapy increased intratumoral infiltration of activated cytotoxic T cells and M1 macrophages but reduced the levels of immunosuppressive fibroblasts and M2 macrophages. Our results support HANP/GKT831 as a cancer nanotherapeutic agent that induces redox and bioenergy stresses in cancer cells for enhanced therapeutic response to radiotherapy.
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Affiliation(s)
- Lumeng Zhang
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, 30322, United States; Department of Nuclear Medicine, China-Japan Union Hospital of Jilin University, Changchun, 130033, China
| | - Tongrui Liu
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, 30322, United States
| | - Minglong Chen
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, 30322, United States; Department of Nuclear Medicine, China-Japan Union Hospital of Jilin University, Changchun, 130033, China
| | - Shi Gao
- Department of Nuclear Medicine, China-Japan Union Hospital of Jilin University, Changchun, 130033, China
| | - Charles A Staley
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, 30322, United States; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, 30322, United States
| | - Lily Yang
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, 30322, United States; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, 30322, United States.
| | - Lei Zhu
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, 30322, United States; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, 30322, United States.
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2
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Gao Y, Song Z, Gan W, Zou X, Bai Y, Zhao X, Chen D, Qiao M. Selective and iron-independent ferroptosis in cancer cells induced by manipulation of mitochondrial fatty acid oxidation. Biomaterials 2025; 320:123259. [PMID: 40112511 DOI: 10.1016/j.biomaterials.2025.123259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Revised: 02/20/2025] [Accepted: 03/14/2025] [Indexed: 03/22/2025]
Abstract
Despite the promise of ferroptosis in cancer therapy, selectively inducing robust ferroptosis in cancer cells remains a significant challenge. In this study, manipulation of fatty acids β-oxidation (FAO) by combination of mild photodynamic therapy (PDT) and inhibition of triglycerides (TGs) synthesis was found to induce robust and iron-independent ferroptosis in cancer cells with dysregulated lipid metabolism for the first time. To achieve that, TGs synthesis inhibitor of xanthohumol (Xan) and FAO initiator of tetrakis (4-carboxyphenyl) porphyrin (TCPP) were co-delivered by a nanoplexes composed of pH-responsive amphiphilic lipopeptide C18-pHis10 and DSPE-PEG2000. TCPP was found to rapidly increase the intracellular ROS under laser irradiation without inducing antioxidant response and apoptosis, activating the AMPK in cancer cells and accelerating mitochondrial FAO. Xan fueled the mitochondrial FAO with substrates by suppressing the conversion of fatty acids (FAs) to TGs. This also led to augmented intracellular polyunsaturated fatty acids (PUFAs) and PUFAs-phospholipids levels, increasing the intrinsic susceptibility of cancer cells to lipid peroxidization. As a result, the excessive ROS generated from the sustained mitochondrial FAO caused remarkably lipid peroxidation and ultimately ferroptosis. Collectively, our study provides a new approach to selectively induce iron-independent ferroptosis in cancer cells by taking advantage of dysregulated lipid metabolism.
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Affiliation(s)
- Yan Gao
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Zilin Song
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Wenxin Gan
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Xue Zou
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Yaning Bai
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Xiuli Zhao
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Dawei Chen
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Mingxi Qiao
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China.
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3
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Kavita, Adiani V, Sharma D, Mishra BB. Effect of gamma irradiation on different components of onion (Allium cepa) skin waste and enhancement of bioactive potentials. Food Chem 2025; 484:144395. [PMID: 40286711 DOI: 10.1016/j.foodchem.2025.144395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 04/15/2025] [Accepted: 04/16/2025] [Indexed: 04/29/2025]
Abstract
The current study was aimed to use gamma irradiation (10-25 kGy) as pre-treatment technique for improved extraction of phenolics and oil from onion dry skin powder (OSP) which was evaluated by TLC, FT/IR and GC/MS methods. Gamma irradiation (10 kGy) enhanced the extractability of oil and phenolics by 80 % and 50 %, respectively. The ethyl acetate extract (EAE) of irradiated (10 kGy) OSP showed significant anti-cancer activity by inhibiting proliferation, migration and inducing apoptosis in mice breast cancer cell line (4T1) at lower concentration of 0.01 % in comparison with pure quercetin. In addition, compositional changes in oil showed oleic, linoleic and palmitic acids as major among eight identified fatty acids. The surface morphology of isolated MCC was also characterized using SEM. These findings demonstrated the valorization of OSP in a zero waste approach using gamma irradiation (10 kGy) which concomitantly improved yield and bioactivities of phenolic constituents for various health applications.
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Affiliation(s)
- Kavita
- Food Technology Division, Bhabha Atomic Research Centre, Mumbai 400085, India; Homi Bhabha National Institute, Anushakti Nagar, Mumbai 400094, India
| | - Vanshika Adiani
- Food Technology Division, Bhabha Atomic Research Centre, Mumbai 400085, India; Homi Bhabha National Institute, Anushakti Nagar, Mumbai 400094, India
| | - Deepak Sharma
- Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai 400085, India; Homi Bhabha National Institute, Anushakti Nagar, Mumbai 400094, India
| | - Bibhuti Bhusan Mishra
- Food Technology Division, Bhabha Atomic Research Centre, Mumbai 400085, India; Homi Bhabha National Institute, Anushakti Nagar, Mumbai 400094, India.
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Rogalewicz B, Czylkowska A. Recent advances in the discovery of copper(II) complexes as potential anticancer drugs. Eur J Med Chem 2025; 292:117702. [PMID: 40328033 DOI: 10.1016/j.ejmech.2025.117702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Revised: 04/13/2025] [Accepted: 04/27/2025] [Indexed: 05/08/2025]
Abstract
This review article offers a literature search of the most active, new copper (II) anticancer complexes based on nitrogen-containing ligands, reported in the literature over the past 5 years: from the beginning of 2019, until mid-2024. In the modern world, cancer remains one of the deadliest diseases of all. Although years of the ongoing research allowed us to better understand its nature, and thus aim more precisely at specific molecular targets and pathways, many of its aspects remain unclear. Today, chemotherapy still remains at the forefront of cancer treatment. With the ever-growing struggles to overcome chemoresistance and occurrence of serious side effects, the discovery of new, more selective and active drugs is a task of an utmost importance. At the same time, copper (II)-based compounds offer a wide array of biological activities and valuable biochemical properties. This review article provides the update on the recent advances in the discovery of new potential anticancer drugs among copper (II)-based compounds in the recent five years.
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Affiliation(s)
- Bartłomiej Rogalewicz
- Institute of General and Ecological Chemistry, Faculty of Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924, Lodz, Poland.
| | - Agnieszka Czylkowska
- Institute of General and Ecological Chemistry, Faculty of Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924, Lodz, Poland.
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5
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Duan D, Yang X, Guo X, Li M, Jin X, Wang L, Xiao J, Wang X, Song P. Interaction of glaucocalyxin a with glutathione and thioredoxin reductase for triple-negative breast cancer treatment. Bioorg Chem 2025; 161:108572. [PMID: 40359839 DOI: 10.1016/j.bioorg.2025.108572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Revised: 05/06/2025] [Accepted: 05/07/2025] [Indexed: 05/15/2025]
Abstract
Glaucocalyxin A (GLA) is a bioactive diterpenoid isolated from Rabdosia japonica var. that has been applied for centuries in traditional Chinese medicine. Although GLA exhibits potent anticancer activity against various human cancer cells, its cellular targets remain largely unidentified. We reported here that GLA covalently modifies glutathione and selectively inhibits TrxR activity by primarily targeting the Sec498 residue of the protein. Pharmacologic inhibition of TrxR with GLA results in accumulation of reactive oxygen species, decreased total glutathione and thiols, collapse of the intracellular redox balance, and eventually induction of oxidative stress mediated apoptosis in triple-negative breast cancer cells. Importantly, knockdown of TrxR1 increases the sensitivity cells to GLA. Targeting TrxR by GLA thus discloses a newly identified molecular mechanism underlying the biological activity of GLA, and provides an in-depth insight in understanding the action of GLA in treatment of cancer.
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Affiliation(s)
- Dongzhu Duan
- Shaanxi Key Laboratory of Phytochemistry and College of Chemistry and Chemical Engineering, Baoji University of Arts and Sciences, Baoji 721013, China.
| | - Xing Yang
- Shaanxi Key Laboratory of Phytochemistry and College of Chemistry and Chemical Engineering, Baoji University of Arts and Sciences, Baoji 721013, China
| | - Xiangyu Guo
- Shaanxi Key Laboratory of Phytochemistry and College of Chemistry and Chemical Engineering, Baoji University of Arts and Sciences, Baoji 721013, China
| | - Mi Li
- School of Pharmacy, Gansu University Key Laboratory for Molecular Medicine & Chinese Medicine Prevention and Treatment of Major Diseases, and Affiliated Hospital of Gansu University of Chinese Medicine and Key Laboratory of Prevention and Treatment for Chronic Diseases by TCM, Gansu University of Chinese Medicine, Lanzhou 730000, China
| | - Xiaojie Jin
- School of Pharmacy, Gansu University Key Laboratory for Molecular Medicine & Chinese Medicine Prevention and Treatment of Major Diseases, and Affiliated Hospital of Gansu University of Chinese Medicine and Key Laboratory of Prevention and Treatment for Chronic Diseases by TCM, Gansu University of Chinese Medicine, Lanzhou 730000, China
| | - Le Wang
- Shaanxi Key Laboratory of Phytochemistry and College of Chemistry and Chemical Engineering, Baoji University of Arts and Sciences, Baoji 721013, China
| | - Jian Xiao
- Shaanxi Key Laboratory of Phytochemistry and College of Chemistry and Chemical Engineering, Baoji University of Arts and Sciences, Baoji 721013, China
| | - Xiaoling Wang
- Shaanxi Key Laboratory of Phytochemistry and College of Chemistry and Chemical Engineering, Baoji University of Arts and Sciences, Baoji 721013, China.
| | - Peng Song
- School of Pharmacy, Gansu University Key Laboratory for Molecular Medicine & Chinese Medicine Prevention and Treatment of Major Diseases, and Affiliated Hospital of Gansu University of Chinese Medicine and Key Laboratory of Prevention and Treatment for Chronic Diseases by TCM, Gansu University of Chinese Medicine, Lanzhou 730000, China.
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6
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Verma N, Patel B, Sharma B, Kumari S, Hussain S, Patel HD, Priya K. Methyl Gallate: A Potent Bioactive Compound Promoting Osteogenic Differentiation by Regulating Runx2 and Cbfa1 in Osteoblastic Cell Lines. Biotechnol Appl Biochem 2025. [PMID: 40566992 DOI: 10.1002/bab.2784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Accepted: 05/03/2025] [Indexed: 06/28/2025]
Abstract
Osteoporosis is a widespread condition, particularly affecting women and high-aged groups, with limited allopathic treatment options leading to adverse effects. The interest in natural remedies for osteoporosis is growing, and plant-based compounds are being explored for their potential to promote bone regeneration. Vachellia nilotica, known for its various medicinal properties, has shown promise in traditional medicine but lacks scientific evidence for its role in osteoporosis treatment. This study focused on isolating from V. nilotica leaves and characterizing a compound, methyl 3,4,5-trihydroxybenzoate (methyl gallate), and its action upon osteoblastic cell lines to deal with osteoporotic disease. Methyl gallate is a phenolic compound. Methyl gallate is a substance that is used for many functions in the body; for example, it is used as an anti-inflammatory, an antioxidant, a neuroprotector, a hepato-protector, and an immunomodulator, as well as leading a range of research and development activities. The compound exhibited no cytotoxic effects at low concentrations on the MG 63 cell line, indicating its safety. It also demonstrated significant antioxidant activity, with the ability to scavenge radicals and reduce oxidative stress. Moreover, the isolated compound showed a stimulating effect on alkaline phosphatase activity, a marker of early differentiation of osteoblasts, thereby decreasing the activity of osteoclasts and thus leading to increased mineralization. The above results suggest the compound's potential to promote bone regeneration and healing. Overall, this study provides valuable insights into the compound's osteogenic differentiation properties from V. nilotica leaves and their potential as a natural remedy for osteoporosis.
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Affiliation(s)
- Neha Verma
- Department of Life Sciences, Sharda School of Bio-Science & Technology, Sharda University, Knowledge Park-III, Greater Noida, Uttar Pradesh, India
| | - Bimalkumar Patel
- Department of Chemistry, School of Science, Gujarat University, Ahmedabad, India
| | - Bhawna Sharma
- Department of Life Sciences, Sharda School of Bio-Science & Technology, Sharda University, Knowledge Park-III, Greater Noida, Uttar Pradesh, India
| | - Shilpa Kumari
- Department of Life Sciences, Sharda School of Bio-Science & Technology, Sharda University, Knowledge Park-III, Greater Noida, Uttar Pradesh, India
| | - Showket Hussain
- Division of Molecular Biology, National Institute of Cancer Prevention and Research, ICMR, Noida, Uttar Pradesh, India
| | - Hitesh D Patel
- Department of Chemistry, School of Science, Gujarat University, Ahmedabad, India
| | - Kanu Priya
- Department of Life Sciences, Sharda School of Bio-Science & Technology, Sharda University, Knowledge Park-III, Greater Noida, Uttar Pradesh, India
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7
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Yang X, Yu L, Shao M, Yang H, Qi K, He G, Wang L, Kong D, Gu J, Xu X, Wang L. N6-methyladenosine-modified GPX2 impacts cancer cell stemness and TKI resistance through regulating of redox metabolism. Cell Death Dis 2025; 16:458. [PMID: 40533443 PMCID: PMC12177039 DOI: 10.1038/s41419-025-07764-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 05/13/2025] [Accepted: 06/03/2025] [Indexed: 06/22/2025]
Abstract
As a predominant oncogenic driver in non-small cell lung cancer (NSCLC), EGFR frequently undergoes amplification or mutation, with EGFR-tyrosine kinase inhibitors (EGFR-TKIs) like gefitinib and erlotinib constituting frontline therapy for advanced EGFR-mutant cases. However, both primary and acquired resistance significantly limit clinical efficacy. Here, we revealed that glutathione metabolic pathway controlled by glutathione peroxidase GPX2 was abnormally activated in gefitinib-resistant A549 and HCC827-GR cell lines. Mechanistically, GPX2 triggers Hedgehog signaling activation through releasing GLI transcriptional regulator, promoting cancer stem cell (CSC) characteristics and TKI resistance. Notably, N6-methyladenosine (m6A) modification on GPX2 mRNA mediated by METTL14 diminished its stability. In vivo, GPX2 deletion constrained glutathione metabolism and boosted the effectiveness of TKI in cell line-derived xenograft models. Collectively, these findings demonstrate that GPX2 serves as a positive regulator of both primary and acquired EGFR-TKI resistance and could be a promising therapeutic target for precise treatment of NSCLC.
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Affiliation(s)
- Xu Yang
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Long Yu
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Miaomiao Shao
- School of Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Huiling Yang
- Department of Pathology, The First Affiliated Hospital of Naval Medical University, Shanghai, 200003, China
| | - Kangwei Qi
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Gaofei He
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Lanxin Wang
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Di Kong
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Jianxin Gu
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Xiaolin Xu
- Department of Cardiothoracic Surgery, The Third Affiliated Hospital of Naval Medical University, Shanghai, 200003, China.
| | - Lan Wang
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
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Wang M, Xiao Y, Miao J, Zhang X, Liu M, Zhu L, Liu H, Shen X, Wang J, Xie B, Wang D. Oxidative Stress and Inflammation: Drivers of Tumorigenesis and Therapeutic Opportunities. Antioxidants (Basel) 2025; 14:735. [PMID: 40563367 DOI: 10.3390/antiox14060735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2025] [Revised: 06/08/2025] [Accepted: 06/12/2025] [Indexed: 06/28/2025] Open
Abstract
As two pivotal regulatory factors in cancer biology, oxidative stress and inflammation interact dynamically through complex network mechanisms to influence tumor initiation, progression, and treatment resistance. Oxidative stress induces genomic instability, oncogenic signaling activation, and tumor microenvironment (TME) remodeling via the abnormal accumulation of reactive oxygen species (ROS) or reactive nitrogen species (RNS). Conversely, inflammation sustains malignant phenotypes by releasing pro-inflammatory cytokines and chemokines and promoting immune cell infiltration. These processes create a vicious cycle via positive feedback loops whereby oxidative stress initiates inflammatory signaling, while the inflammatory milieu further amplifies ROS/RNS production, collectively promoting proliferation, migration, angiogenesis, drug resistance, and immune evasion in tumor cells. Moreover, their crosstalk modulates DNA damage repair, metabolic reprogramming, and drug efflux pump activity, significantly impacting the sensitivity of cancer cells to chemotherapy, radiotherapy, and targeted therapies. This review systematically discusses these advances and the molecular mechanisms underlying the interplay between oxidative stress and inflammation in cancer biology. It also explores their potential as diagnostic biomarkers and prognostic indicators and highlights novel therapeutic strategies targeting the oxidative stress-inflammation axis. The goal is to provide a theoretical framework and translational roadmap for developing synergistic anti-tumor therapies.
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Affiliation(s)
- Meimei Wang
- School of Life and Health Technology, Dongguan University of Technology, Dongguan 523808, China
| | - Yaping Xiao
- School of Life and Health Technology, Dongguan University of Technology, Dongguan 523808, China
| | - Jie Miao
- School of Life and Health Technology, Dongguan University of Technology, Dongguan 523808, China
| | - Xin Zhang
- School of Life and Health Technology, Dongguan University of Technology, Dongguan 523808, China
| | - Meng Liu
- School of Life and Health Technology, Dongguan University of Technology, Dongguan 523808, China
| | - Longchao Zhu
- School of Life and Health Technology, Dongguan University of Technology, Dongguan 523808, China
| | - Hongxin Liu
- School of Life and Health Technology, Dongguan University of Technology, Dongguan 523808, China
| | - Xiaoyan Shen
- School of Life and Health Technology, Dongguan University of Technology, Dongguan 523808, China
| | - Jihui Wang
- School of Life and Health Technology, Dongguan University of Technology, Dongguan 523808, China
| | - Biao Xie
- Department of Gastroenterology, Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou 510440, China
| | - Di Wang
- School of Life and Health Technology, Dongguan University of Technology, Dongguan 523808, China
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Zhang J, Wang J, Wang X, Yan Z, Meng L, Zhang Y. Pterostilbene Reduces Cyclophosphamide-Induced Interstitial Cystitis by Facilitating Nrf2 Activation and Suppressing the NLRP3 Inflammasome Pathway. Int J Mol Sci 2025; 26:5490. [PMID: 40564957 DOI: 10.3390/ijms26125490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2025] [Revised: 06/05/2025] [Accepted: 06/05/2025] [Indexed: 06/28/2025] Open
Abstract
Interstitial cystitis/bladder pain syndrome (IC/BPS) causes significant discomfort in patients and impairs the quality of urination. Pterostilbene (PTE), a natural polyphenol antioxidant, has demonstrated beneficial effects in mitigating inflammation, enhancing antioxidant capacity, and ameliorating organ dysfunction in various chronic nonspecific inflammatory conditions. The aim of this study was to evaluate the efficacy of PTE in IC/BPS and elucidate its underlying mechanisms using a rat model of cyclophosphamide (CYP)-induced interstitial cystitis. In comparison, chronic pain progression, histopathological features, and cytokine levels demonstrated that PTE mitigated the severity of symptoms in CYP-induced rats by inhibiting the NLRP3 inflammasome in a dose-dependent manner. Further mechanistic investigations indicated that PTE intervention alleviated oxidative stress in CYP-induced IC in rats via activation of the Nrf2/HO-1 signaling pathway. Moreover, inhibitors of the Nrf2/HO-1 pathway effectively blocked PTE-mediated attenuation of oxidative stress. The suppression of NLRP3 inflammasome activation by PTE could also be reversed by inhibition of the Nrf2/HO-1 pathway. In vitro studies revealed that PTE enhanced the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and suppressed NLRP3 inflammasome activation in SV-HUC-1 cells exposed to lipopolysaccharide (LPS) and Adenosine Triphosphate (ATP). These findings collectively suggest that PTE treatment inhibits oxidative stress and suppresses NLRP3 inflammasome activation through modulation of the Nrf2/HO-1 pathway.
