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Tao W, Lai Y, Zhou X, Yang G, Wu P, Yuan L. A narrative review: Ultrasound-Assisted drug delivery: Improving treatments via multiple mechanisms. ULTRASONICS 2025; 151:107611. [PMID: 40068411 DOI: 10.1016/j.ultras.2025.107611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 02/21/2025] [Accepted: 02/21/2025] [Indexed: 04/02/2025]
Abstract
Safe and efficient drug delivery is as important as drug development. Biological barriers, such as cell membranes, present significant challenges in drug delivery, especially for newly developed protein-, nucleic acid-, and cell-based drugs. Ultrasound-mediated drug delivery systems offer a promising strategy to overcome these challenges. Ultrasound, a mechanical wave with energy, produces thermal effects, cavitation, acoustic radiation, and other biophysical effects. Used alone or in combination with microbubbles or sonosensitizers, it breaks biological barriers, enhances targeted drug delivery, reduces adverse reactions, controls drug release, switches on/off drug functions, and ultimately improves therapeutic efficiency. Various ultrasound-mediated drug delivery methods, including transdermal drug delivery, nebulization, targeted microbubble destruction, and sonodynamic therapy, are being actively explored for the treatment of various diseases. This review article introduces the principles, advantages, and applications of ultrasound-mediated drug delivery methods for improved therapeutic outcomes and discusses future prospects in this field.
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Affiliation(s)
- Wenxin Tao
- Department of Ultrasound Medicine, Tangdu Hospital, Fourth Military Medical University, Shaanxi 710038, China
| | - Yubo Lai
- Department of Ultrasound Medicine, Tangdu Hospital, Fourth Military Medical University, Shaanxi 710038, China
| | - Xueying Zhou
- Department of Ultrasound Medicine, Tangdu Hospital, Fourth Military Medical University, Shaanxi 710038, China
| | - Guodong Yang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Biochemistry and Molecular Biology, Fourth Military Medical University Xi'an, Shaanxi 710032, China
| | - Pengying Wu
- Department of Ultrasound Medicine, Tangdu Hospital, Fourth Military Medical University, Shaanxi 710038, China
| | - Lijun Yuan
- Department of Ultrasound Medicine, Tangdu Hospital, Fourth Military Medical University, Shaanxi 710038, China.
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2
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Jin ZY, Ling ZQ. PAQR4: From spatial regulation of cell signaling to physiological homeostasis and diseases. Biochim Biophys Acta Rev Cancer 2025; 1880:189314. [PMID: 40194713 DOI: 10.1016/j.bbcan.2025.189314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Revised: 04/02/2025] [Accepted: 04/03/2025] [Indexed: 04/09/2025]
Abstract
Progestin and adipoQ receptor family member 4 (PAQR4) gene is a recently discovered seven-transmembrane protein-coding gene that belongs to the PAQR family. An increasing amount of evidence suggests that PAQR4 is upregulated in multiple tumors and participates in tumor progression and chemotherapy resistance via different signaling pathways; PAQR4 regulates cellular ceramide homeostasis by influencing sphingolipid metabolism and glycerol metabolism, and plays a significant role in adipose tissue remodeling. Meanwhile, it is known that the differential expression of PAQR4 is associated with the occurrence of various diseases and is a potential biomarker and therapeutic target. This article conducts a systematic review of the subcellular localization of PAQR4, its topological structure characteristics, and its functions in cancer occurrence, metabolic diseases, and fertility, and provides clues for the future research and translational application of PAQR4.
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Affiliation(s)
- Zi-Yan Jin
- Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China; Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310018, China; Postgraduate Training base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou, Zhejiang 310022, China
| | - Zhi-Qiang Ling
- Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China; Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310018, China.