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Affiliation(s)
- Jiong Zhang
- Peking University Fifth School of Clinical Medicine, Beijing 100730, China
- Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Beijing 100730, China
| | - Jipeng Wang
- Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Beijing 100730, China
| | - Xinhao Wang
- Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Beijing 100730, China
| | - Zehao Yan
- Peking University Fifth School of Clinical Medicine, Beijing 100730, China
| | - Lingfeng Meng
- Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Beijing 100730, China
| | - Yaoguang Zhang
- Peking University Fifth School of Clinical Medicine, Beijing 100730, China
- Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Beijing 100730, China
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10
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Peng H, Ren J, Zhao Y, Fang X, Wang X, Liu C, Wan Z. Unraveling the Connection between PCOS and renal Complications: Current insights and Future Directions. Diabetes Res Clin Pract 2025; 224:112235. [PMID: 40334925 DOI: 10.1016/j.diabres.2025.112235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2025] [Revised: 04/24/2025] [Accepted: 05/05/2025] [Indexed: 05/09/2025]
Abstract
Polycystic ovary syndrome (PCOS) represents the most prevalent endocrine disorder among women of reproductive age, affecting approximately 5-18% of females worldwide. Characterized by irregular ovulation, hyperandrogenism, and polycystic ovaries, hyperandrogenism is the defining feature. Recent evidence highlights that, in addition to its notable reproductive and metabolic consequences, PCOS may also contribute to an elevated risk of renal complications. This increased risk is attributed to chronic low-grade inflammation, hormonal dysregulation, and disturbances in lipid metabolism inherent to the condition. However, the pathological mechanisms, clinical manifestations, and progression of secondary renal damage in this cohort remain insufficiently studied. This review consolidates current understanding of the relationship between PCOS and chronic kidney disease (CKD), aiming to clarify potential mechanisms by which PCOS may induce secondary renal dysfunction, encompassing both direct renal impairment and indirect damage mediated through systemic alterations. Furthermore, it advocates for comprehensive management strategies to mitigate renal risks in patients with PCOS, emphasizing the necessity of multidisciplinary approaches and further research to address these critical gaps.
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Affiliation(s)
- Haoyu Peng
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
| | - Junyi Ren
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Yang Zhao
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China; Department of Health Management Center & Institute of Health Management, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Xinyi Fang
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Xiaoxiao Wang
- Department of Organ Transplantation, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Chi Liu
- Department of Nephrology, Sichuan Clinical Research Center for Kidney Disease, Sichuan Provincial People's Hospital, University of Electronic Science and Technology, Chengdu, China.
| | - Zhengwei Wan
- Department of Health Management Center & Institute of Health Management, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
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11
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Abdalbari FH, Forgie BN, Zorychta E, Goyeneche AA, Noman ASM, Telleria CM. The gold complex auranofin sensitizes platinum resistant epithelial ovarian cancer cells to cisplatin. Biochem Biophys Rep 2025; 42:101996. [PMID: 40230496 PMCID: PMC11995746 DOI: 10.1016/j.bbrep.2025.101996] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2025] [Revised: 03/26/2025] [Accepted: 03/27/2025] [Indexed: 04/16/2025] Open
Abstract
Although numerous drugs have been tested to treat ovarian cancer (OC), survival rates remain low as there has been no major improvement from platinum (Pt)-based therapy and there is a high rate of Pt resistance in these tumors. Following several rounds of chemotherapy, OC cells develop Pt-resistance by increasing DNA repair and antioxidant defense mechanisms. This study aimed to design a treatment to combat recurrent stages of OC by repurposing the anti-rheumatic gold complex auranofin (AF). We demonstrate that AF enhances the efficacy of cisplatin (CDDP) in Pt-resistant epithelial OC (EOC) cells. The drug combination enhanced mitochondrial-dependent apoptosis, PARP cleavage, DNA damage, and ROS overproduction. These results suggest the potential to combine AF with CDDP as a strategy to improve CDDP sensitivity in recurrent EOCs.
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Affiliation(s)
- Farah H. Abdalbari
- Experimental Pathology Unit, Department of Pathology, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, H3A 2B4, Canada
| | - Benjamin N. Forgie
- Experimental Pathology Unit, Department of Pathology, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, H3A 2B4, Canada
| | - Edith Zorychta
- Experimental Pathology Unit, Department of Pathology, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, H3A 2B4, Canada
| | - Alicia A. Goyeneche
- Experimental Pathology Unit, Department of Pathology, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, H3A 2B4, Canada
- Cancer Research Program, Research Institute, McGill University Health Centre, Montreal, QC, H4A 3J1, Canada
| | - Abu Shadat M. Noman
- Department of Biochemistry and Molecular Biology, Chittagong University, Chittagong, Bangladesh
- Department of Pharmacology & Therapeutics, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, H3A 2B4, Canada
| | - Carlos M. Telleria
- Experimental Pathology Unit, Department of Pathology, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, H3A 2B4, Canada
- Cancer Research Program, Research Institute, McGill University Health Centre, Montreal, QC, H4A 3J1, Canada
- Gerald Bronfman Department of Oncology, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, H4A 3T2, Canada
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12
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Cornu M, Lemaitre T, Kieffer C, Voisin-Chiret AS. PROTAC 2.0: Expanding the frontiers of targeted protein degradation. Drug Discov Today 2025; 30:104376. [PMID: 40348076 DOI: 10.1016/j.drudis.2025.104376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2025] [Revised: 04/24/2025] [Accepted: 05/02/2025] [Indexed: 05/14/2025]
Abstract
Proteolysis targeting chimera (PROTAC) technology has revolutionized targeted protein degradation via the ubiquitin-proteasome system. Despite their efficacy in degrading previously undruggable proteins, classical PROTACs face challenges such as poor permeability, dose-dependent effects, and off-target toxicity, prompting the rise of next-generation PROTACs (PROTAC 2.0). This review explores emerging PROTAC-based strategies aimed at enhancing selectivity, bioavailability, and pharmacokinetics. We discuss innovative approaches such as photoactivable PROTACs, hypoxia-responsive degraders, dual and trivalent PROTACs, and antibody-conjugated degraders. Additionally, nanotechnology-based delivery systems are highlighted as promising tools to overcome membrane permeability issues. By analyzing these novel strategies, we highlight the evolution of PROTACs and their growing therapeutic potential. Advances in PROTAC 2.0 technologies are expected to expand their clinical applications, offering more selective and efficient degradation mechanisms.
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Affiliation(s)
- Marie Cornu
- Université de Caen Normandie, CERMN UR4258, Normandie Université, F-14000 Caen, France
| | - Thomas Lemaitre
- Université de Caen Normandie, CERMN UR4258, Normandie Université, F-14000 Caen, France
| | - Charline Kieffer
- Université de Caen Normandie, CERMN UR4258, Normandie Université, F-14000 Caen, France
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13
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Gencheva R, Coppo L, Arnér ESJ, Ren X. Selenium supplementation protects cancer cells from the oxidative stress and cytotoxicity induced by the combination of ascorbate and menadione sodium bisulfite. Free Radic Biol Med 2025; 233:317-329. [PMID: 40180024 DOI: 10.1016/j.freeradbiomed.2025.03.049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Revised: 03/28/2025] [Accepted: 03/31/2025] [Indexed: 04/05/2025]
Abstract
The combination of ascorbate (vitamin C) and menadione sodium bisulfite (MSB, vitamin K3), here called VC/VK3 (also named Apatone®, or M/A), has shown selective cytotoxicity in cancer cells and is under clinical investigation as a cancer therapy. However, the mechanisms of VC/VK3-induced cell death are not fully understood. In this in vitro study using human glioblastoma and non-transformed glial cell lines, we found that VC/VK3 caused higher toxicity in cancer cells in an H2O2- and iron-dependent manner, suggesting that ferroptosis may play a role in the cell death process. Furthermore, selenium supplementation significantly protected cancer cells from VC/VK3 treatment concomitantly with enhanced expression levels and enzymatic activity of antioxidant selenoproteins, including thioredoxin reductases (TXNRDs) and glutathione reductases (GPXs). We also found that VC/VK3 competes for electrons with thioredoxin (TXN), impairing peroxiredoxin 1 (PRDX1) in cells. Finally, chemically inhibiting TXNRDs or the glutathione-dependent antioxidant systems exaggerated the toxicity of VC/VK3. Overall, this study elucidated parts of the cell death mechanisms of VC/VK3 and identified combination strategies to overcome selenium-mediated resistance, advancing the translational potential of this prooxidant treatment.
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Affiliation(s)
- Radosveta Gencheva
- Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, 17177, Sweden
| | - Lucia Coppo
- Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, 17177, Sweden
| | - Elias S J Arnér
- Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, 17177, Sweden; Department of Selenoprotein Research, National Tumor Biology Laboratory, National Institute of Oncology, 1122, Budapest, Hungary
| | - Xiaoyuan Ren
- Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, 17177, Sweden; IC-MedTech Corporation, Las Vegas, NV, USA.
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14
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Mao L, Lu J, Wen X, Song Z, Sun C, Zhao Y, Huang F, Chen S, Jiang D, Che W, Zhong C, Yu C, Li K, Lu X, Shi J. Cuproptosis: mechanisms and nanotherapeutic strategies in cancer and beyond. Chem Soc Rev 2025. [PMID: 40433941 DOI: 10.1039/d5cs00083a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/29/2025]
Abstract
Cuproptosis, a novel form of copper (Cu)-dependent programmed cell death, is induced by directly binding Cu species to lipoylated components of the tricarboxylic acid (TCA) cycle. Since its discovery in 2022, cuproptosis has been closely linked to the field of materials science, offering a biological basis and bright prospects for the use of Cu-based nanomaterials in various disease treatments. Owing to the unique physicochemical properties of nanomaterials, Cu delivery nanosystems can specifically increase Cu levels at disease sites, inducing cuproptosis to achieve disease treatment while minimizing the undesirable release of Cu in normal tissues. This innovative nanomaterial-mediated cuproptosis, termed as "nanocuproptosis", positions at the intersection of chemistry, materials science, pharmaceutical science, and clinical medicine. This review aims to comprehensively summarize and discuss recent advancements in cuproptosis across various diseases, with a particular focus on cancer. It delves into the biochemical basis of nanomaterial-mediated cuproptosis, the rational design for cuproptosis inducers, strategies for enhancing therapeutic specificity, and cuproptosis-centric synergistic cancer therapeutics. Beyond oncology, this review also explores the expanded applications of cuproptosis, such as antibacterial, wound healing, and bone tissue engineering, highlighting its great potential to open innovative therapeutic strategies. Furthermore, the clinical potential of cuproptosis is assessed from basic, preclinical to clinical research. Finally, this review addresses current challenges, proposes potential solutions, and discusses the future prospects of this burgeoning field, highlighting cuproptosis nanomedicine as a highly promising alternative to current clinical therapeutics.
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Affiliation(s)
- Lijie Mao
- Department of Cardiology, Shanghai Tenth People's Hospital, Shanghai Frontiers Science Center of Nanocatalytic Medicine, School of Medicine, Tongji University, Shanghai 200092, China
- Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, China.
| | - Ji Lu
- Department of Cardiology, Shanghai Tenth People's Hospital, Shanghai Frontiers Science Center of Nanocatalytic Medicine, School of Medicine, Tongji University, Shanghai 200092, China
| | - Xinyu Wen
- Shanghai Skin Disease Hospital, Institute of Dermatology, School of Medicine, Tongji University, Shanghai 200443, China
| | - Zhiyi Song
- Department of Cardiology, Shanghai Tenth People's Hospital, Shanghai Frontiers Science Center of Nanocatalytic Medicine, School of Medicine, Tongji University, Shanghai 200092, China
| | - Cai Sun
- Department of Cardiology, Shanghai Tenth People's Hospital, Shanghai Frontiers Science Center of Nanocatalytic Medicine, School of Medicine, Tongji University, Shanghai 200092, China
| | - Yuanru Zhao
- Department of Cardiology, Shanghai Tenth People's Hospital, Shanghai Frontiers Science Center of Nanocatalytic Medicine, School of Medicine, Tongji University, Shanghai 200092, China
| | - Fang Huang
- Department of Cardiology, Shanghai Tenth People's Hospital, Shanghai Frontiers Science Center of Nanocatalytic Medicine, School of Medicine, Tongji University, Shanghai 200092, China
| | - Si Chen
- Department of Cardiology, Shanghai Tenth People's Hospital, Shanghai Frontiers Science Center of Nanocatalytic Medicine, School of Medicine, Tongji University, Shanghai 200092, China
- Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, China.
| | - Dongyang Jiang
- Department of Cardiology, Shanghai Tenth People's Hospital, Shanghai Frontiers Science Center of Nanocatalytic Medicine, School of Medicine, Tongji University, Shanghai 200092, China
| | - Wenliang Che
- Department of Cardiology, Shanghai Tenth People's Hospital, Shanghai Frontiers Science Center of Nanocatalytic Medicine, School of Medicine, Tongji University, Shanghai 200092, China
| | - Cheng Zhong
- Department of Nephrology, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200065, China.
| | - Chen Yu
- Department of Nephrology, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200065, China.
| | - Ke Li
- School of Materials Science and Engineering, Hainan University, Haikou 570228, China.
| | - Xiangyu Lu
- Department of Nephrology, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200065, China.
- Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, China.
| | - Jianlin Shi
- Department of Cardiology, Shanghai Tenth People's Hospital, Shanghai Frontiers Science Center of Nanocatalytic Medicine, School of Medicine, Tongji University, Shanghai 200092, China
- Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, China.
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15
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Li Z, Lu Y, Wang L, Shi L, Wang T. Reactive oxygen species-dependent nanomedicine therapeutic modalities for gastric cancer. NANOSCALE ADVANCES 2025; 7:3210-3227. [PMID: 40308560 PMCID: PMC12038724 DOI: 10.1039/d5na00321k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/06/2025] [Accepted: 04/15/2025] [Indexed: 05/02/2025]
Abstract
Reactive oxygen species (ROS) play a double-edged role in gastric cancer (GC). Higher levels of ROS in tumor cells compared to normal cells facilitate tumor progression. Once ROS concentrations rise rapidly to toxic levels, they cause GC cell death, which is instead beneficial for GC treatment. Based on these functions, nano-delivery systems taking the therapeutic advantages of ROS have been widely employed in tumor therapy in recent years, overcoming the drawbacks of conventional drug delivery techniques, such as non-specific systemic effects. In this review, the precise impacts of ROS on GC have been detailed, along with ROS-based nanomedicine therapeutic schemes. These strategies mainly focused on the use of excess ROS in the tumor microenvironment for controlled drug release and a substantial enhancement of ROS concentrations for tumor killing. The challenges and opportunities for the advancement of these anticancer therapies are also emphasized.
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Affiliation(s)
- Zhiyan Li
- Department of Thoracic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School Nanjing 210008 China
| | - Yanjun Lu
- Division of Gastric Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School Nanjing 210008 China
| | - Lulu Wang
- Department of Thoracic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School Nanjing 210008 China
| | - Liuyi Shi
- Yangzhou University Medical College Yangzhou 225001 China
| | - Tao Wang
- Department of Thoracic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School Nanjing 210008 China
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16
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Fu Y, Hao H, Fang Y, Sun S, Wen S, Liu Y, Tang J, Wang T, Wu M. Copper Peroxide-Ring Stabilized Bicelle Loaded with GSH-Responsive Derivative of Doxorubicin to Induce Amplified Cuproptosis. Adv Healthc Mater 2025:e2500691. [PMID: 40424095 DOI: 10.1002/adhm.202500691] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Revised: 05/12/2025] [Indexed: 05/29/2025]
Abstract
The traditional copper ion carrier, elesclomol, relies on transporting extracellular copper ions into cells. However, the limited extracellular copper ions hinder the copper accumulation inside cells, limiting the cuproptosis effects and thus reducing its therapeutic efficacy in cancer treatment. Although metal peroxides are effective in transporting metals and inducing oxidative stress, their application is constrained by poor safety. To address these challenges, we develop a safe bicelle nanosystem for metal peroxide delivery. Typically, the assembly of lipid-based nanoparticles into non-spherical shapes requires stabilizing agents such as membrane-stabilizing proteins (MSPs). In this study, the hydrophobic effect within the bicelle cavities is leveraged to encapsulate copper peroxide (CP), ensuring efficient delivery. CP forms a stabilizing ring around the bicelle, mimicking the function of MSPs to reinforce bicelle stability. Furthermore, considering the inhibitory effect of reduced glutathione (GSH) on cuproptosis, a GSH-sensitive derivative of doxorubicin (cDOX) is designed to reduce intracellular GSH levels. In tumor cells, cDOX interacts with CP to preferentially induce cuproptosis and oxidative stress, facilitating chemoimmunotherapy. These interactions collectively address the challenges of cuproptosis in cancer treatment by promoting efficient copper ion accumulation, effective induction of oxidative stress, and robust immunogenic cell death, providing a promising strategy for cancer therapy.
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Affiliation(s)
- Yanan Fu
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, 518107, P. R. China
| | - Huisong Hao
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, 518107, P. R. China
| | - Yixuan Fang
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, 518107, P. R. China
| | - Shengjie Sun
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, 518107, P. R. China
| | - Simin Wen
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, 518107, P. R. China
| | - Yuanqi Liu
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, 518107, P. R. China
| | - Jia Tang
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, 518107, P. R. China
| | - Tianqi Wang
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, 518107, P. R. China
| | - Meiying Wu
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, 518107, P. R. China
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17
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Jiang C, Chen Z, Yang R, Luogu Z, Ren Q, Hu H, Wang K, Li S, Deng C, Li M, Zheng L. Carbon-Based Flexible Electrode for Efficient Electrochemical Generation of Reactive Chlorine Species in Tumor Therapy. Adv Healthc Mater 2025:e2500369. [PMID: 40411849 DOI: 10.1002/adhm.202500369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Revised: 04/02/2025] [Indexed: 05/26/2025]
Abstract
Reactive chlorine species (RCS) are alternatives to reactive oxygen species (ROS) in tumor therapeutics. Unlike ROS, whose generation is limited by hypoxic conditions or insufficient H2O2 levels in the tumor, RCS can be generated through the electrochemical oxidation of abundant Cl- present in body fluids. However, traditional electrochemical therapy modalities have shown suboptimal outcomes. Herein, a flexible anodic electrode is fabricated by growing a carbon nanowire network (C-NWN) onto carbon cloth (CC). Attributing to its excellent hydrophilicity, high specific surface area, and electrochemical surface area, CC@C-NWN demonstrates a superior capability for RCS generation. Additionally, the carbon vacancies in CC@C-NWN not only enhance Cl- adsorption but also reduce the reaction free energy of the chlorine evolution reaction (CER) more significantly compared to that of the oxygen evolution reaction, thereby promoting the CER process. RCS generated from the CC@C-NWN electrochemical system induces severe oxidative stress, disrupting the redox homeostasis in tumor cells and promoting the synergistic anti-tumor effect of apoptosis and ferroptosis. The pliability of CC@C-NWN enables it to conform closely to the tumor, and it has demonstrated remarkable tumor-suppressive efficacy under low-voltage (3 V) condition in in vivo experiments. Therefore, the work holds significant promise for the development of novel tumor treatment strategies.
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Affiliation(s)
- Cuinan Jiang
- Department of Hepatobiliary Surgery, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Zhaoyu Chen
- National Innovation Center for Industry-Education Integration of Energy Storage Technology, MOE Key Laboratory of Low-Grade Energy Utilization Technologies and Systems, CQU-NUS Renewable Energy Materials & Devices Joint Laboratory, School of Energy and Power Engineering, Chongqing University, Chongqing, 400044, China
| | - Ruihao Yang
- Department of Hepatobiliary Surgery, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Ziga Luogu
- National Innovation Center for Industry-Education Integration of Energy Storage Technology, MOE Key Laboratory of Low-Grade Energy Utilization Technologies and Systems, CQU-NUS Renewable Energy Materials & Devices Joint Laboratory, School of Energy and Power Engineering, Chongqing University, Chongqing, 400044, China
| | - Qian Ren
- Department of Hepatobiliary Surgery, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Hao Hu
- Department of Hepatobiliary Surgery, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Kaixin Wang
- National Innovation Center for Industry-Education Integration of Energy Storage Technology, MOE Key Laboratory of Low-Grade Energy Utilization Technologies and Systems, CQU-NUS Renewable Energy Materials & Devices Joint Laboratory, School of Energy and Power Engineering, Chongqing University, Chongqing, 400044, China
| | - Senlin Li
- Department of Hepatobiliary Surgery, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Changlin Deng
- Department of Hepatobiliary Surgery, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Meng Li
- National Innovation Center for Industry-Education Integration of Energy Storage Technology, MOE Key Laboratory of Low-Grade Energy Utilization Technologies and Systems, CQU-NUS Renewable Energy Materials & Devices Joint Laboratory, School of Energy and Power Engineering, Chongqing University, Chongqing, 400044, China
| | - Lu Zheng
- Department of Hepatobiliary Surgery, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
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18
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Schiele P, Japp AS, Stark R, Sattelberg JJ, Nikolaou C, Kornhuber G, Abbasi P, Ding N, Rosnev S, Meinke S, Mühle K, Loyal L, Braun J, Dingeldey M, Durlanik S, Matzmohr N, Ponikwicka-Tyszko D, Wolczynski S, Rahman NA, Taniuchi I, Schlickeiser S, Giesecke-Thiel C, Blankenstein T, Na IK, Thiel A, Frentsch M. CD8 + T cell-derived CD40L mediates noncanonical cytotoxicity in CD40-expressing cancer cells. SCIENCE ADVANCES 2025; 11:eadr9331. [PMID: 40397730 DOI: 10.1126/sciadv.adr9331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 04/17/2025] [Indexed: 05/23/2025]
Abstract
T cells and their effector functions, in particular the canonical cytotoxicity of CD8+ T cells involving perforin, granzymes, Fas ligand (FasL), and tumor necrosis factor related apoptosis inducing ligand (TRAIL), are crucial for tumor immunity. Here, we reveal a previously unidentified mechanism by which CD40L-expressing CD8+ T cells induce cytotoxicity in cancer cells. In murine models, up to 50% of tumor-specific CD8+ T cells expressed CD40L, and conditional CD40L ablation in CD8+ T cells alone led to tumor formation. Mechanistically, CD40L+CD8+ T cells can induce cell death in CD40-expressing cancer cells by triggering caspase-8 activation. We demonstrate that a gene signature for resistance to CD40 signaling-induced cell death strongly correlates with worse survival in different human cancer cohorts. Our results introduce CD40L as a rather counterintuitive, noncanonical cytotoxic factor that complements the capabilities of CD8+ T cells to combat cancers and has the potential to enhance the efficacy of immunotherapies.
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Affiliation(s)
- Phillip Schiele
- Therapy-Induced Remodeling in Immuno-Oncology, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Alberto Sada Japp
- Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
- Captain T Cell GmbH, 12529 Berlin, Germany
| | - Regina Stark
- Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
- Tissue Immunology, BIH Center for Regenerative Therapies, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Joanna J Sattelberg
- Max-Delbrück-Center for Molecular Medicine and Institute for Immunology, Charité-Universitätsmedizin Berlin, 13125 Berlin, Germany
| | - Christos Nikolaou
- Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Gereon Kornhuber
- Therapy-Induced Remodeling in Immuno-Oncology, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Parya Abbasi
- Therapy-Induced Remodeling in Immuno-Oncology, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Nina Ding
- Therapy-Induced Remodeling in Immuno-Oncology, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Stanislav Rosnev
- Therapy-Induced Remodeling in Immuno-Oncology, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Stefan Meinke
- Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Kerstin Mühle
- Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Lucie Loyal
- Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
- Si-M/"Der Simulierte Mensch," Technische Universität Berlin and Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Julian Braun
- Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
- Si-M/"Der Simulierte Mensch," Technische Universität Berlin and Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Manuela Dingeldey
- Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
- Si-M/"Der Simulierte Mensch," Technische Universität Berlin and Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Sibel Durlanik
- Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Nadine Matzmohr
- Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Donata Ponikwicka-Tyszko
- Institute of Biomedicine, University of Turku, 20520 Turku, Finland
- Department of Biology and Pathology of Human Reproduction, Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, 10-748 Olsztyn, Poland
| | - Slawomir Wolczynski
- Department of Reproduction and Gynecological Endocrinology, Medical University of Bialystok, 15-276 Bialystok, Poland
| | - Nafis A Rahman
- Institute of Biomedicine, University of Turku, 20520 Turku, Finland
- Department of Reproduction and Gynecological Endocrinology, Medical University of Bialystok, 15-276 Bialystok, Poland
| | - Ichiro Taniuchi
- RIKEN Research Center for Allergy and Immunology, Yokohama 230-0045, Japan
| | - Stephan Schlickeiser
- Institute for Medical Immunology, Charité-Universitätsmedizin Berlin, Corporate members of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | | | - Thomas Blankenstein
- Max-Delbrück-Center for Molecular Medicine and Institute for Immunology, Charité-Universitätsmedizin Berlin, 13125 Berlin, Germany
| | - Il-Kang Na
- Therapy-Induced Remodeling in Immuno-Oncology, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
- Department of Hematology, Oncology and Tumor Immunology, and ECRC Experimental and Clinical Research Center, both Charité-Universitätsmedizin Berlin, Corporate members of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- German Cancer Consortium (DKTK), Berlin, Germany
- ECRC Experimental and Clinical Research Center, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Andreas Thiel
- Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
- Si-M/"Der Simulierte Mensch," Technische Universität Berlin and Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Marco Frentsch
- Therapy-Induced Remodeling in Immuno-Oncology, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
- Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
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19
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Chen D, Guo Z, Yao L, Sun Y, Dian Y, Zhao D, Ke Y, Zeng F, Zhang C, Deng G, Li L. Targeting oxidative stress-mediated regulated cell death as a vulnerability in cancer. Redox Biol 2025; 84:103686. [PMID: 40424719 DOI: 10.1016/j.redox.2025.103686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2025] [Accepted: 05/17/2025] [Indexed: 05/29/2025] Open
Abstract
Reactive oxygen species (ROS), regulators of cellular behaviors ranging from signaling to cell death, have complex production and control mechanisms to maintain a dynamic redox balance under physiological conditions. Redox imbalance is frequently observed in tumor cells, where ROS within tolerable limits promote oncogenic transformation, while excessive ROS induce a range of regulated cell death (RCD). As such, targeting ROS-mediated regulated cell death as a vulnerability in cancer. However, the precise regulatory networks governing ROS-mediated cancer cell death and their therapeutic applications remain inadequately characterized. In this Review, we first provide a comprehensive overview of the mechanisms underlying ROS production and control within cells, highlighting their dynamic balance. Next, we discuss the paradoxical nature of the redox system in tumor cells, where ROS can promote tumor growth or suppress it, depending on the context. We also systematically explored the role of ROS in tumor signaling pathways and revealed the complex ROS-mediated cross-linking networks in cancer cells. Following this, we focus on the intricate regulation of ROS in RCD and its current applications in cancer therapy. We further summarize the potential of ROS-induced RCD-based therapies, particularly those mediated by drugs targeting specific redox balance mechanisms. Finally, we address the measurement of ROS and oxidative damage in research, discussing existing challenges and future prospects of targeting ROS-mediated RCD in cancer therapy. We hope this review will offer promise for the clinical application of targeting oxidative stress-mediated regulated cell death in cancer therapy.
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Affiliation(s)
- Danyao Chen
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, China; Furong Laboratory, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, China; Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ziyu Guo
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, China; Furong Laboratory, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, China
| | - Lei Yao
- Department of Liver Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yuming Sun
- Department of Plastic and Cosmetic Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan Province, China
| | - Yating Dian
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, China; Furong Laboratory, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, China
| | - Deze Zhao
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yizhe Ke
- The First Affliated Hospital of Shihezi University, China
| | - Furong Zeng
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
| | - Chunfang Zhang
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.
| | - Guangtong Deng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, China; Furong Laboratory, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, China.
| | - Linfeng Li
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.
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20
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Ma C, Gao L, Song K, Gu B, Wang B, Yu Y, Wang X, Li X, Hu J, Pu W, Wang Y, Wang N, Lu D, Han Z, Chen H. Targeted Dual-Responsive Liposomes Co-Deliver Jolkinolide B and Ce6 to Synergistically Enhance the Photodynamic/Immunotherapy Efficacy in Gastric Cancer through the PANoptosis Pathway. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e02289. [PMID: 40387011 DOI: 10.1002/advs.202502289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Revised: 04/20/2025] [Indexed: 05/20/2025]
Abstract
Improving the efficacy of gastric cancer (GC) treatment remains an ongoing challenge. Considering the increasing importance of PANoptosis, a novel form of programmed cell death, the current study integrates photodynamic therapy (PDT) and chemodynamic therapy (CDT) into nanoliposomes. This approach utilizes the ability of photosensitizer Chlorin e6 (Ce6) to generate reactive oxygen species (ROS) and the function of the natural targeting agent Jolkinolide B to activate the PANoptosis molecular switch, inducing the ROS-caspase8/PANoptosis pathway to promote GC cell death. The designed CJP-TiN liposome targets GC via internalizing RGD peptide (iRGD), and demonstrates ROS/pH dual responsiveness in the tumor microenvironment. In vitro and in vivo experiments show effective ROS generation ability under light exposure, killing tumor cells and triggers thioether bond cleavage for dual-controlled drug release. The combined therapy enhances antitumor effect, converting "cold tumors" into "hot tumors," thereby enhancing the success of immunotherapy. The role of CJP-TiN as a PANoptosis inducer in the tumor microenvironment is confirmed, thereby expanding its application potential as a molecularly targeted therapy for GC treatment, and providing a novel perspective for therapeutic strategies.
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Affiliation(s)
- Chenhui Ma
- The Second Clinical Medical College, Lanzhou University, Lanzhou, 730000, China
| | - Lei Gao
- The Second Clinical Medical College, Lanzhou University, Lanzhou, 730000, China
| | - Kewei Song
- The Second Clinical Medical College, Lanzhou University, Lanzhou, 730000, China
| | - Baohong Gu
- The Second Clinical Medical College, Lanzhou University, Lanzhou, 730000, China
| | - Bofang Wang
- The Second Clinical Medical College, Lanzhou University, Lanzhou, 730000, China
| | - Yang Yu
- Department of Thyroid Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China
| | - Xueyan Wang
- The Second Clinical Medical College, Lanzhou University, Lanzhou, 730000, China
| | - Xuemei Li
- Gansu Provincial Key Laboratory of Environmental Oncology, Lanzhou, Gansu, 730030, China
| | - Jike Hu
- The Second Clinical Medical College, Lanzhou University, Lanzhou, 730000, China
| | - Weigao Pu
- The Second Clinical Medical College, Lanzhou University, Lanzhou, 730000, China
| | - Yunpeng Wang
- The Second Clinical Medical College, Lanzhou University, Lanzhou, 730000, China
| | - Na Wang
- National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen, 361102, China
| | - Dedai Lu
- Key Laboratory of Eco-Functional Polymer Materials of the Ministry of Education, Northwest Normal University, Lanzhou, 730070, China
| | - Zhijian Han
- Gansu Provincial Key Laboratory of Environmental Oncology, Lanzhou, Gansu, 730030, China
| | - Hao Chen
- Gansu Provincial Key Laboratory of Environmental Oncology, Lanzhou, Gansu, 730030, China
- Department of Tumor Surgery, Lanzhou University Second Hospital, Lanzhou, 730030, China
- Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China
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21
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Guo L, Yang Z, Dong H, Lai K, Fu H, Gong Y, Li S, Yue M, Liu Z. Systematic Investigation of Coordination Chemistry in Iridium(III) and Ruthenium(II) Complexes Derived from Pyridyl-Amine Ligands and Their Anticancer Evaluation. Inorg Chem 2025. [PMID: 40380917 DOI: 10.1021/acs.inorgchem.4c05599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/19/2025]
Abstract
A systematic investigation of the coordination chemistry of iridium(III) and ruthenium(II) complexes synthesized from pyridyl-amine ligands was performed, focusing on how ligand steric hindrance and metal centers affect oxidation behavior, coordination modes, and biological activities. The study revealed that steric hindrance at the ligand's bridge carbon strongly influenced both oxidation behavior and coordination modes. Smaller substituents (e.g., H and Me) facilitated oxidation to form pyridyl-imine species under adventitious oxygen, whereas bulky substituents (e.g., i-Bu and mesityl) suppressed oxidation, yielding stable pyridyl-amine or 16-electron pyridyl-amido complexes. Moreover, iridium(III) complexes were more prone to oxidation than the corresponding ruthenium(II) complexes under similar conditions. The aqueous stability of the newly synthesized complexes was confirmed. Cytotoxicity assays demonstrated that most of the complexes exhibited notable anticancer potency against A549, HeLa and cisplatin-resistant A549/DDP cancer cells. Mechanistic studies suggested a redox-driven pathway involving the catalytic oxidation of NADH to NAD+, the elevation of ROS levels and depolarization of the mitochondrial membrane. Notably, pyridyl-amine complexes induced apoptosis, while 16-electron pyridyl-amido complexes did not, though both caused S phase cell cycle arrest. Additionally these complexes can inhibit A549 cell migration, suggesting their potential to reduce cancer metastasis.
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Affiliation(s)
- Lihua Guo
- Key Laboratory of Life-Organic Analysis of Shandong Province, Key Laboratory of Green Natural Products and Pharmaceutical Intermediates in Colleges and Universities of Shandong Province, School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, P. R. China
| | - Zhihao Yang
- Key Laboratory of Life-Organic Analysis of Shandong Province, Key Laboratory of Green Natural Products and Pharmaceutical Intermediates in Colleges and Universities of Shandong Province, School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, P. R. China
| | - Heqian Dong
- Key Laboratory of Life-Organic Analysis of Shandong Province, Key Laboratory of Green Natural Products and Pharmaceutical Intermediates in Colleges and Universities of Shandong Province, School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, P. R. China
| | - Kangning Lai
- Key Laboratory of Life-Organic Analysis of Shandong Province, Key Laboratory of Green Natural Products and Pharmaceutical Intermediates in Colleges and Universities of Shandong Province, School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, P. R. China
| | - Hanxiu Fu
- Key Laboratory of Life-Organic Analysis of Shandong Province, Key Laboratory of Green Natural Products and Pharmaceutical Intermediates in Colleges and Universities of Shandong Province, School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, P. R. China
| | - Yuwen Gong
- Key Laboratory of Life-Organic Analysis of Shandong Province, Key Laboratory of Green Natural Products and Pharmaceutical Intermediates in Colleges and Universities of Shandong Province, School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, P. R. China
| | - Susu Li
- Key Laboratory of Life-Organic Analysis of Shandong Province, Key Laboratory of Green Natural Products and Pharmaceutical Intermediates in Colleges and Universities of Shandong Province, School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, P. R. China
| | - Mingbo Yue
- Key Laboratory of Life-Organic Analysis of Shandong Province, Key Laboratory of Green Natural Products and Pharmaceutical Intermediates in Colleges and Universities of Shandong Province, School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, P. R. China
| | - Zhe Liu
- Key Laboratory of Life-Organic Analysis of Shandong Province, Key Laboratory of Green Natural Products and Pharmaceutical Intermediates in Colleges and Universities of Shandong Province, School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, P. R. China
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Mei J, Tian HX, Zhang XY, Chen YS, Wang LY, Zhang Z, Zhang YL, Rong DC, Zeng J, Dong M, Gao Y, Yin JY, Wu HJ, Wang PY, Zhang W. Heme oxygenase 1 (HO-1) is a drug target for reversing cisplatin resistance in non-small cell lung cancer. J Adv Res 2025:S2090-1232(25)00347-9. [PMID: 40389113 DOI: 10.1016/j.jare.2025.05.033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Revised: 04/22/2025] [Accepted: 05/12/2025] [Indexed: 05/21/2025] Open
Abstract
INTRODUCTION Platinum-based drugs, the most widely used chemotherapeutic drugs in clinical oncology, have long faced the problem of drug resistance, which is urgently in need of resolution. Identifying biomarkers of drug resistance may help reduce platinum resistance and improve therapeutic efficacy. OBJECTIVES This study aims to identify potential biomarkers associated with the development of cisplatin resistance in non-small cell lung cancer (NSCLC) and explore mechanisms to overcome chemoresistance. METHODS NSCLC cisplatin resistance cell lines were constructed, and transcriptome sequencing was performed. Results were validated using Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Molecular docking, proteomics sequencing, and in vitro and in vivo experiments were conducted to evaluate the role of Heme Oxygenase 1 (HO-1) in cisplatin resistance. RESULTS NSCLC cisplatin resistance cell lines, GEO and TCGA data identified HMOX1, downstream of Nrf2, as a key drug resistance gene induced by cisplatin. Activation of the Nrf2/HO-1 pathway was found to induce ferroptosis resistance, a critical mechanism of cisplatin resistance. Candidate compounds SB 202190 and Nordihydroguaiaretic acid (NDGA) effectively reactivated ferroptosis by inhibiting HO-1, thereby increasing cisplatin sensitivity. CONCLUSION The Nrf2/HO-1 pathway is a significant contributor to cisplatin resistance in NSCLC. Targeting HO-1 with SB 202190 and NDGA presents a promising strategy to overcome resistance and improve chemotherapy outcomes.