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3
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Chen JF, Guo SJ, He B, Zheng W, Jiang WJ, Yuan Z, Xiang Y, Peng C, Xiong W, Shi JY. Advances of dual inhibitors based on ALK for the treatment of cancer. Bioorg Chem 2025; 159:108417. [PMID: 40168884 DOI: 10.1016/j.bioorg.2025.108417] [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: 02/03/2025] [Revised: 03/17/2025] [Accepted: 03/25/2025] [Indexed: 04/03/2025]
Abstract
Anaplastic lymphoma kinase (ALK), which encodes a highly conserved receptor tyrosine kinase (RTK), is important for the development and progression of many tumors, especially non-small cell lung cancer (NSCLC). Currently, third-generation ALK inhibitors are used to treat ALK-mutant NSCLC, but the rapid emergence of resistance during treatment greatly limits their efficacy in clinic. In comparison to single-target inhibitors, ALK dual inhibitors offer the benefits of reducing the emergence of drug resistance, improving treatment efficacy, and optimizing pharmacokinetic features due to the synergistic function of ALK and other associated targets involved in tumor progression. Therefore, we outline the development of ALK dual inhibitors, highlight their design approaches and structure-activity relationship (SAR), and offer insights into new challenges and potential future directions in this area.
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Affiliation(s)
- Jin-Feng Chen
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 611731. China; Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China
| | - Shu-Jin Guo
- Department of Health Management Center, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Bin He
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China
| | - Wei Zheng
- Department of Integrative Medicine, Xinqiao Hospital, Army Medical University, Chongqing 400037, China
| | - Wen-Jie Jiang
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China
| | - Zhuo Yuan
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yu Xiang
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China
| | - Cheng Peng
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; State Key Laboratory of Southwestern Chinese Medicine Resources, School of Medical Technology, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
| | - Wei Xiong
- Department of urology, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, Chengdu 610072, China.
| | - Jian-You Shi
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China.
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4
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Birikorang PA, Menendez DM, Edinger R, Kohanbash G, Edwards WB. Developing and Characterizing the Tumor-Targeting Efficiency of an Anti-EphA2-CD11b Bispecific Antibody. Bioconjug Chem 2025. [PMID: 40434019 DOI: 10.1021/acs.bioconjchem.5c00070] [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
Targeting molecules, such as antibodies and peptides, play a key role in the precise delivery of cytotoxic payloads to tumor sites by binding to specific tumor-associated antigens or other proteins within the tumor microenvironment. This investigation evaluates the potential therapeutic application of a bispecific antibody (BsAb), which simultaneously targets EphA2, a tumor-associated antigen, and CD11b, a protein expressed by tumor-associated macrophages and myeloid-derived suppressor cells (TAMCs). Recombinantly produced anti-EphA2-CD11b-BsAb was conjugated to a bifunctional chelator, NOTA-SCN, and then radiolabeled with copper-64 (64Cu). The [64Cu]Cu-NOTA-anti-EphA2-CD11b-BsAb radioimmunoconjugate was subsequently administered to HT1080-fibrosarcoma-bearing nude mice via tail vein injection. Positron Emission Tomography (PET) and ex vivo biodistribution analyses were performed to determine tumor uptake and pharmacokinetic localization. At 4, 24, and 48 h postinjection (p.i.), the percent injected dose per gram (%ID/g) of [64Cu]Cu-NOTA-anti-EphA2-CD11b-BsAb in HT1080 xenografts were 5.35 ± 2.24, 4.44 ± 1.90, and 4.10 ± 0.60, respectively. There was high uptake in the liver as well as in CD11b-expressing organs, including the spleen, bone marrow, and lung. Binding in these CD11b-rich organs was significantly reduced by coadministering the dose with nonradiolabeled anti-CD11b-IgG and anti-EphA2-CD11b-BsAb, with a concurrent increase in tumor uptake compared to nonblocked mice (8.39 ± 1.37%ID/g for blocked and 4.44 ± 1.90%ID/g for nonblocked at 24 h p.i., p = 0.0175). Further optimization studies showed that at lower molar activity (3.7 MBq/nmol, 100 μCi/nmol), there were significantly higher tumor accumulations and reduced uptake in CD11b-expressing organs compared to higher molar activity (22.2 MBq/nmol, 600 μCi/nmol). Anti-EphA2-CD11b-BsAb is a functional targeting molecule and would require optimization through molar activity or blocking with nonradiolabeled antibody to maximize tumor targeting.