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Affiliation(s)
- Jie Mei
- Department of Clinical Pharmacology, Xiangya Hospital, Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics and National Clinical Research Center for Geriatric Disorders, Engineering Research Center of Applied Technology of Pharmacogenomics (Ministry of Education, China), Key Laboratory of Pharmacomicrobiomics of Hunan Province, Central South University, Changsha 410078, People's Republic of China; Central Laboratory of Hunan Cancer Hospital, Central South University, Changsha 410013, People's Republic of China; FuRong Laboratory, Changsha 410078 Hunan, People's Republic of China; Oujiang Laboratory, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Institute of Aging, Wenzhou Medical University, Wenzhou 325000, People's Republic of China
| | - Hui-Xiang Tian
- Department of Clinical Pharmacology, Xiangya Hospital, Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics and National Clinical Research Center for Geriatric Disorders, Engineering Research Center of Applied Technology of Pharmacogenomics (Ministry of Education, China), Key Laboratory of Pharmacomicrobiomics of Hunan Province, Central South University, Changsha 410078, People's Republic of China
| | - Xiao-Ye Zhang
- Department of Clinical Pharmacology, Xiangya Hospital, Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics and National Clinical Research Center for Geriatric Disorders, Engineering Research Center of Applied Technology of Pharmacogenomics (Ministry of Education, China), Key Laboratory of Pharmacomicrobiomics of Hunan Province, Central South University, Changsha 410078, People's Republic of China; Central Laboratory of Hunan Cancer Hospital, Central South University, Changsha 410013, People's Republic of China
| | - Yuan-Shen Chen
- The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, People's Republic of China
| | - Lei-Yun Wang
- Department of Pharmacy, Traditional Chinese and Western Medicine Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People's Republic of China
| | - Zhao Zhang
- Central South University Xiangya Medical School, Changsha 410013, People's Republic of China
| | - Yu-Long Zhang
- Department of Clinical Pharmacology, Xiangya Hospital, Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics and National Clinical Research Center for Geriatric Disorders, Engineering Research Center of Applied Technology of Pharmacogenomics (Ministry of Education, China), Key Laboratory of Pharmacomicrobiomics of Hunan Province, Central South University, Changsha 410078, People's Republic of China
| | - Ding-Chao Rong
- Department of Orthopedics, The First Affiliated Hospital of Shaoyang University, Shaoyang 422000, People's Republic of China
| | - Jun Zeng
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha 410008, People's Republic of China
| | - Min Dong
- Pharmaceutical College, Guangxi Medical University, Nanning 530021, People's Republic of China
| | - Yang Gao
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha 410008, People's Republic of China
| | - Ji-Ye Yin
- Department of Clinical Pharmacology, Xiangya Hospital, Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics and National Clinical Research Center for Geriatric Disorders, Engineering Research Center of Applied Technology of Pharmacogenomics (Ministry of Education, China), Key Laboratory of Pharmacomicrobiomics of Hunan Province, Central South University, Changsha 410078, People's Republic of China.
| | - Hai-Jun Wu
- Department of Oncology, Xiangya Hospital of Central South University, Changsha 410008, People's Republic of China.
| | - Peng-Yuan Wang
- Oujiang Laboratory, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Institute of Aging, Wenzhou Medical University, Wenzhou 325000, People's Republic of China.
| | - Wei Zhang
- Department of Clinical Pharmacology, Xiangya Hospital, Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics and National Clinical Research Center for Geriatric Disorders, Engineering Research Center of Applied Technology of Pharmacogenomics (Ministry of Education, China), Key Laboratory of Pharmacomicrobiomics of Hunan Province, Central South University, Changsha 410078, People's Republic of China; Central Laboratory of Hunan Cancer Hospital, Central South University, Changsha 410013, People's Republic of China; FuRong Laboratory, Changsha 410078 Hunan, People's Republic of China; The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, People's Republic of China.
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23
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Chintakindi J, Lahane GP, Dhar A, Mir A. Engineered Ti 3C 2(O,Cl) MXenes with dual functionalization: a new Frontier in targeted head and neck squamous cell carcinoma and breast adenocarcinoma. J Mater Chem B 2025. [PMID: 40375828 DOI: 10.1039/d5tb00302d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/18/2025]
Abstract
Ti3C2Tx MXenes have attracted significant attention in the realm of anticancer therapeutics owing to their remarkable properties, including cyto-compatibility and targeted drug delivery capabilities. In this study, Ti3C2 was intentionally modified with both chlorine and oxygen surface groups, as each of these functional groups have individually demonstrated promising anticancer properties. Our aim was to combine them in a single compound to explore how this dual-functionalized material might perform in a therapeutic context. This study synthesizes Ti3C2(O,Cl) MXenes using a novel electrochemical etching technique that allows for precise tailoring of the surface terminations with O and Cl groups. The synthesised Ti3C2(O,Cl) has biological activity in two cancerous (FaDu and MCF-7) and two normal (H9C2 and HEK-293) cell lines. The results of cytotoxicity data showed that the observed toxic effects were higher against cancerous cells (∼91%) than normal cells (∼40%). The mechanisms of potential toxicity were also elucidated. The synthesized Ti3C2(O,Cl) MXene has an effect on oxidative stress, resulting in an increase of more than 91.44% in reactive oxygen species (ROS) production in malignant cells. The results of this study provide major insights to date into the biological activity of Ti3C2(O,Cl) MXenes and develop their application in anticancer treatments.
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Affiliation(s)
- Jhansi Chintakindi
- Department of Chemical Engineering, BITS Pilani, Hyderabad Campus, Telangana, India.
| | | | - Arti Dhar
- Department of Pharmacy, BITS Pilani, Hyderabad Campus, Telangana, India.
| | - Afkham Mir
- Department of Chemical Engineering, BITS Pilani, Hyderabad Campus, Telangana, India.
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24
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Hong R, Min S, Huang J, Zou M, Zhou D, Liang Y. High-dose vitamin C promotes mitochondrial biogenesis in HCT116 colorectal cancer cells by regulating the AMPK/PGC-1α signaling pathway. J Cancer Res Clin Oncol 2025; 151:167. [PMID: 40372538 PMCID: PMC12081527 DOI: 10.1007/s00432-025-06211-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Accepted: 04/23/2025] [Indexed: 05/16/2025]
Abstract
BACKGROUND Mitochondrial dysfunction is closely associated with cancer development. Colorectal cancer (CRC) cells often exhibit altered energy metabolism, characterized by increased glycolysis and reduced oxidative phosphorylation. Enhancing mitochondrial biogenesis and function may represent a promising therapeutic approach. High-dose vitamin C has demonstrated anti-tumor properties and the ability to reverse the Warburg effect, but its role in regulating mitochondrial biogenesis and function remains unclear. METHODS We evaluated the altered mitochondrial functional status of HCT116 colorectal cancer cells compared to FHC colorectal epithelial cells, assessed the effects of high-dose vitamin C on mitochondrial biogenesis and function in HCT116 cells, and explored the underlying regulatory mechanisms. RESULTS HCT116 cells exhibited mitochondrial dysfunction compared to FHC cells, including decreased expression of electron transport chain complexes III and IV, reduced TFAM levels, and lower mtDNA content. Vitamin C treatment significantly enhanced mitochondrial biogenesis and function, as reflected by increased AMPK phosphorylation, upregulation of PGC-1α, SOD2, NRF2, TFAM, MT-CYB, and MTCO1, elevated mtDNA content, restored membrane potential, enhanced oxidative phosphorylation, and reduced glycolytic activity. Furthermore, vitamin C markedly suppressed HCT116 cell viability and clonogenic capacity, while these effects were substantially diminished by cotreatment with Compound C. CONCLUSION This study demonstrates that high-dose vitamin C ameliorates mitochondrial dysfunction and promotes mitochondrial biogenesis and function in colorectal cancer cells through activation of the AMPK-PGC-1α signaling pathway, thereby suppressing tumor cell proliferation. These findings suggest that vitamin C may serve as a promising therapeutic agent for targeting mitochondrial metabolism in colorectal cancer.
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Affiliation(s)
- RuiYang Hong
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Su Min
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
| | - Jia Huang
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Mou Zou
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - DongYu Zhou
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yun Liang
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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25
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Gao Q, Li P, Lu Z, Ma M, Zhang N, Lu Y, Yu J. Association of frailty and its trajectory with the risk of cancer: evidence from the China health and retirement longitudinal study (CHARLS). BMC Public Health 2025; 25:1797. [PMID: 40375252 PMCID: PMC12080056 DOI: 10.1186/s12889-025-22959-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Accepted: 04/28/2025] [Indexed: 05/18/2025] Open
Abstract
BACKGROUND Frailty can be identified in both middle-aged and older adults. However, longitudinal studies that examine whether frailty is associated with incident cancer are currently lacking. This study aimed to comprehensively examine the impact of baseline frailty levels and their changing trajectories over time on the risk of cancer. METHODS We assessed frailty status using the frailty index based on data from the China Health and Retirement Longitudinal Study (CHARLS) from 2011 to 2020. First, the association between baseline frailty and cancer risk was analyzed using the Cox proportional hazards model. Second, based on the CHARLS data from 2011 to 2020, we used Group-based trajectory modeling (GBTM) to identify trajectories of frailty development during the four follow-up periods from 2011 to 2020. Cox proportional hazards model was used to analyze the association between frailty trajectories and the risk of cancer incidence during the follow-up period. RESULTS A total of 17,708 participants were involved at the baseline survey in CHARLS 2011. During a mean follow-up period of 8.05 years, 248 cancer events occurred. Compared with non-frailty individuals, participants in pre-frailty and frailty states had a 34% (hazard ratio [HR]: 1.34, 95% confidence interval [CI]: 1.03-1.75) and 66% (HR: 1.66, 95% CI: 1.07-2.56) increased risk of overall cancer incidence, respectively. Based on repeated measurements from 2011 to 2018, three trajectories of frailty were identified among 9,173 participants. Compared to the low-level stable group, the high-level increase group had the highest risk of cancer, with an associated HR (95% CI) of 5.43 (1.07-5.73). This was followed by the medium-level increase group, with an associated HR (95% CI 2.86 (1.27-6.43). When stratified by sex and age, participants aged ≥ 60 years and female participants in the high-level increase frailty group had a higher risk of developing cancer. CONCLUSION Frailty is associated with cancer risk. Medium and high levels of the frailty index are significantly associated with an increased risk of cancer incidence. In addition, more attention should be paid to the risk of cancer in people aged ≥ 60 years and in women with high levels of frailty.
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Affiliation(s)
- Qian Gao
- School of Public Health, Shandong Second Medical University, Weifang, Shandong, 261053, China
| | - Pengfei Li
- School of Public Health, Shandong Second Medical University, Weifang, Shandong, 261053, China
| | - Zhengyang Lu
- School of Public Health, Shandong Second Medical University, Weifang, Shandong, 261053, China
| | - Muye Ma
- School of Public Health, Shandong Second Medical University, Weifang, Shandong, 261053, China
| | - Nan Zhang
- Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China
| | - Youhua Lu
- Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China.
| | - Jinming Yu
- Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China.
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Li XY, Yu ZY, Li HJ, Yan DM, Yang C, Liu XZ. Biomarker identification associated with M2 tumor-associated macrophage infiltration in glioblastoma. Front Neurol 2025; 16:1545608. [PMID: 40438577 PMCID: PMC12117037 DOI: 10.3389/fneur.2025.1545608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2024] [Accepted: 04/08/2025] [Indexed: 06/01/2025] Open
Abstract
Purpose M2 phenotype tumor-associated macrophages (TAMs) can promote tumor growth, invasion, chemotherapy resistance and so on, leading to malignant progression. The aim of this study was to identify novel prognostic profiles in glioblastoma (GBM) by integrating single-cell RNA sequencing (scRNA-seq) with bulk RNA-seq. Methods We identified M2-associated genes by intersecting TAM marker genes derived from scRNA-seq with macrophage module genes from WGCNA RNA-seq data. Prognostic M2 TAM-related genes were determined using univariate Cox and LASSO regression analyses. In the following steps, prognostic characteristics, risk groups, and external validation were constructed and validated. The immune landscape of patients with GBM was examined by evaluating immune cells, functions, evasion scores, and checkpoint genes. Results Analysis of scRNA-seq and bulk-seq data revealed 107 genes linked to M2 TAMs. Using univariate Cox and LASSO regression, 16 genes were identified as prognostic for GBM, leading to the creation and validation of a prognostic signature for GBM survival prediction. Conclusion Our findings reveal the immune landscape of GBM and enhance understanding of the molecular mechanisms associated with M2 TAMs.
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Affiliation(s)
| | | | | | | | - Chao Yang
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xian-zhi Liu
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Cini N, Atasoy Ö, Uyanikgil Y, Yaprak G, Erdoğan MA, Erbas O. Ceftriaxone has a neuroprotective effect in a whole-brain irradiation-induced neurotoxicity model by increasing GLT-1 and reducing oxidative stress. Strahlenther Onkol 2025:10.1007/s00066-025-02405-z. [PMID: 40353856 DOI: 10.1007/s00066-025-02405-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 03/30/2025] [Indexed: 05/14/2025]
Abstract
BACKGROUND Radiation-induced brain injury is a prominent side effect of whole-brain irradiation (IR) due to triggered oxidative and inflammatory processes, often resulting in severe and debilitating cognitive dysfunction and neuronal damage. The development of persistent oxidative stress results from radiation-induced reactive oxygen species. Another result is the initiation of glutamate excitotoxicity, which is closely associated with changes in glutamate levels. Elevated release or reduced glutamate uptake disrupts neuronal homeostasis, leading to oxidative stress, mitochondrial dysfunction, and neuroinflammation. The neuroprotective and antioxidant properties of ceftriaxone (CTX) have been linked to its ability to reduce glutamate excitotoxicity, inflammation, and to modulate oxidative stress. MATERIALS AND METHODS Twenty-one female Wistar rats were included in the study, and 14 of them underwent whole-brain IR with a single dose of 20 Gy on day 7. Saline and CTX applications continued for 21 days. The animals were divided into three groups: group 1: normal control; group 2: IR + saline; and group 3: IR + CTX. To compare the groups, a one-way analysis of variance (ANOVA) statistical test was employed, with a significance threshold set at p < 0.05. RESULTS Ceftriaxone treatment had a positive impact on the results of various assessments, e.g., behavioral tests including the three-chamber sociability test, the open-field test, and passive avoidance learning. It also led to increased counts of hippocampal CA1, CA3, and Purkinje neurons as well as elevated brain levels of brain-derived neurotrophic factor (BDNF), glutamate transporter 1 (GLT-1), and superoxide dismutase (SOD) activity. Conversely, CTX reduced the glial fibrillary acidic protein (GFAP) immunostaining index as well as brain levels of malondialdehyde (MDA) and tumor necrosis factor alpha (TNF-α). CONCLUSION Ceftriaxone demonstrated promising effectiveness in mitigating radiation-induced neurocognitive impairments and the deterioration of social memory capacity. This effect is achieved by reducing neuronal loss, oxidative stress, and neuroinflammation in irradiated rat brains. Furthermore, the application of CTX facilitated removal of excess glutamate from synapses, thus preventing glutamate excitotoxicity and protecting neurons from excitotoxic cell death.
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Affiliation(s)
- Nilsu Cini
- Department of Radiation Oncology, Kartal Dr. Lütfi Kırdar City Hospital, Istanbul, Turkey.
| | - Özüm Atasoy
- Department of Radiation Oncology, Giresun Education and Research Hospital, Giresun, Turkey
- Department of Medical Biochemistry, Istanbul Medeniyet University, Faculty of Medicine, Istanbul, Turkey
| | - Yigit Uyanikgil
- Department of Histology and Embryology, Ege University, Faculty of Medicine, Izmir, Turkey
| | - Gökhan Yaprak
- Department of Radiation Oncology, Kartal Dr. Lütfi Kırdar City Hospital, Istanbul, Turkey
| | - Mümin Alper Erdoğan
- Department of Physiology, Izmir Katip Celebi University, Faculty of Medicine, Izmir, Turkey
| | - Oytun Erbas
- Department of Physiology, Demiroğlu Bilim University, Faculty of Medicine, Istanbul, Turkey
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Farmanbar A, Kneller R, Firouzi S. The Use of Mutational Signatures to Decipher the Inter-Relationship of Reactive Oxygen Species with Homologous Recombination and Non-Homologous End-Joining Deficiencies as Well as Their Effects on APOBEC Mutagenesis in Breast Cancer. Cancers (Basel) 2025; 17:1627. [PMID: 40427126 PMCID: PMC12110613 DOI: 10.3390/cancers17101627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2025] [Revised: 05/02/2025] [Accepted: 05/08/2025] [Indexed: 05/29/2025] Open
Abstract
Background: Defective DNA repair systems result in the accumulation of mutations, loss of genomic integrity, and eventually cancer. Following initial malignant transformation due to specific DNA damage and defective DNA repair, cancer cells become reliant upon other DNA repair pathways for their survival. The co-occurrence of specific repair deficiencies brings catastrophic outcomes such as cell death for cancer cells and thus holds promise as a potential therapeutic strategy. Exploring the co-occurrence and mutual exclusivity of mutational signatures provides valuable knowledge regarding combinations of defective repair pathways that are cooperative and confer selective advantage to cancer cells and those that are detrimental and cannot be tolerated by them. Methods: Taking advantage of mutational signature profiling, we analyzed whole-genome sequences of 1014 breast cancers to reveal the underlying mutational processes and their interrelationships. Results: We found an inverse relationship between deficiencies of homologous recombination (HRd) and non-homologous end joining (NHEJd) with reactive oxygen species (ROS). Moreover, HRd and NHEJd co-occurred with APOBEC but were mutually exclusive with mismatch repair deficiency (MMRd) and ROS. Our analysis revealed that SBS8 and SBS39 signatures of currently unknown etiology correlate with NHEJd. ID1 and ID2 signatures co-occur with ROS and have mutual exclusivity with HRd, SBS8, SBS39 and NHEJd. The ID4 signature, with currently unknown etiology, has mutual exclusivity with HRd and NHEJd and co-occurred with ROS. On the other hand, the ID15 signature, with currently unknown etiology, co-occurred with SBS8, SBS39, HRd, NHEJd and DBS2, while having an inverse relationship with MMRd and ROS. Comparing the mutational signatures of HRd and non-HRd TNBC genomes reveals the unique presence of ROS signatures in non-HRd tumors and the lack of ROS signature in HRd tumors. Conclusion: Taken together, these analyses indicate the possible application of mutation signatures and their interactions in advancing patient stratification and suggest appropriate therapies targeting the make-up of individual tumors' mutational processes. Ultimately, this information provides the opportunity to discover promising synthetic lethal candidates targeting DNA repair systems.
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Affiliation(s)
- Amir Farmanbar
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo 108-8639, Japan
- Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan
| | - Robert Kneller
- Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan
| | - Sanaz Firouzi
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo 108-8639, Japan
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Błachnio-Zabielska AU, Sadowska P, Chlabicz U, Pogodzińska K, Le Stunff H, Laudański P, Szamatowicz J, Kuźmicki M. Differential Effects of Sphingolipids on Cell Death and Antioxidant Defenses in Type 1 and Type 2 Endometrial Cancer Cells. Int J Mol Sci 2025; 26:4472. [PMID: 40429618 PMCID: PMC12110862 DOI: 10.3390/ijms26104472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2025] [Revised: 05/03/2025] [Accepted: 05/07/2025] [Indexed: 05/29/2025] Open
Abstract
Endometrial cancer (EC) is classified into two main subtypes with distinct molecular profiles. Sphingolipids, particularly ceramide and sphingosine-1-phosphate (S1P), are crucial regulators of cell survival, apoptosis, and oxidative stress. This study examined the impact of sphingolipid metabolism in Ishikawa (type 1) and HEC-1A (type 2) EC cells following the silencing of Sptlc1 and Sptlc2, which encode subunits of serine palmitoyltransferase (SPT), a key enzyme in de novo sphingolipid synthesis. Gene silencing was confirmed by RT-PCR and Western blot, while sphingolipid levels were quantified using UHPLC/MS/MS and the sphingolipid rheostat (S1P/ceramide ratio) was calculated. Cell viability (MTT assay), cell death, ROS levels (ELISA), total antioxidant capacity (TAC), catalase and caspase-3 activity, and mitochondrial membrane potential were also assessed. The obtained data showed higher ceramide levels in Ishikawa(CON) cells and higher S1P levels in HEC-1A(CON) cells, resulting in a higher sphingolipid rheostat in HEC-1A cells. SPT knockdown reduced sphingolipid levels, increased cell viability, elevated ROS levels, and decreased cell death, particularly in Ishikawa cells. Furthermore, after gene silencing, these cells exhibited reduced catalase activity and diminished TAC, indicating an impaired redox balance. These findings reveal subtype-specific responses to disrupted sphingolipid synthesis and highlight the importance of sphingolipid homeostasis in the behavior of EC cells.
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Affiliation(s)
| | - Patrycja Sadowska
- Department of Hygiene, Epidemiology and Metabolic Disorders, Medical University of Bialystok, 15-089 Bialystok, Poland
| | - Urszula Chlabicz
- Department of Hygiene, Epidemiology and Metabolic Disorders, Medical University of Bialystok, 15-089 Bialystok, Poland
| | - Karolina Pogodzińska
- Department of Hygiene, Epidemiology and Metabolic Disorders, Medical University of Bialystok, 15-089 Bialystok, Poland
| | - Hervé Le Stunff
- CNRS UMR 9197, Institut des Neurosciences Paris-Saclay, Université Paris-Saclay, 91400 Saclay, France
| | - Piotr Laudański
- Department of Obstetrics, Gynecology and Gynecological Oncology, Medical University of Warsaw, 02-091 Warsaw, Poland
- Women’s Health Research Institute, Calisia University, 62-800 Kalisz, Poland
- OVIklinika Infertility Center, 01-377 Warsaw, Poland
| | - Jacek Szamatowicz
- Department of Gynecology and Gynecological Oncology, Medical University of Bialystok, 15-089 Bialystok, Poland
| | - Mariusz Kuźmicki
- Department of Gynecology and Gynecological Oncology, Medical University of Bialystok, 15-089 Bialystok, Poland
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Malarz K, Kuczak M, Rurka P, Rawicka P, Boguszewska-Czubara A, Jampilek J, Mularski J, Musiol R, Mrozek-Wilczkiewicz A. Unveiling the role of Ndrg1 gene on the oxidative stress induction behind the anticancer potential of styrylquinazoline derivatives. Sci Rep 2025; 15:16081. [PMID: 40341822 PMCID: PMC12062220 DOI: 10.1038/s41598-025-99277-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 04/18/2025] [Indexed: 05/11/2025] Open
Abstract
This work presents a multifaceted mechanism of the anticancer action of a 2-styrylquinazoline derivative. Extensive analysis of various aspects related to tyrosine kinase inhibition and effects on cellular targets at both the gene and protein levels revealed the potential of this IS20 compound for future research. This study presents a detailed analysis of the relationship between ABL and SRC kinase affecting the inhibition of the EGFR/mTOR signaling pathway in a non-obvious manner. The study was supported by experiments using various molecular biology techniques to confirm the induction of oxidative stress, inhibition of the cell cycle in the G2/M phase and the triggering of cell death via both the apoptosis and autophagy pathways. The cell models included those with different p53 protein status, which affected the cellular response in the form of altered Ndrg1 expression. Finally, the appropriate physicochemical properties of IS20 for adequate bioavailability and toxicity to the body were observed in an in vivo model.
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Affiliation(s)
- Katarzyna Malarz
- Department of Systems Biology and Engineering, Silesian University of Technology, Akademicka 16, Gliwice, 44-100, Poland.
- Institute of Physics, University of Silesia in Katowice, 75 Pułku Piechoty 1a, Chorzów, 41-500, Poland.
| | - Michał Kuczak
- Institute of Chemistry, University of Silesia in Katowice, 75 Pułku Piechoty 1a, Chorzów, 41-500, Poland
| | - Patryk Rurka
- Institute of Physics, University of Silesia in Katowice, 75 Pułku Piechoty 1a, Chorzów, 41-500, Poland
| | - Patrycja Rawicka
- Institute of Physics, University of Silesia in Katowice, 75 Pułku Piechoty 1a, Chorzów, 41-500, Poland
| | - Anna Boguszewska-Czubara
- Department of Medical Chemistry, Medical University of Lublin, Chodźki 4a, Lublin, 20-093, Poland
| | - Josef Jampilek
- Department of Chemical Biology, Palacky University Olomouc, Slechtitelu 27, Olomouc, 779 00, Czech Republic
| | - Jacek Mularski
- Institute of Chemistry, University of Silesia in Katowice, 75 Pułku Piechoty 1a, Chorzów, 41-500, Poland
| | - Robert Musiol
- Institute of Chemistry, University of Silesia in Katowice, 75 Pułku Piechoty 1a, Chorzów, 41-500, Poland
| | - Anna Mrozek-Wilczkiewicz
- Department of Systems Biology and Engineering, Silesian University of Technology, Akademicka 16, Gliwice, 44-100, Poland
- Institute of Physics, University of Silesia in Katowice, 75 Pułku Piechoty 1a, Chorzów, 41-500, Poland
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31
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Kawauchi D, Narita Y. The curse of blood-brain barrier and blood-tumor barrier in malignant brain tumor treatment. Int J Clin Oncol 2025:10.1007/s10147-025-02777-3. [PMID: 40338447 DOI: 10.1007/s10147-025-02777-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2025] [Accepted: 04/24/2025] [Indexed: 05/09/2025]
Abstract
The blood-brain barrier (BBB) is crucial for brain homeostasis but is a major obstacle in delivering anticancer drugs to brain tumors. However, this perspective requires re-evaluation, particularly for malignant brain tumors, such as gliomas and brain metastases. In these aggressive tumors, the BBB undergoes significant alterations, leading to the formation of a more permeable blood-tumor barrier. While this increased permeability allows better drug penetration, heterogeneity in blood-tumor barrier (BTB) integrity across different tumor regions remains a challenge. Additionally, the main challenge in treating brain tumors lies not in BBB penetration but in the lack of effective drugs. Conventional chemotherapies, including temozolomide and nitrosourea agents, have shown limited efficacy, and resistance mechanisms often reduce their long-term benefits. The "BBB curse" has often been blamed for the slow progress in drug development. However, emerging evidence suggests that even larger-molecule therapies, such as antibody-drug conjugates, can successfully target brain tumors. This review aims to critically reassess the roles of the BBB and BTB in brain tumor therapy, highlighting their impact on drug delivery and evaluating the current landscape of chemotherapeutic strategies. Furthermore, it explores new approaches to overcome treatment limitations, emphasizing the need for personalized and targeted therapeutic strategies.
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Affiliation(s)
- Daisuke Kawauchi
- Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Chuo City, Japan
| | - Yoshitaka Narita
- Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Chuo City, Japan.
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32
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Borbényi-Galambos K, Erdélyi K, Ditrói T, Jurányi EP, Szántó N, Szatmári R, Czikora Á, Schmidt EE, Garai D, Cserepes M, Liszkay G, Tóth E, Tóvári J, Nagy P. Realigned transsulfuration drives BRAF-V600E-targeted therapy resistance in melanoma. Cell Metab 2025; 37:1171-1188.e9. [PMID: 40037361 DOI: 10.1016/j.cmet.2025.01.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Revised: 12/13/2024] [Accepted: 01/22/2025] [Indexed: 03/06/2025]
Abstract
BRAF V600E-inhibition effectively treats melanoma, but acquired resistance rapidly develops. Protein expression profiles, mitochondrial energetics, metabolomics and fluxomics data in cell line, xenograft, and patient-derived xenograft systems revealed that concerted reprogramming of metabolic pathways (including glutaminolysis, glycolysis, TCA cycle, electron transport chain [ETC], and transsulfuration), along with an immediate cytoprotective response to drug-induced oxidative stress, underpins drug-tolerant persister cancer cell survival. Realignment of cysteine (Cys) metabolism, in particular an immediate upregulation of cystathionine-γ-lyase (CSE), was vital in persister cells. The oxidative cellular environment, drug-induced elevated cystine uptake and oxidative Cys catabolism, increased intracellular cystine/Cys ratios, thereby favoring cystine as a CSE substrate. This produces persulfides and hydrogen sulfide to protect protein thiols and support elevated energy demand in persister cells. Combining BRAF V600E inhibitors with CSE inhibitors effectively diminished proliferative relapse in culture models and increased progression-free survival of xenografted mice. This, together with induced CSE expression in patient samples under BRAF-V600E-inhibition, reveals an approach to increase BRAF-V600E-targeted therapeutic efficacy.
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Affiliation(s)
- Klaudia Borbényi-Galambos
- Department of Molecular Immunology and Toxicology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, 1122, Hungary; Kálmán Laki Doctoral School, University of Debrecen, Debrecen, Hajdú-Bihar County, 4032, Hungary
| | - Katalin Erdélyi
- Department of Molecular Immunology and Toxicology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, 1122, Hungary
| | - Tamás Ditrói
- Department of Molecular Immunology and Toxicology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, 1122, Hungary
| | - Eszter Petra Jurányi
- Department of Molecular Immunology and Toxicology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, 1122, Hungary; Semmelweis University Doctoral School, Semmelweis University, Budapest, 1094, Hungary
| | - Noémi Szántó
- Department of Molecular Immunology and Toxicology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, 1122, Hungary
| | - Réka Szatmári
- Department of Molecular Immunology and Toxicology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, 1122, Hungary; Kálmán Laki Doctoral School, University of Debrecen, Debrecen, Hajdú-Bihar County, 4032, Hungary; Chemistry Coordinating Institute, University of Debrecen, Debrecen, Hajdú-Bihar County, 4012, Hungary
| | - Ágnes Czikora
- Department of Molecular Immunology and Toxicology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, 1122, Hungary
| | - Edward E Schmidt
- Department of Anatomy and Histology, HUN-REN-UVMB Laboratory of Redox Biology, University of Veterinary Medicine, Budapest, 1078, Hungary; Department of Microbiology and Cell Biology, Montana State University, Bozeman, Montana, 59717, United States of America
| | - Dorottya Garai
- Department of Molecular Immunology and Toxicology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, 1122, Hungary; Kálmán Laki Doctoral School, University of Debrecen, Debrecen, Hajdú-Bihar County, 4032, Hungary
| | - Mihály Cserepes
- Department of Experimental Pharmacology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, 1122, Hungary
| | - Gabriella Liszkay
- Department of Dermatology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, 1122, Hungary
| | - Erika Tóth
- Department of Surgical and Molecular Pathology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, 1122, Hungary
| | - József Tóvári
- Department of Experimental Pharmacology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, 1122, Hungary
| | - Péter Nagy
- Department of Molecular Immunology and Toxicology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, 1122, Hungary; Chemistry Coordinating Institute, University of Debrecen, Debrecen, Hajdú-Bihar County, 4012, Hungary; Department of Anatomy and Histology, HUN-REN-UVMB Laboratory of Redox Biology, University of Veterinary Medicine, Budapest, 1078, Hungary.
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Lin H, Sui H, Yu Y, Xie C, Shen Y, Cheng L, Wang J, Yu Y, Xie C, Cui R. Dihydrotanshinone I potentiates the anti-tumor activity of cisplatin by activating ROS-mediated ER stress through targeting HSPD1 in lung cancer cells. Eur J Pharmacol 2025; 994:177378. [PMID: 39952584 DOI: 10.1016/j.ejphar.2025.177378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 01/20/2025] [Accepted: 02/11/2025] [Indexed: 02/17/2025]
Abstract
Lung cancer represents one of the most lethal malignancies, characterized by the highest incidence and mortality rates globally. Cisplatin-based chemotherapy exerts powerful anti-tumor activities in lung cancer, whereas its clinical application was limited due to the severe side effects. Dihydrotanshinone I (DHTS), a root extract from Salvia miltiorrhiza, exhibits diverse biological functions, encompassing liver protection, anti-inflammatory properties, promotion of osteoclast differentiation, and induction of apoptosis in tumor cells. DHTS exerts anti-tumor effects in various cancers, however, its biological functions in lung cancer are largely unknown. We demonstrated that DHTS synergistically increased the tumor suppressive effects of cisplatin in lung cancer cells by activating reactive oxygen species (ROS)-mediated endoplasmic reticulum stress (ER stress) and c-Jun N-terminal kinase (JNK) signaling pathways, both in vitro and in vivo. Additionally, DHTS induced excessive ROS accumulation by inhibiting the expression of Heat Shock Proteins 60 (HSPD1). Silencing HSPD1 augmented the anti-tumor effects of DHTS in lung cancer cells, primarily through the stimulation of ROS-mediated ER stress and JNK pathways. Our study suggests that DHTS possesses druggable potential, and combined therapy with DHTS and cisplatin may be a promising therapeutic strategy for certain lung cancer patients.
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Affiliation(s)
- Haizhen Lin
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China; Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China; State Key Laboratory of Macromolecular Drugs and Large-scale Manufacturing, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Hehuan Sui
- Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China; State Key Laboratory of Macromolecular Drugs and Large-scale Manufacturing, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Ying Yu
- Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China; State Key Laboratory of Macromolecular Drugs and Large-scale Manufacturing, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Chenjun Xie
- Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China; State Key Laboratory of Macromolecular Drugs and Large-scale Manufacturing, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Yiwei Shen
- Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China; State Key Laboratory of Macromolecular Drugs and Large-scale Manufacturing, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Liyuan Cheng
- Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China; State Key Laboratory of Macromolecular Drugs and Large-scale Manufacturing, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Jiaying Wang
- Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China; State Key Laboratory of Macromolecular Drugs and Large-scale Manufacturing, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Yun Yu
- Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China; State Key Laboratory of Macromolecular Drugs and Large-scale Manufacturing, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Congying Xie
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China; Wenzhou Key Laboratory of Basic Science and Translational Research of Radiation Oncology, Wenzhou, Zhejiang, 325000, China.
| | - Ri Cui
- Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China; State Key Laboratory of Macromolecular Drugs and Large-scale Manufacturing, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China; Wenzhou Key Laboratory of Basic Science and Translational Research of Radiation Oncology, Wenzhou, Zhejiang, 325000, China.
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Chakraborty S, Choudhuri A, Mishra A, Sengupta R. S-nitrosylation and S-glutathionylation: Lying at the forefront of redox dichotomy or a visible synergism? Biochem Biophys Res Commun 2025; 761:151734. [PMID: 40179738 DOI: 10.1016/j.bbrc.2025.151734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 03/06/2025] [Accepted: 03/29/2025] [Indexed: 04/05/2025]
Abstract
The discovery of novel oxidoreductases and their specific functional revelations as cellular disulfide reductants, S-denitrosylases, or S-deglutathionylases, alongside the well-established major redoxins/antioxidant systems comprising thioredoxin and glutaredoxin, enlarges the spectrum of redox players in the intracellular milieu as well as pushes us to stand at the crossroads concerning the choice of antioxidants that can serve the benefit of catalyzing their cognate protein/non-protein substrates with better efficiencies than the rest. The complexity is extended to exploring the redundancy amongst the redoxin systems and identifying their overlapping or unique substrate preferences to intervene with oxidative or nitrosative stress-induced reversible protein posttranslational modifications such as S-nitrosylation and S-glutathionylation. Contrary to popular expectations of reiterating the theoretical and evidence-based existence of these modifications, the current review aims to take the first leap in delineating the logical reasons behind the competing susceptibility of reactive cysteine thiols toward either or both redox modifications and their subsequent extent of stability in the presence of cellular reductants (thioredoxin, glutaredoxin, thioredoxin-like mimetic or lipoic acid, dihydrolipoic acid, and glutathione), thus rebuilding the underpinnings of a 'redox-interactome' that can further pave the way for the global mapping of ideal substrates exhibiting stringencies or synergism in the context of translational redox research.
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Affiliation(s)
- Surupa Chakraborty
- Amity Institute of Biotechnology Kolkata, Amity University Kolkata, Action Area II, Rajarhat, Newtown, Kolkata, West Bengal, 700135, India
| | - Ankita Choudhuri
- Amity Institute of Biotechnology Kolkata, Amity University Kolkata, Action Area II, Rajarhat, Newtown, Kolkata, West Bengal, 700135, India
| | - Akansha Mishra
- Amity Institute of Biotechnology Kolkata, Amity University Kolkata, Action Area II, Rajarhat, Newtown, Kolkata, West Bengal, 700135, India
| | - Rajib Sengupta
- Amity Institute of Biotechnology Kolkata, Amity University Kolkata, Action Area II, Rajarhat, Newtown, Kolkata, West Bengal, 700135, India.