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Affiliation(s)
- Peggy A Birikorang
- Department of Biochemistry, University of Missouri-Columbia, 503 S College Avenue, Columbia, Missouri 65211, United States
- Molecular Imaging and Theranostics Center, University of Missouri-Columbia, 1514 Research Park Drive, Columbia, Missouri 65203, United States
| | - Dominic M Menendez
- Department of Biochemistry, University of Missouri-Columbia, 503 S College Avenue, Columbia, Missouri 65211, United States
- Molecular Imaging and Theranostics Center, University of Missouri-Columbia, 1514 Research Park Drive, Columbia, Missouri 65203, United States
| | - Robert Edinger
- Department of Radiation Oncology, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, Pennsylvania 15213, United States
| | - Gary Kohanbash
- Department of Neurological Surgery, University of Pittsburgh, 503 45th Street, Pittsburgh, Pennsylvania 15201, United States
| | - W Barry Edwards
- Department of Biochemistry, University of Missouri-Columbia, 503 S College Avenue, Columbia, Missouri 65211, United States
- Molecular Imaging and Theranostics Center, University of Missouri-Columbia, 1514 Research Park Drive, Columbia, Missouri 65203, United States
- Department of Chemistry, University of Missouri-Columbia, 601 S College Avenue, Columbia, Missouri 65211, United States
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Fares O, Hamed O, Assali M, Berisha A, Saadeh H, Lail BA, Dagdag O, Samaro A, Mansour W, Jaradat N, Abu-Jabal S. Design, synthesis, anticancer properties, and molecular docking of imidazolone derivatives with lipophilic moiety. Sci Rep 2025; 15:18537. [PMID: 40425784 PMCID: PMC12117022 DOI: 10.1038/s41598-025-97478-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Accepted: 04/04/2025] [Indexed: 05/29/2025] Open
Abstract
As part of an ongoing investigation into imidazolone derivatives with anticancer activities, herein we present the synthesis of a new series of imidazolones with various substituents, including lipophilic and hydrophilic. All synthesized imidazolones (3a-3g and 5a-5g) were characterized by various spectroscopic methods (1H and 13C NMR, FT-IR, and mass spectrometry). The preparation was performed by condensation cyclization of vanillin-based oxazolones with various amines. The anticancer efficiencies of the prepared imidazolones were tested against four different cancer cell lines liver cancer cells (HepG2), cervical adenocarcinoma cells (HeLa), colon cancer cells (CaCo-2), breast cancer cells (MCF-7). Among the prepared imidazolones the one with dodecyl chain displayed excellent efficiency against the tested cancer cell lines with an IC50 value of 65.3 ± 3.2 µM against HepG2 and 20.02 ± 3.5 µM against MCF-7. Imidazolone 2d with amino alkyl moiety displayed an IC50 value of 35.6 ± 4.1 µM against HeLa cell and 24.6 ± 3.8 µM against CaCo-2 cell line. Imidazolone 5g with thiophene and pyridyl group showed the highest activity among all tested derivatives with IC50 value of 18.6 ± 2.3 µM and 5.9 ± 2.3 µM against HeLa and CaCo-2 cell lines, respectively. Imidazolone 5b with a chlorophenyl moiety displayed an IC50 value of 2.2 ± 0.7 µM and 5.5 ± 1.1 µM against HepG2 and Hela cell lines, respectively. The study used computational tools to assess the pharmacokinetics and antitumor potential of the synthesized imidazolone molecules with the highest activities. They were evaluated through ADME analysis and molecular docking. ADME properties confirm favorable drug-likeness under Lipinski's guidelines, with molecular weights ranging from 357.43 (5d) to 468.65 g/mol (5f). Molecules 2g, 2f, and 5f show optimal hydrogen bonding, moderate bioavailability (0.55), and synthetic accessibility scores from 3.78 to 4.76. Docking studies with proteins 4MAN and 1HNJ highlight strong interactions for 2g, 2f, and 5f, with molecule 3g showing the best binding for 4MAN (- 52.13 kcal/mol) and 5f for 1HNJ (- 38.63 kcal/mol). These results identify 3g and 5f as promising candidates for targeted cancer therapy.