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Tang S, Li J, Tian W, Feng Y, Deng Y, Tan Z, Han Z, He H, Wu Y, Huang C, Ning K, Liu F, Luo H, Cai S, Ye J, Zhong W. Characterization of the Biochemical Recurrence Prediction Ability and Progression Correlation of Peroxiredoxins Family in Prostate Cancer Based on Integrating Single-Cell RNA-Seq and Bulk RNA-Seq Cohorts. Cancer Med 2025; 14:e70855. [PMID: 40281661 PMCID: PMC12031674 DOI: 10.1002/cam4.70855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 03/25/2025] [Accepted: 03/26/2025] [Indexed: 04/29/2025] Open
Abstract
INTRODUCTION The peroxiredoxins (PRDXs) family plays a crucial role in balancing reactive oxygen species (ROS) levels in tumor cells. However, its potential role in prognosis and therapy response of prostate cancer (PCa) remains unknown. METHODS In this study, we utilized 2 public single-cell RNA datasets and 8 bulk-RNA datasets to investigate the clinical value of six PRDXs family members in PCa. Expression comparison, biochemical recurrence analysis, and therapy response analysis were measured. Pathway enrichments were utilized to predict the potential down-stream pathway it may involve. In vitro experiments were used to validate the function of PRDX5 in the progression of castration-resistant prostate cancer (CRPC) cell lines. RESULT Among the PRDXs family, PRDX5 was most related to the advancement of prostate cancer. A nomogram integrating the expression of PRDX5 with clinical features was developed to better predict clinical outcomes in PCa patients compared to 30 published signatures. Immunohistochemistry was used to verify that PRDX5 expression was higher in advanced levels of PCa tissue. Gene Set Enrichment Analysis (GSEA) and pathway predictive analysis revealed that the PRDX5 related genes were mainly relevant to ROS Pathway, Mitochondria-related functions, cellular respiration, and oxidative phosphorylation. In vitro cell proliferation assays, ROS determination assay, and apoptosis assay together revealed that depletion of PRDX5 induces apoptosis via ROS accumulation in CRPC cells. Moreover, the expression of PRDX5 in CRPC cells also affects the sensitivity to the ARSI therapy. CONCLUSION This study offers new evidence for determining that the expression of PRDX5 is associated with advanced tumor grade, poor prognosis, and suboptimal response to multiple therapies in PCa within the PRDXs family. Last but not least, our study provides new insights into precision medicine in PCa and provides a reference for further research on PRDX5.
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Affiliation(s)
- Shan Tang
- Urology DepartmentThe Central Hospital of ShaoyangShaoyangChina
| | - Jinchuang Li
- Department of UrologyGuangzhou First People's Hospital, School of Medicine, South China University of TechnologyGuangzhouChina
- Guangdong Key Laboratory of Clinical Molecular Medicine and DiagnosticsGuangzhou First People's Hospital, School of Medicine, South China University of TechnologyGuangzhouChina
| | - Weicheng Tian
- Guangdong Provincial Key Laboratory of UrologyThe First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical UniversityGuangzhouChina
| | - Yuanfa Feng
- Guangdong Provincial Key Laboratory of UrologyThe First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical UniversityGuangzhouChina
- Guangzhou National LaboratoryGuangzhouChina
| | - Yulin Deng
- Department of UrologyThe First Dongguan Affiliated Hospital, Guangdong Medical UniversityDongguanChina
| | - Zeheng Tan
- Department of UrologyGuangzhou First People's Hospital, School of Medicine, South China University of TechnologyGuangzhouChina
- Guangdong Key Laboratory of Clinical Molecular Medicine and DiagnosticsGuangzhou First People's Hospital, School of Medicine, South China University of TechnologyGuangzhouChina
| | - Zhaodong Han
- Department of UrologyGuangzhou First People's Hospital, School of Medicine, South China University of TechnologyGuangzhouChina
- Guangdong Key Laboratory of Clinical Molecular Medicine and DiagnosticsGuangzhou First People's Hospital, School of Medicine, South China University of TechnologyGuangzhouChina
| | - Huichan He
- Guangdong Provincial Key Laboratory of UrologyThe First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical UniversityGuangzhouChina
| | - Yongding Wu
- Guangdong Key Laboratory of Clinical Molecular Medicine and DiagnosticsGuangzhou First People's Hospital, School of Medicine, South China University of TechnologyGuangzhouChina
| | - Chuyang Huang
- Urology DepartmentThe Central Hospital of ShaoyangShaoyangChina
| | - Keping Ning
- Urology DepartmentThe Central Hospital of ShaoyangShaoyangChina
| | - Feng Liu
- Urology DepartmentThe Central Hospital of ShaoyangShaoyangChina
| | - Hongwei Luo
- Urology DepartmentThe Central Hospital of ShaoyangShaoyangChina
| | - Shanghua Cai
- Guangdong Provincial Key Laboratory of UrologyThe First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical UniversityGuangzhouChina
- Guangzhou National LaboratoryGuangzhouChina
| | - Jianheng Ye
- Department of UrologyGuangzhou First People's Hospital, School of Medicine, South China University of TechnologyGuangzhouChina
- Guangdong Key Laboratory of Clinical Molecular Medicine and DiagnosticsGuangzhou First People's Hospital, School of Medicine, South China University of TechnologyGuangzhouChina
| | - Weide Zhong
- Department of UrologyGuangzhou First People's Hospital, School of Medicine, South China University of TechnologyGuangzhouChina
- Guangdong Key Laboratory of Clinical Molecular Medicine and DiagnosticsGuangzhou First People's Hospital, School of Medicine, South China University of TechnologyGuangzhouChina
- Guangdong Provincial Key Laboratory of UrologyThe First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical UniversityGuangzhouChina
- Guangzhou National LaboratoryGuangzhouChina
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Zhu X, Yuan F, Sun Q, Yang C, Jiang H, Xiang X, Zhang X, Sun Z, Wei Y, Chen Q, Cai L. N-acetylcysteine remodels the tumor microenvironment of primary and recurrent mouse glioblastoma. J Neurooncol 2025; 173:131-145. [PMID: 39954037 DOI: 10.1007/s11060-025-04971-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Accepted: 02/08/2025] [Indexed: 02/17/2025]
Abstract
PURPOSE Glioblastoma (GBM) exhibits a high ROS character, giving rise to an immunosuppressive microenvironment and tumor vascular abnormality. This study investigated the potential effect of N-acetylcysteine (NAC), an antioxidant, on primary and recurrent mouse brain tumors. METHODS We measured reactive oxygen species (ROS)/ glutathione (GSH) levels in human GBM. Additionally, we conducted NAC trials on primary mouse brain tumor models (GL261-Luc, CT2A-Luc) and a recurrent mouse GBM model (GL261-iCasp9-Luc). After brain tumor inoculation, mice received a daily 100 mg/kg NAC treatment, and the tumor volume was monitored via IVIS imaging. The efficacy of NAC was evaluated through survival time, tumor volume, ROS/GSH levels, M1/M2 macrophages, immune cells infiltration, and tumor vascularization. RESULTS Human GBM suffered from significant oxidative stress. With NAC treatment, mouse brain tumors exhibited a lower ROS level, more M1-like tumor-associated macrophages/microglia (TAMs), more CD8 + T cell infiltration, and a normalized vascular character. NAC inhibited tumor growth and suppressed recurrence in mouse brain tumor models. CONCLUSION NAC is a promising adjunctive drug to remodel the brain tumors microenvironment.
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Affiliation(s)
- Xiwei Zhu
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People's Republic of China
| | - Fanen Yuan
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People's Republic of China
| | - Qian Sun
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People's Republic of China
| | - Chen Yang
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People's Republic of China
| | - Hongxiang Jiang
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People's Republic of China
| | - Xi Xiang
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People's Republic of China
| | - Xinyi Zhang
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People's Republic of China
| | - Zhiqiang Sun
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People's Republic of China
| | - Yuxin Wei
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People's Republic of China
| | - Qianxue Chen
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People's Republic of China.
| | - Linzhi Cai
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People's Republic of China.
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Tan J, Ding B, Chen H, Meng Q, Li J, Zhang W, Yang Z, Ma X, Han D, Yang M, Zheng P, Ma P, Lin J. Gallium-Magnesium Layered Double Hydroxide for Elevated Tumor Immunotherapy Through Multi-Network Synergistic Regulation. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2025; 37:e2501256. [PMID: 40190140 DOI: 10.1002/adma.202501256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/18/2025] [Revised: 03/12/2025] [Indexed: 05/28/2025]
Abstract
Immunotherapeutic efficacy is often limited by poor immunogenicity, immunosuppressive tumor microenvironment (TME), and cytoprotective mechanisms, leading to low immune activation. To this end, here, L-amino acid oxidase (LAAO) loaded gallium-magnesium layered double hydroxide (MG-LAAO) is prepared for significantly enhanced tumor immunotherapy through multi-network synergistic regulation. First, MG-LAAO induces tumor cell pyroptosis by initiating caspase-1/GSDMD and caspase-3/GSDME pathways, further triggering immunogenic cell death (ICD). Then the released Ga3+ induces mitochondrial iron overload, resulting in ferroptosis. In addition, MG-LAAO also hinders autophagy of tumor cells, and reshapes the immunosuppressive tumor microenvironment (TME) by neutralizing H+ and inhibiting lactic acid accumulation, thus destroying the cytoprotective mechanism and avoiding immune escape. Furthermore, this multi-network synergy further activates the cGAS-STING signaling pathway, generating powerful antitumor immunotherapy. This work highlights the critical role of synergies between autophagy block, pyroptosis, ferroptosis, and ICD in tumor immunotherapy, demonstrating the important role of this multi-network synergy in effectively overcoming immunosuppressive TME and enhancing immunogenicity. In particular, the mechanism of gallium-induced pyroptosis is revealed for the first time, providing theoretical support for the design of new materials for tumor immunotherapy in the future.
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Affiliation(s)
- Jia Tan
- State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, P. R. China
- School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, 230026, P. R. China
| | - Binbin Ding
- State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, P. R. China
- School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, 230026, P. R. China
| | - Hao Chen
- State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, P. R. China
- School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, 230026, P. R. China
| | - Qi Meng
- State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, P. R. China
- School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, 230026, P. R. China
| | - Jing Li
- State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, P. R. China
- School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, 230026, P. R. China
| | - Wenying Zhang
- State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, P. R. China
- School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, 230026, P. R. China
| | - Zhuang Yang
- State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, P. R. China
- School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, 230026, P. R. China
| | - Xinyu Ma
- State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, P. R. China
- School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, 230026, P. R. China
| | - Di Han
- State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, P. R. China
- School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, 230026, P. R. China
| | - Mingkai Yang
- State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, P. R. China
- School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, 230026, P. R. China
| | - Pan Zheng
- State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, P. R. China
- Key Laboratory of Superlight Materials and Surface Technology of Ministry of Education, College of Material Sciences and Chemical Engineering, Harbin Engineering University, Harbin, 150001, P. R. China
| | - Ping'an Ma
- State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, P. R. China
- School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, 230026, P. R. China
| | - Jun Lin
- State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, P. R. China
- School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, 230026, P. R. China
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Liu Y, Zhang X, Zhang X, Wang G, Li X, Xing S, Cao C, Li Y, Han L, Wang S. Histone deacetylase inhibiting nanoprodrugs for enhanced chemodynamic therapy through multistage downregulating glutathione. Int J Biol Macromol 2025; 305:141184. [PMID: 39971061 DOI: 10.1016/j.ijbiomac.2025.141184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 01/26/2025] [Accepted: 02/15/2025] [Indexed: 02/21/2025]
Abstract
The unique redox homeostasis in tumor cells makes chemodynamic therapy (CDT) a promising strategy for cancer treatment. However, high glutathione (GSH) level within tumor cells severely impacts the efficacy of CDT. Therefore, reducing intracellular GSH levels has become an approach to enhance CDT. Here, we propose a HDAC inhibiting nanoprodrug consisting of an amphiphilic reactive oxygen species (ROS)-responsive polyprodrug and a GSH-responsive dimer. The high ROS level in tumor tissues can trigger the release of cinnamaldehyde and ferrocene to upregulate intracellular ROS levels through generation of hydroxyl radicals. Additionally, the dimer can react with intracellular GSH to release histone deacetylase (HDAC) inhibitors for inhibiting HDAC, thereby suppressing GSH synthesis by reducing precursor supply. The multistage depletion of GSH can further enhance oxidative damage of hydroxyl radicals to cancer cells. This study provides a promising HDAC-inhibiting strategy to achieve GSH depletion for enhanced CDT.
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Affiliation(s)
- Yongxin Liu
- School of Life Sciences, Faculty of Medicine, Tianjin University, Tianjin 300072, China
| | - Xinlu Zhang
- School of Life Sciences, Faculty of Medicine, Tianjin University, Tianjin 300072, China
| | - Xu Zhang
- School of Life Sciences, Faculty of Medicine, Tianjin University, Tianjin 300072, China.
| | - Guocheng Wang
- School of Life Sciences, Faculty of Medicine, Tianjin University, Tianjin 300072, China
| | - Xue Li
- School of Life Sciences, Faculty of Medicine, Tianjin University, Tianjin 300072, China
| | - Suixin Xing
- School of Life Sciences, Faculty of Medicine, Tianjin University, Tianjin 300072, China
| | - Chen Cao
- School of Life Sciences, Faculty of Medicine, Tianjin University, Tianjin 300072, China
| | - Yuewei Li
- School of Life Sciences, Faculty of Medicine, Tianjin University, Tianjin 300072, China
| | - Lei Han
- Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin Medical University General Hospital, Tianjin 300052, China.
| | - Sheng Wang
- School of Life Sciences, Faculty of Medicine, Tianjin University, Tianjin 300072, China.
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Wang S, Yang J, Zhen C, Wang H, Shang P. Electromagnetic fields regulate iron metabolism: From mechanisms to applications. J Adv Res 2025:S2090-1232(25)00288-7. [PMID: 40311754 DOI: 10.1016/j.jare.2025.04.044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2024] [Revised: 04/06/2025] [Accepted: 04/28/2025] [Indexed: 05/03/2025] Open
Abstract
BACKGROUND Electromagnetic fields (EMFs), as a form of physical therapy, have been widely applied in biomedicine. Iron, the most abundant trace metal in living organisms, plays a critical role in various physiological processes, and imbalances in its metabolism are closely associated with the development and progression of numerous diseases. Numerous studies have demonstrated that EMF exposureinduces significant changes in both systemic and cellular iron metabolism. AIM OF REVIEW This review aims to summarize the evidence and potential biophysical mechanisms underlying the role of EMFs in regulating iron metabolism, thereby enhancing the understanding of their biological mechanisms and expanding their potential applications in biomedical fields. KEY SCIENTIFIC CONCEPTS OF REVIEW In this review, we have synthesized research findings and proposed the hypothesis that the biophysical mechanisms of EMFs regulate iron metabolism involve the special electromagnetic properties of iron-containing proteins and iron-enriched tissues, as well as the modulation of membrane structure and function, ion channels, and the generation and activity of Reactive Oxygen Species (ROS). Then, the review summarizes the latest advances in the effects of EMFs on iron metabolism and their safety, as well as their impact on immunoregulation, cardiovascular diseases, neurological diseases, orthopedic diseases, diabetes, liver injury, and cancer.
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Affiliation(s)
- Shenghang Wang
- Department of Spine Surgery, People's Hospital of Longhua, Shenzhen, China; Research & Development Institute of Northwestern Polytechnical University in Shenzhen, Shenzhen, China
| | - Jiancheng Yang
- Department of Osteoporosis, Honghui Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Chenxiao Zhen
- Department of Spine Surgery, People's Hospital of Longhua, Shenzhen, China; Research & Development Institute of Northwestern Polytechnical University in Shenzhen, Shenzhen, China; School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Huiru Wang
- Research & Development Institute of Northwestern Polytechnical University in Shenzhen, Shenzhen, China; School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Peng Shang
- Research & Development Institute of Northwestern Polytechnical University in Shenzhen, Shenzhen, China.
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Świderska-Kołacz G, Madej M, Zmorzynski S, Styk W, Surowiec I, Witek B, Wojciechowska A, Czerwik-Marcinkowska J, Nowakowska A. Effects of bortezomib on intracellular antioxidant and apoptosis in HepG2cells. PeerJ 2025; 13:e19235. [PMID: 40313384 PMCID: PMC12045286 DOI: 10.7717/peerj.19235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Accepted: 03/10/2025] [Indexed: 05/03/2025] Open
Abstract
Bortezomib, as a proteasome inhibitor, is used in clinical trials related to solid cancers. However, its use is not always associated with a good response to treatment. Taking into account the above, we decided to analyze the effect of the time-dependency (24 vs. 48 h) and the dose-dependency of bortezomib (2, 4, 8 and 16 nM) on apoptosis and activities of antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD), glutathione reductase (GR), glutathione peroxidase (GPx) and glutathione transferase (GST), as well as concentrations of reduced glutathione (GSH) and malondialdehyde (MDA) in hepatoblastoma cell line (HepG2) cells. We have shown that increasing concentrations of bortezomib caused (I) a gradual decrease in the levels of GSH; (II) changes in MDA concentrations and antioxidant enzymes activities; (III) increase in apoptosis levels in HepG2 cells. We did not find significant association between antioxidant parameters and number of apoptotic cells. Our study showed that the analyzed parameters (such as: CAT, SOD, GR, GPx, GST, GSH, MDA) changed after bortezomib treatment. It is important to search for new anti-cancer therapies based on next-generation proteasome inhibitors. It is possible that the use of proteins associated with oxidative stress will help enhance the action of these inhibitors and will provide a better treatment effect.
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Affiliation(s)
| | - Magdalena Madej
- Institute of Biology, Jan Kochanowski University, Kielce, Poland
| | | | - Wojciech Styk
- Academic Laboratory of Psychological Tests, Medical University of Lublin, Lublin, Poland
| | - Iwona Surowiec
- Institute of Biology, Jan Kochanowski University, Kielce, Poland
| | - Bożena Witek
- Institute of Biology, Jan Kochanowski University, Kielce, Poland
| | - Anna Wojciechowska
- Department of Geobotany and Landscape Planning, Nicolaus Copernicus University of Torun, Toruń, Poland
| | | | - Anna Nowakowska
- Department of Animal Physiology and Neurobiology, Nicolaus Copernicus University of Torun, Toruń, Poland
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Li C, Cheng H, Zhuang Z, Cao F, Liu H, Zhao L, Rizvi SFA, Wang K, Yang L, Lu X, Zheng Y, Zhang Y, He P, Mao J, Wen X, Zhang L, Jiang L, Lin J, Li D, Chu C, Zeng Y, Lu Z, Liu C, Thompson EW, Chen Z, Wang P, Liu G. FlexiPlasma Microcatheter-Embolic Material (FPM-EM) Platform: A Non-Inflammatory Pyroptosis Strategy for Precision Hepatocellular Carcinoma Therapy. SMALL METHODS 2025:e2500231. [PMID: 40285389 DOI: 10.1002/smtd.202500231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Revised: 04/03/2025] [Indexed: 04/29/2025]
Abstract
Hepatocellular carcinoma (HCC) remains a global challenge, with conventional locoregional therapies like transarterial chemoembolization (TACE) lacking tumor specificity and promoting metastasis and inflammation. Cold atmospheric plasma (CAP) offers a tumor-selective ablation strategy but suffers from limited tissue penetration. To overcome this, the FlexiPlasma microcatheter (FPM) is developed, integrating flexible non-metallic microtubes and ring-shaped electrodes for precise CAP delivery to deep tumors. The optimized FPM-generated CAP eliminates cytotoxic UV and ozone while inducing tumor-specific pyroptosis via a ROS/Caspase-8/GSDMC pathway. Gasdermin-C (GSDMC) is highly expressed in liver tumors but absent in normal tissues, ensuring selective targeting with minimal inflammation. FPM is combined with embolic material (EM), PPP@CD hydrogel, enhancing injectability, tumor embolization, and sustained drug release. This FPM-EM strategy potentiates antitumor immunity, particularly CD4+ and CD8+ T-cell responses. These findings establish FPM-EM as a safe, effective, and minimally invasive therapy for HCC, revealing a non-inflammatory pyroptosis mechanism and broadening the potential of CAP-based cancer treatments. The FPM-EM combination offers promising new therapeutic options for HCC, addressing the limitations of TACE. Furthermore, the FPM-EM platform can be extended to the interventional therapy of other tumors and adapted to incorporate various drugs and nano-/micro-materials, highlighting the strong potential for future clinical translation.
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Affiliation(s)
- Changhong Li
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, 361102, China
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, National Innovation Platform for Industry-Education Integration in Vaccine Research, Fujian Engineering Research Center of Molecular Theranostic Technology, Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
| | - Hongwei Cheng
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, National Innovation Platform for Industry-Education Integration in Vaccine Research, Fujian Engineering Research Center of Molecular Theranostic Technology, Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
- Joint Key Laboratory of the Ministry of Education, Institute of Applied Physics and Materials Engineering, University of Macau, Macau, 999078, China
- Zhuhai UM Science & Technology Research Institute, University of Macau, Macau, 999078, China
| | - Ziqi Zhuang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, National Innovation Platform for Industry-Education Integration in Vaccine Research, Fujian Engineering Research Center of Molecular Theranostic Technology, Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
| | - Fei Cao
- Paul C Lauterbur Research Center for Biomedical Imaging, Institute of Biomedical and Health Engineering, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China
| | - Hui Liu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, National Innovation Platform for Industry-Education Integration in Vaccine Research, Fujian Engineering Research Center of Molecular Theranostic Technology, Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
| | - Liqian Zhao
- Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310000, China
| | - Syed Faheem Askari Rizvi
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, National Innovation Platform for Industry-Education Integration in Vaccine Research, Fujian Engineering Research Center of Molecular Theranostic Technology, Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
| | - Kanqi Wang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, National Innovation Platform for Industry-Education Integration in Vaccine Research, Fujian Engineering Research Center of Molecular Theranostic Technology, Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
- Institute of Artificial Intelligence, Xiamen University, Xiamen, 361102, China
| | - Liuyin Yang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, National Innovation Platform for Industry-Education Integration in Vaccine Research, Fujian Engineering Research Center of Molecular Theranostic Technology, Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
- Institute of Artificial Intelligence, Xiamen University, Xiamen, 361102, China
| | - Xiaowei Lu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, National Innovation Platform for Industry-Education Integration in Vaccine Research, Fujian Engineering Research Center of Molecular Theranostic Technology, Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
- Institute of Artificial Intelligence, Xiamen University, Xiamen, 361102, China
| | - Yating Zheng
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, National Innovation Platform for Industry-Education Integration in Vaccine Research, Fujian Engineering Research Center of Molecular Theranostic Technology, Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
| | - Yu Zhang
- Department of Hepatobiliary and Pancreas Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Pan He
- Department of Hepatobiliary and Pancreas Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Jingsong Mao
- The Sixth School of Clinical Medicine, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Guangdong, 511518, China
| | - Xiaofei Wen
- Department of Vascular & Tumor Interventional Radiology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361000, China
| | - Liang Zhang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, National Innovation Platform for Industry-Education Integration in Vaccine Research, Fujian Engineering Research Center of Molecular Theranostic Technology, Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
- Department of Dermatology, The Fourth Affiliated Hospital of Harbin Medical University, No.37, Yiyuan Street, Nangang District, Harbin, 150001, China
| | - Lili Jiang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, National Innovation Platform for Industry-Education Integration in Vaccine Research, Fujian Engineering Research Center of Molecular Theranostic Technology, Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
| | - Jinyong Lin
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, National Innovation Platform for Industry-Education Integration in Vaccine Research, Fujian Engineering Research Center of Molecular Theranostic Technology, Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
| | - Dong Li
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, National Innovation Platform for Industry-Education Integration in Vaccine Research, Fujian Engineering Research Center of Molecular Theranostic Technology, Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
- College of Ocean Food and Biological Engineering, Jimei University, Xiamen, 361021, China
| | - Chengchao Chu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, National Innovation Platform for Industry-Education Integration in Vaccine Research, Fujian Engineering Research Center of Molecular Theranostic Technology, Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
- Xiamen University Affiliated Xiamen Eye Center, Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361102, China
- The Key Laboratory of Biomedical Imaging Science and System, Chinese Academy of Sciences, Shenzhen, 518055, China
| | - Yun Zeng
- Department of Pharmacy, Xiamen Medical College, Xiamen, 361023, China
| | - Zhixiang Lu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, National Innovation Platform for Industry-Education Integration in Vaccine Research, Fujian Engineering Research Center of Molecular Theranostic Technology, Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
- State Key Laboratory of Stress Biology and Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China
| | - Chao Liu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, National Innovation Platform for Industry-Education Integration in Vaccine Research, Fujian Engineering Research Center of Molecular Theranostic Technology, Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
- Shenzhen Research Institute of Xiamen University, Shenzhen, 518000, China
| | - Erik W Thompson
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology (QUT), Brisbane, Queensland, 4059, Australia
- Translational Research Institute, Woolloongabba, Queensland, 4102, Australia
| | - Zhitong Chen
- Paul C Lauterbur Research Center for Biomedical Imaging, Institute of Biomedical and Health Engineering, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China
- Advanced Therapeutic Center, National Innovation Center for Advanced Medical Devices, Shenzhen, 518100, China
- Key Laboratory of Biomedical Imaging Science and System, Chinese Academy of Sciences, Shenzhen, 518055, China
| | - Peiyu Wang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, National Innovation Platform for Industry-Education Integration in Vaccine Research, Fujian Engineering Research Center of Molecular Theranostic Technology, Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
| | - Gang Liu
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, 361102, China
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, National Innovation Platform for Industry-Education Integration in Vaccine Research, Fujian Engineering Research Center of Molecular Theranostic Technology, Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
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Qu Y, Ma Q, Wang C, Zhang L, Feng H, Lai S. Pulsatilla Powder Ameliorates Damp-Heat Diarrhea in Piglets Through the Regulation of Intestinal Mucosal Barrier and the Pentose Phosphate Pathway Involving G6PD and NOX. Vet Sci 2025; 12:403. [PMID: 40431496 PMCID: PMC12116046 DOI: 10.3390/vetsci12050403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 04/15/2025] [Accepted: 04/19/2025] [Indexed: 05/29/2025] Open
Abstract
Damp-heat diarrhea (DHD) in piglets presents as diarrhea and intestinal bleeding, significantly affecting both piglet health and the pig industry. Pulsatilla powder (PP), a herbal formulation composed of Pulsatilla, Rhizoma Coptidis, Phellodendron Bark, and Fraxini Cortex, has proven to be an effective treatment for DHD. Although the pentose phosphate pathway (PPP) has been associated with its therapeutic effects, the exact mechanism of action remains unclear. In this study, the DHD model in piglets was established to evaluate clinical symptoms, organ index, serum index, histological changes, colonic metabolites, and molecular mechanisms using techniques such as QPCR, ELISA, WB and metabolomics. PP improved intestinal health by restoring spleen and lung index, increasing LDL-C and HDL-C levels (HDL-C: p < 0.05), decreasing mRNA expression levels of IFN-γ and TNF-α mRNA (p < 0.01), and increasing MUC1 and MUC2 expression. Metabolomics analysis has identified 44 pathways, including pentose phosphate and glutathione pathways, and 132 differential metabolites have involved in DHD treatment. PP significantly reduced G6PD (p < 0.01), inhibited the pentose phosphate pathway, reduced NOX production (p < 0.01), and suppressed ROS production (p < 0.01). These effects alleviated oxidative stress and intestinal damage, demonstrating PP's effectiveness in treating DHD by targeting critical enzymes and ROS levels.
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Affiliation(s)
- Yunqi Qu
- Department of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Southwest University, Chongqing 402460, China; (Y.Q.); (C.W.); (L.Z.); (H.F.); (S.L.)
| | - Qi Ma
- Department of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Southwest University, Chongqing 402460, China; (Y.Q.); (C.W.); (L.Z.); (H.F.); (S.L.)
- Institute of Traditional Chinese Veterinary Medicine, Southwest University, Chongqing 402460, China
| | - Chenying Wang
- Department of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Southwest University, Chongqing 402460, China; (Y.Q.); (C.W.); (L.Z.); (H.F.); (S.L.)
| | - Lifang Zhang
- Department of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Southwest University, Chongqing 402460, China; (Y.Q.); (C.W.); (L.Z.); (H.F.); (S.L.)
| | - Haolian Feng
- Department of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Southwest University, Chongqing 402460, China; (Y.Q.); (C.W.); (L.Z.); (H.F.); (S.L.)
| | - Siyue Lai
- Department of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Southwest University, Chongqing 402460, China; (Y.Q.); (C.W.); (L.Z.); (H.F.); (S.L.)
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43
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Yeon Chae S, Jang SY, Kim J, Hwang S, Malani D, Kallioniemi O, Yun SG, Kim JS, Kim HI. Mechanisms of chemotherapy failure in refractory/relapsed acute myeloid leukemia: the role of cytarabine resistance and mitochondrial metabolism. Cell Death Dis 2025; 16:331. [PMID: 40268906 PMCID: PMC12019594 DOI: 10.1038/s41419-025-07653-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 04/05/2025] [Accepted: 04/09/2025] [Indexed: 04/25/2025]
Abstract
Acute myeloid leukemia (AML) is an aggressive hematological malignancy. Patients with wild-type FLT3 relapsed or refractory (R/R) AML face significant therapeutic challenges due to the persistent lack of effective treatments. A comprehensive understanding of the mechanisms underlying chemotherapy resistance is needed to the development of effective treatment strategies. Therefore, we investigated the molecular mechanisms underlying cytarabine (Ara-C) resistance and daunorubicin (DNR) tolerance in Ara-C-resistant RHI-1 cells derived from the wild-type FLT3 AML cell line SHI-1. Quantitative analysis of intracellular drug concentrations, proteomics, and phosphoproteomics showed that DNR resistance in Ara-C-resistant RHI-1 cells is driven by metabolic remodeling toward mitochondrial metabolism, upregulation of DNA repair pathways, and enhanced reactive oxygen species (ROS) detoxification rather than reduced drug uptake. Moreover, targeting these compensatory mechanisms, particularly the OXPHOS complex I proteins, significantly improved the efficacy of both Ara-C and DNR. Conclusively, these findings highlight mitochondrial metabolism and DNA repair as critical factors in chemotherapy resistance and offer valuable insights into potential therapeutic targets for enhancing treatment outcomes in patients with wild-type FLT3 R/R AML.
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MESH Headings
- Cytarabine/pharmacology
- Cytarabine/therapeutic use
- Humans
- Leukemia, Myeloid, Acute/drug therapy
- Leukemia, Myeloid, Acute/metabolism
- Leukemia, Myeloid, Acute/pathology
- Leukemia, Myeloid, Acute/genetics
- Mitochondria/metabolism
- Mitochondria/drug effects
- Drug Resistance, Neoplasm/drug effects
- Cell Line, Tumor
- Daunorubicin/pharmacology
- Reactive Oxygen Species/metabolism
- DNA Repair/drug effects
- Treatment Failure
- Oxidative Phosphorylation/drug effects
- fms-Like Tyrosine Kinase 3/metabolism
- fms-Like Tyrosine Kinase 3/genetics
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Affiliation(s)
- Soo Yeon Chae
- Department of Chemistry, Korea University, Seoul, Republic of Korea
- Center for Proteogenome Research, Korea University, Seoul, Republic of Korea
| | - Se-Young Jang
- School of Biological Sciences, Seoul National University, Seoul, Republic of Korea
| | - Jinhui Kim
- Department of Chemistry, Korea University, Seoul, Republic of Korea
| | - Sehyun Hwang
- Department of Chemistry, Korea University, Seoul, Republic of Korea
- Center for Proteogenome Research, Korea University, Seoul, Republic of Korea
| | - Disha Malani
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland
| | - Olli Kallioniemi
- Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland
- Science for Life Laboratory, Department of Oncology and Pathology, Karolinska Institute, Solna, Sweden
| | - Seung Gyu Yun
- Department of Laboratory Medicine, Korea University College of Medicine, Seoul, Korea.
| | - Jong-Seo Kim
- School of Biological Sciences, Seoul National University, Seoul, Republic of Korea.
- Center for RNA Research, Institute of Basic Science, Seoul National University, Seoul, Korea.
| | - Hugh I Kim
- Department of Chemistry, Korea University, Seoul, Republic of Korea.
- Center for Proteogenome Research, Korea University, Seoul, Republic of Korea.
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44
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Park MN, Kim M, Lee S, Kang S, Ahn CH, Tallei TE, Kim W, Kim B. Targeting Redox Signaling Through Exosomal MicroRNA: Insights into Tumor Microenvironment and Precision Oncology. Antioxidants (Basel) 2025; 14:501. [PMID: 40427384 PMCID: PMC12108341 DOI: 10.3390/antiox14050501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2025] [Revised: 04/18/2025] [Accepted: 04/20/2025] [Indexed: 05/29/2025] Open
Abstract
Reactive oxygen species (ROS) play a dual role in cancer progression, acting as both signaling molecules and drivers of oxidative damage. Emerging evidence highlights the intricate interplay between ROS, microRNAs (miRNAs), and exosomes within the tumor microenvironment (TME), forming a regulatory axis that modulates immune responses, angiogenesis, and therapeutic resistance. In particular, oxidative stress not only stimulates exosome biogenesis but also influences the selective packaging of redox-sensitive miRNAs (miR-21, miR-155, and miR-210) via RNA-binding proteins such as hnRNPA2B1 and SYNCRIP. These miRNAs, delivered through exosomes, alter gene expression in recipient cells and promote tumor-supportive phenotypes such as M2 macrophage polarization, CD8+ T-cell suppression, and endothelial remodeling. This review systematically explores how this ROS-miRNA-exosome axis orchestrates communication across immune and stromal cell populations under hypoxic and inflammatory conditions. Particular emphasis is placed on the role of NADPH oxidases, hypoxia-inducible factors, and autophagy-related mechanisms in regulating exosomal output. In addition, we analyze the therapeutic relevance of natural products and herbal compounds-such as curcumin, resveratrol, and ginsenosides-which have demonstrated promising capabilities to modulate ROS levels, miRNA expression, and exosome dynamics. We further discuss the clinical potential of leveraging this axis for cancer therapy, including strategies involving mesenchymal stem cell-derived exosomes, ferroptosis regulation, and miRNA-based immune modulation. Incorporating insights from spatial transcriptomics and single-cell analysis, this review provides a mechanistic foundation for the development of exosome-centered, redox-modulating therapeutics. Ultimately, this work aims to guide future research and drug discovery efforts toward integrating herbal medicine and redox biology in the fight against cancer.
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Affiliation(s)
- Moon Nyeo Park
- College of Korean Medicine, Kyung Hee University, 1-5 Hoegidong, Dongdaemun-gu, Seoul 02447, Republic of Korea; (M.N.P.); (M.K.); (S.L.); (S.K.); (C.-H.A.); (W.K.)
| | - Myoungchan Kim
- College of Korean Medicine, Kyung Hee University, 1-5 Hoegidong, Dongdaemun-gu, Seoul 02447, Republic of Korea; (M.N.P.); (M.K.); (S.L.); (S.K.); (C.-H.A.); (W.K.)
| | - Soojin Lee
- College of Korean Medicine, Kyung Hee University, 1-5 Hoegidong, Dongdaemun-gu, Seoul 02447, Republic of Korea; (M.N.P.); (M.K.); (S.L.); (S.K.); (C.-H.A.); (W.K.)
| | - Sojin Kang
- College of Korean Medicine, Kyung Hee University, 1-5 Hoegidong, Dongdaemun-gu, Seoul 02447, Republic of Korea; (M.N.P.); (M.K.); (S.L.); (S.K.); (C.-H.A.); (W.K.)
| | - Chi-Hoon Ahn
- College of Korean Medicine, Kyung Hee University, 1-5 Hoegidong, Dongdaemun-gu, Seoul 02447, Republic of Korea; (M.N.P.); (M.K.); (S.L.); (S.K.); (C.-H.A.); (W.K.)
| | - Trina Ekawati Tallei
- Department of Biology, Faculty of Mathematics and Natural Sciences, Universitas Sam Ratulangi, Manado 95115, Indonesia;
- Department of Biology, Faculty of Medicine, Universitas Sam Ratulangi, Manado 95115, Indonesia
| | - Woojin Kim
- College of Korean Medicine, Kyung Hee University, 1-5 Hoegidong, Dongdaemun-gu, Seoul 02447, Republic of Korea; (M.N.P.); (M.K.); (S.L.); (S.K.); (C.-H.A.); (W.K.)
- Korean Medicine-Based Drug Repositioning Cancer Research Center, College of Korean Medicine, Kyung Hee University, Hoegi-dong, Dongdaemun-gu, Seoul 02447, Republic of Korea
| | - Bonglee Kim
- College of Korean Medicine, Kyung Hee University, 1-5 Hoegidong, Dongdaemun-gu, Seoul 02447, Republic of Korea; (M.N.P.); (M.K.); (S.L.); (S.K.); (C.-H.A.); (W.K.)