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Affiliation(s)
- Oswa Fares
- Department of Chemistry, Faculty of Science, An-Najah National University, P.O. Box 7, Nablus, Palestine
| | - Othman Hamed
- Department of Chemistry, Faculty of Science, An-Najah National University, P.O. Box 7, Nablus, Palestine.
| | - Mohyeddin Assali
- Department of Pharmacy, Faculty of Medicine and Health Sciences, An-Najah National University, P.O. Box 7, Nablus, Palestine.
| | - Avni Berisha
- Department of Chemistry, Faculty of Natural and Mathematics Science, University of Prishtina, 10000, Prishtina, Kosovo.
- Materials Science-Nanochemistry Research Group, Nano Alb-Unit of Albanian Nanoscience and Nanotechnology, 1000, Tirana, Albania.
| | - Haythem Saadeh
- Department of Chemistry, Faculty of Science, The University of Jordan, Amman, 11942, Jordan
| | - Bahia Abu Lail
- Department of Chemistry, Faculty of Science, An-Najah National University, P.O. Box 7, Nablus, Palestine
| | - Omar Dagdag
- Department of Mechanical Engineering, Gachon University, Seongnam, 13120, Republic of Korea
| | - Abdullah Samaro
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, An-Najah National University, P.O. Box 7, Nablus, Palestine
| | - Waseem Mansour
- Department of Chemistry, Faculty of Science, An-Najah National University, P.O. Box 7, Nablus, Palestine
| | - Nidal Jaradat
- Department of Pharmacy, Faculty of Medicine and Health Sciences, An-Najah National University, P.O. Box 7, Nablus, Palestine
| | - Saber Abu-Jabal
- Department of Chemistry, Faculty of Science, An-Najah National University, P.O. Box 7, Nablus, Palestine
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6
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Karoonkiani F, Homayouni Tabrizi M, Goodarzi MT, Jalali A. Targeted pancreatic cancer therapy using 4-farnesyloxycoumarin conjugated nanocrystalline cellulose and Chitosan nanoparticles. Sci Rep 2025; 15:17313. [PMID: 40389619 PMCID: PMC12089437 DOI: 10.1038/s41598-025-02344-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Accepted: 05/13/2025] [Indexed: 05/21/2025] Open
Abstract
This study investigates the effects of 4-farnesyloxycoumarin (4-FOC)-conjugated NCC/CTAB/CS nanoparticles (NPs) on PANC-1 pancreatic cancer cells, highlighting their cytotoxicity and antioxidant properties. Dynamic light scattering (DLS) analysis revealed a Z-average particle size of 275.68 nm, with a polydispersity index of 0.3020. The mean intensity diameter was 334.68 nm, and the mean volume diameter was 380.97 nm. The zeta potential was recorded at 28.88 ± 12.64 mV, confirming good stability due to electrostatic repulsion. Field emission scanning electron microscopy (FESEM) confirmed the successful conjugation of 4-FOC to the NPs, and Fourier-transform infrared (FTIR) spectroscopy validated the incorporation of functional groups. In contrast, the encapsulation efficiency of 4-FOC was measured at 88.49%. Cytotoxicity assays indicated a significant reduction in PANC-1 cell viability, with an IC50 value of 61.23 µg/mL; in contrast, human dermal fibroblast (HDF) cells exhibited greater resilience, maintaining 92.61 ± 2.33% viability at 100 µg/mL. Apoptotic assays revealed a dose-dependent increase in early and late apoptotic cells, with late apoptosis rising to 54.1% at 81 µg/mL. Gene expression analysis showed significant upregulation of caspase 3 (2.25 ± 0.33), p21 (1.70 ± 0.05), and p53 (2.71 ± 0.29 at 61 µg/mL), underscoring the NPs' role in apoptosis and cell cycle regulation. Additionally, the antioxidant capacity of the NPs was confirmed through ABTS and DPPH radical scavenging assays, achieving 38.82% and 68.25% scavenging activity at the highest concentrations, respectively. These findings suggest that 4-FOC-conjugated NCC/CTAB/CS NPs hold promise as a therapeutic strategy for treating pancreatic cancer.