- Korean Medicine-Based Drug Repositioning Cancer Research Center, College of Korean Medicine, Kyung Hee University, Hoegi-dong, Dongdaemun-gu, Seoul 02447, Republic of Korea
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Bhattacharyya T, Das P, Ansari A, Mohan AA, Chandra Y, Narayan KP, Banerjee R. Glucocorticoid Receptor-Targeted Nanoliposome for STAT3 Inhibition-Led Myeloid-Derived Suppressor Cell Modulation and Efficient Colon Cancer Treatment. ACS APPLIED BIO MATERIALS 2025; 8:3185-3204. [PMID: 40162961 DOI: 10.1021/acsabm.5c00002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
STAT3 is an important protein responsible for cellular proliferation, motility, and immune tolerance and is hyperactive in colorectal cancer, instigating metastasis, cellular proliferation, migration, as well as inhibition. It helps in proliferation of myeloid-derived suppressor cells (MDSCs), which within the tumor microenvironment (TME) suppress T cells to encourage tumor growth, metastasis, and resistance to immunotherapy, besides playing dynamic role in regulating macrophages within the tumor. Thus, MDSC is a potential target to augment immune surveillance within the TME. Herein, we report targeting both colorectal cancer and MDSCs using a glucocorticoid receptor (GR)-targeted nanoliposomal formulation carrying GR-ligand, dexamethasone (Dex), and a STAT3 inhibitor, niclosamide (N). Our main objective was to selectively inhibit STAT3, the key immunomodulatory factor in most TME-associated cells including MDSCs, and also repurpose the use of this antihelminthic, low-cost drug N for cancer treatment. The resultant formulation D1XN exhibited better tumor regression and survivability compared to GR nontargeted formulation. Further, bone marrow cell-derived MDSCs were engineered by D1XN treatment ex vivo and were inoculated back to tumor-bearing mice. Significant tumor growth inhibition with enhanced antiproliferative immune cell signatures, such as T cell infiltration, decrease in Treg cells, and increased M1/M2 macrophage ratio within the TME were observed. This reveals the effectiveness of engineered MDSCs to modulate tumor surveillance besides reversing the aggressiveness of the tumor. Therefore, D1XN and D1XN-mediated engineered MDSCs alone or in combination can be considered as potent selective chemo-immunotherapeutic nanoliposomal agent(s) against colorectal cancer.
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Affiliation(s)
- Tithi Bhattacharyya
- Division of Oils, Lipids Science and Technology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Pritam Das
- Division of Oils, Lipids Science and Technology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Aasia Ansari
- Division of Oils, Lipids Science and Technology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Adrij A Mohan
- Department of Biotechnology, Manipal Institute of Technology, Manipal, Karnataka 576104, India
| | - Yogesh Chandra
- Applied Biology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
| | - Kumar Pranav Narayan
- Department of Biological Sciences, BITS Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad 500078, India
| | - Rajkumar Banerjee
- Division of Oils, Lipids Science and Technology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
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Ding M, Chen H, He L, Wang Z, Zhao X, Sun P, Mei Q, Li D, Fan Q. NIR-II D-A-D-Type Small-Molecule Coordination with Carboxylatopillar[5]Arene: a Multifunctional Phototheranostic for Low-Temperature NIR-II Photothermal/Platinum-Based/Chemodynamic Combination Cancer Immunotherapy. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2025:e2501903. [PMID: 40255101 DOI: 10.1002/smll.202501903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/26/2025] [Revised: 04/03/2025] [Indexed: 04/22/2025]
Abstract
Low-temperature second near-infrared region (NIR-II) photothermal therapy (PTT) has shown significant potential in minimizing damage to normal tissues and reducing inflammation. However, it still faces challenge of insufficient immune response. Thus, a multifunctional phototheranostic nanoparticle (BDPB/Pt/Fe@P[5]) is developed by co-loading BDPB, CDHPt, and Fe2⁺ with a pH-sensitive lipid DSPE-PEOz2K. The carboxylatopillar[5]arene (CP[5]) used to construct this nanoparticle exhibits strong host-guest recognition with pyridine salts, alleviating aggregation caused quench (ACQ) effect and enhancing the NIR-II emission of the donor-acceptor-donor (D-A-D)-type organic small molecule (BDPB). CP[5] provides suitable vehicles for encapsulating platinum (IV) prodrugs (CDHPt) and Fe2⁺ ions via metal coordination for controllable reactive oxygen species (ROS) release. Under low-intensity NIR-II laser irradiation and an acidic tumor microenvironment, the nanoparticles degrade, releasing CDHPt and Fe2⁺ ions for platinum-based therapy and chemodynamic therapy (CDT). CDHPt facilitates the direct production of superoxide anions (O₂·⁻) from O₂ and partially converts it into the highly cytotoxic hydroxyl radicals, thereby promoting the Fenton reaction process. The therapeutic efficacy is further synergized by immunogenic cell death (ICD) effect.
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Affiliation(s)
- Miaomiao Ding
- State Key Laboratory of Flexible Electronics (LoFE) & Institute of Advanced Materials (IAM), Nanjing University of Posts & Telecommunications, 9 Wenyuan Road, Nanjing, 210023, China
| | - Haoran Chen
- State Key Laboratory of Flexible Electronics (LoFE) & Institute of Advanced Materials (IAM), Nanjing University of Posts & Telecommunications, 9 Wenyuan Road, Nanjing, 210023, China
| | - Liuliang He
- Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Zhichao Wang
- Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Xianghua Zhao
- College of Chemistry and Chemical Engineering, Xinyang Normal University, Xinyang, Henan, 464000, China
| | - Pengfei Sun
- State Key Laboratory of Flexible Electronics (LoFE) & Institute of Advanced Materials (IAM), Nanjing University of Posts & Telecommunications, 9 Wenyuan Road, Nanjing, 210023, China
| | - Qunbo Mei
- State Key Laboratory of Flexible Electronics (LoFE) & Institute of Advanced Materials (IAM), Nanjing University of Posts & Telecommunications, 9 Wenyuan Road, Nanjing, 210023, China
| | - Daifeng Li
- Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Quli Fan
- State Key Laboratory of Flexible Electronics (LoFE) & Institute of Advanced Materials (IAM), Nanjing University of Posts & Telecommunications, 9 Wenyuan Road, Nanjing, 210023, China
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Feng Z, Ou L, Li H, Hao Y, Wei R, Zhang G, Yao M. Unveiling the therapeutic potential of HZQYF: exploring the inhibitory impact of a clinical herbal formula on gastric cancer through network pharmacology and transcript analysis. BMC Complement Med Ther 2025; 25:142. [PMID: 40247271 PMCID: PMC12004866 DOI: 10.1186/s12906-025-04871-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 03/27/2025] [Indexed: 04/19/2025] Open
Abstract
Hezi Qingyou Formula (HZQYF) is a clinical formulation known for its efficacy in treating gastrointestinal diseases. Nevertheless, its specific impact and underlying mechanism of action in gastric cancer remain to be fully elucidated. The major components of the formula were precisely identified and characterized using ultra-high-performance liquid chromatography coupled with a tandem mass spectrometer (UHPLC-MS/MS). Network pharmacology and transcript analysis were utilized to identify the targets associated with drug-disease interactions. Subsequently, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome analyses were conducted to unravel the pivotal pathways involved. Furthermore, in vitro experiments were performed to validate the anti-gastric cancer activity of HZQYF, including assessments of cell viability and clonogenic potential. These results revealed that 260 co-expressed targets were identified as shared between HZQYF and gastric cancer. These genes were significantly enriched in biological processes and pathways related to steroid metabolism, gamma-aminobutyric acid (GABA)-A receptor complex, steroid binding activity, extracellular ligand-gated ion channel activity, chemical carcinogenesis-reactive oxygen species, and GABAergic synapse. Furthermore, the principal components of the formula were characterized. Subsequent cell experiments confirmed the formula's ability to inhibit gastric cancer activity and suppress colony formation in vitro. In conclusion, these findings suggest that Hezi Qingyou Formula may exert its anti-gastric cancer activity by influencing reactive oxygen species and modulating GABAergic synapses in-silico methods. This study provides a foundation for further exploration of HZQYF as a potential therapeutic agent for gastric cancer.
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Affiliation(s)
- Zhong Feng
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-Sen University, Shenzhen, 518107, China
- International Pharmaceutical Engineering Lab of Shandong Province, Feixian, Shandong, 273400, China
| | - Ling Ou
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-Sen University, Shenzhen, 518107, China.
| | - Hui Li
- International Pharmaceutical Engineering Lab of Shandong Province, Feixian, Shandong, 273400, China
| | - Yajie Hao
- International Pharmaceutical Engineering Lab of Shandong Province, Feixian, Shandong, 273400, China
| | - Ruixia Wei
- Lunan Pharmaceutical Group Co., Ltd, Linyi, Shandong, 276000, China
| | - Guimin Zhang
- Lunan Pharmaceutical Group Co., Ltd, Linyi, Shandong, 276000, China.
| | - Meicun Yao
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-Sen University, Shenzhen, 518107, China.
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48
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Hayashi M, Nakamura K, Harada S, Tanaka M, Kobayashi A, Saito H, Tsuji T, Yamamoto D, Moriyama H, Kinoshita J, Inaki N. GLUT1 inhibition by BAY-876 induces metabolic changes and cell death in human colorectal cancer cells. BMC Cancer 2025; 25:716. [PMID: 40247224 PMCID: PMC12004878 DOI: 10.1186/s12885-025-14141-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Accepted: 04/11/2025] [Indexed: 04/19/2025] Open
Abstract
BACKGROUND Glucose transporter 1 (GLUT1) is known to play a crucial role in glucose uptake in malignant tumors. GLUT1 inhibitors reportedly exhibit anti-tumor effects by suppressing cancer cell proliferation. BAY-876, a selective GLUT1 inhibitor, has been shown to inhibit tumor growth in ovarian and breast cancers. In this study, we investigated the anti-proliferative effects of BAY-876 treatment in human colorectal cancer (CRC) cell lines. METHODS We investigated the metabolic changes and effects on proliferation from BAY-876 treatment in HCT116, DLD1, COLO205, LoVo, and Caco-2 cells in vitro. Additionally, a mouse xenograft model was established using HCT116 cells to examine the tumor-inhibitory effects of BAY-876 treatment in vivo. RESULTS BAY-876 treatment inhibited cell proliferation in HCT116, DLD1, COLO205, and LoVo cells. Reduced GLUT1 protein expression levels were observed through western blot analysis. Flux analysis indicated enhanced mitochondrial respiration, accompanied by increased reactive oxygen species levels and apoptosis rates. Tumor-inhibitory effects were also observed in the xenograft model, with the BAY-876-treated groups showing GLUT1 suppression. CONCLUSIONS BAY-876 treatment induced metabolic changes and inhibited cell proliferation in human CRC cell lines. Using BAY-876 is a potential novel approach for treating CRC.
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Affiliation(s)
- Masato Hayashi
- Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, 920-8641, Japan
| | - Keishi Nakamura
- Department of Surgery, Public Central Hospital of Matto Ishikawa, 3-8 Kuramitsu, Hakusan, Ishikawa, 924-8588, Japan.
| | - Shinichi Harada
- Center for Biomedical Research and Education, School of Medicine, Kanazawa University, Kanazawa, Ishikawa, 920-8640, Japan
| | - Mariko Tanaka
- Center for Biomedical Research and Education, School of Medicine, Kanazawa University, Kanazawa, Ishikawa, 920-8640, Japan
| | - Akiko Kobayashi
- Center for Biomedical Research and Education, School of Medicine, Kanazawa University, Kanazawa, Ishikawa, 920-8640, Japan
| | - Hiroto Saito
- Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, 920-8641, Japan
| | - Toshikatsu Tsuji
- Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, 920-8641, Japan
| | - Daisuke Yamamoto
- Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, 920-8641, Japan
| | - Hideki Moriyama
- Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, 920-8641, Japan
| | - Jun Kinoshita
- Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, 920-8641, Japan
| | - Noriyuki Inaki
- Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, 920-8641, Japan
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Gao X, Li Y, Xu H, Ni S, Pan H, Ma C, Zhao X, Zhang H. Xanthatin induces apoptosis through ROS-mediated c-FLIP inhibition in human retinoblastoma cells. Front Med (Lausanne) 2025; 12:1554934. [PMID: 40309730 PMCID: PMC12041067 DOI: 10.3389/fmed.2025.1554934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Accepted: 03/24/2025] [Indexed: 05/02/2025] Open
Abstract
Retinoblastoma is widely considered the most frequent primary intraocular malignancy during childhood. Xanthatin has been reported to selectively inhibit the proliferation of RB cells, but the underlying mechanism remains uncertain. In this study, human RB cells were treated with different doses of xanthatin, and then cell survival, cell apoptosis, and protein expression were assessed using CCK8 assays, flow cytometry, and western blotting to investigate the possible mechanism of xanthatin in RB cells. A human RB xenograft model was established to demonstrate the effect of xanthatin in vivo. Our study shows that xanthatin inhibited cell survival and induced apoptosis in human RB cells. Moreover, xanthatin induced the downregulation of CASP8 and FADD-like apoptosis regulating protein (c-FLIP) and increased the cleavage of caspase-8, caspase-9, caspase-3, and PARP. c-FLIP overexpression impaired xanthatin-induced apoptosis. Furthermore, NAC, which can reduce xanthatin-triggered Reactive oxygen species (ROS), alleviated xanthin-induced apoptosis and c-FLIP downregulation. In vivo, analysis confirmed that xanthatin was an efficacious drug against xenograft tumors. Xanthatin induced apoptosis of the human RB cells both in vivo and in vitro through ROS-mediated c-FLIP inhibition. Our research provides important mechanistic insight into potential cancer treatments with ROS/c-FLIP axis in xanthatin-induced apoptosis and makes them candidates for developing new directed therapies.
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Affiliation(s)
- Xue Gao
- Department of Ophthalmology, The Second Hospital of Shandong University, Jinan, China
| | - Yixiao Li
- Department of Ophthalmology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Haoran Xu
- Department of Ophthalmology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Shouxiang Ni
- Department of Ophthalmology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Hong Pan
- Department of Ophthalmology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Chunli Ma
- Department of Ophthalmology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Xiaofei Zhao
- Department of Ophthalmology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Han Zhang
- Department of Ophthalmology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Department of Ophthalmology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
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Chen H, Wang M, Yang Q, Liu J, Liu F, Zhu X, Huang S, Yin P, Wang X, Li H, Zhang Y, Liu M, Wei M, Yao S, Liu Y. Multifunctional porphyrinic metal-organic framework-based nanoplatform regulating reactive oxygen species achieves efficient imaging-guided cascaded nanocatalytic therapy. J Colloid Interface Sci 2025; 684:423-438. [PMID: 39799625 DOI: 10.1016/j.jcis.2025.01.041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 01/05/2025] [Accepted: 01/06/2025] [Indexed: 01/15/2025]
Abstract
The integration of reactive oxygen species (ROS) related photodynamic therapy (PDT) with the strategy of reshaping the tumor microenvironment (TME) has emerged as a potential approach for nanodiagnostic and therapeutic interventions. However, the therapeutic efficacy based on ROS treatments may be hindered by intracellular antioxidants such as glutathione (GSH) and tumor hypoxia. To address these challenges, a nanoplatform based on GSH-responsive multifunctional porphyrinic metal-organic framework (PCN-224@Au@MnO2@HA, PAMH) was proposed. It was developed through a layer-by-layer in-situ growth method. This method avoids the need for high-temperature calcination and complex modification processes while improving the stability of PCN-224 in a phosphate-rich environment. GSH depletion leads to oxidation-reduction imbalance in TME. With the inactivation of GSH peroxidase 4 (GPX4), the content of hydrogen peroxide (H2O2) increases, ultimately triggering lipid peroxidation (LPO) and promoting ferroptosis. The catalase-like activity of Au nanozymes facilitates the generation of oxygen (O2), thereby mitigating tumor hypoxia and downregulating hypoxia-inducing factors (HIF-1α). Due to the presence of porphyrin ligands in PCN-224, the generated O2 can be further converted to toxic singlet oxygen (1O2) under laser irradiation. Additionally, the platform allows near-infrared (NIR) fluorescence imaging, providing real-time information on intracellular GSH changes during PDT and ferroptosis. The PAMH nanoplatform has shown effective inhibition of tumor growth in subcutaneous models via both intravenous and intratumoral injection, indicating its potential in modulating reactive oxygen/sulfur species and reshaping TME, thereby facilitating imaging-guided cascaded nanocatalytic therapy.
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Affiliation(s)
- Haoyu Chen
- Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research (Ministry of Education, China), College of Chemistry and Chemical Engineering, Hunan Normal University, Changsha 410081, China; Department of Chemistry, Kay Lab of Bioorganic Phosphorus Chemistry and Chemical Biology of Ministry of Education, Beijing Key Laboratory for Analytical Methods and Instrumentation, Tsinghua University, 100084 Beijing, China
| | - Minjuan Wang
- School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning 437100, China
| | - Qiquan Yang
- Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research (Ministry of Education, China), College of Chemistry and Chemical Engineering, Hunan Normal University, Changsha 410081, China
| | - Jing Liu
- Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research (Ministry of Education, China), College of Chemistry and Chemical Engineering, Hunan Normal University, Changsha 410081, China
| | - Feng Liu
- Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research (Ministry of Education, China), College of Chemistry and Chemical Engineering, Hunan Normal University, Changsha 410081, China
| | - Xiaohua Zhu
- Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research (Ministry of Education, China), College of Chemistry and Chemical Engineering, Hunan Normal University, Changsha 410081, China
| | - Shu Huang
- Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research (Ministry of Education, China), College of Chemistry and Chemical Engineering, Hunan Normal University, Changsha 410081, China
| | - Peng Yin
- Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research (Ministry of Education, China), College of Chemistry and Chemical Engineering, Hunan Normal University, Changsha 410081, China
| | - Xingfeng Wang
- School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning 437100, China
| | - Haitao Li
- Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research (Ministry of Education, China), College of Chemistry and Chemical Engineering, Hunan Normal University, Changsha 410081, China
| | - Youyu Zhang
- Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research (Ministry of Education, China), College of Chemistry and Chemical Engineering, Hunan Normal University, Changsha 410081, China
| | - Meiling Liu
- Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research (Ministry of Education, China), College of Chemistry and Chemical Engineering, Hunan Normal University, Changsha 410081, China.
| | - Mingjie Wei
- School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning 437100, China.
| | - Shouzhuo Yao
- Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research (Ministry of Education, China), College of Chemistry and Chemical Engineering, Hunan Normal University, Changsha 410081, China
| | - Yang Liu
- Department of Chemistry, Kay Lab of Bioorganic Phosphorus Chemistry and Chemical Biology of Ministry of Education, Beijing Key Laboratory for Analytical Methods and Instrumentation, Tsinghua University, 100084 Beijing, China.
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