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Affiliation(s)
- Fariba Karoonkiani
- Department of Chemistry, Shahrood Branch, Islamic Azad University, Shahrood, Iran
| | | | | | - Alireza Jalali
- Department of Chemistry, Shahrood Branch, Islamic Azad University, Shahrood, Iran
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Deng Q, Yue S, You F, Zhai Z, Sun H, Liang L, Li C, Yang L, Zhong Z. Vincristine/Volasertib Polymersome Injection Enables High-Efficiency Synergistic Treatment of Acute Lymphoblastic Leukemia. Acta Biomater 2025:S1742-7061(25)00366-6. [PMID: 40383350 DOI: 10.1016/j.actbio.2025.05.041] [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: 12/31/2024] [Revised: 05/12/2025] [Accepted: 05/15/2025] [Indexed: 05/20/2025]
Abstract
Acute lymphoblastic leukemia (ALL), one of the most frequently diagnosed malignancies in children, is associated with a high relapse rate and drug resistance, even with intensive multidrug chemotherapy regimens. The rational combination with molecular targeted agents holds promise for sensitizing patients to chemotherapies and overcoming drug resistance. However, precise codelivery of different drugs in vivo is challenging, often leading to suboptimal therapeutic effects. Herein, we report a vincristine/volasertib polymersome (Ps-VCR/Vol)-based nanocombo for synergistic inhibition of microtubules and polo-like kinase 1, enabling high-efficacy treatment of ALL in vivo. Ps-VCR/Vol, which has a small size (∼26 nm) and tailored VCR/Vol mass ratios from 1:12 to 1:48, exhibited strong synergy in different ALL cells, with 3.3-6.8-fold greater anti-ALL activity than the free VCR/Vol combination. Intriguingly, treatment with Ps-VCR/Vol at a VCR/Vol dosage of 0.25/6 mg/kg markedly inhibited leukemia progression and invasion in orthotopic CCRF-CEM, Nalm-6-Luc and patient-derived xenograft ALL mouse models without inducing toxicity, resulting in a significantly prolonged survival time compared with that of the free drug combination and single-drug polymersome formulations. Ps-VCR/Vol polymersome injection provides a powerful synergistic combination therapy for ALL. STATEMENT OF SIGNIFICANCE: Multidrug combination therapies have increased the remission rates of acute lymphoblastic leukemia (ALL) patients. However, the therapeutic efficacy remains suboptimal due to the dissimilar physicochemical properties of the different drugs involved, and overlapping toxicities pose a critical concern. Herein, we show that intelligent polymersomes mediate the precise codelivery of vincristine sulfate (VCR), a frontline drug for ALL, and volasertib (Vol), a polo-like kinase 1 inhibitor, enabling synergistic treatment of ALL. Compared with free VCR/Vol, VCR/Vol polymersomes with tailored drug ratios substantially inhibited leukemia progression in both cell line- and patient-derived orthotopic ALL models without inducing toxicity, leading to a significant survival benefit. This synergistic polymersome injection may provide a powerful and safe combination therapy for ALL patients.
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Affiliation(s)
- Qing Deng
- State Key Laboratory of Bioinspired Interfacial Materials Science, and Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, 215123, China
| | - Shujing Yue
- State Key Laboratory of Bioinspired Interfacial Materials Science, and Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, 215123, China
| | - Fengtao You
- PersonGen BioTherapeutics (Suzhou) Co., Ltd., Suzhou, China
| | - Zhenzhen Zhai
- State Key Laboratory of Bioinspired Interfacial Materials Science, and Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, 215123, China
| | - Huanli Sun
- State Key Laboratory of Bioinspired Interfacial Materials Science, and Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, 215123, China..
| | - Lanlan Liang
- State Key Laboratory of Bioinspired Interfacial Materials Science, and Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, 215123, China
| | - Chenming Li
- State Key Laboratory of Bioinspired Interfacial Materials Science, and Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, 215123, China
| | - Lin Yang
- PersonGen BioTherapeutics (Suzhou) Co., Ltd., Suzhou, China.; Cyrus Tang Medical Institute, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, 215123, China..
| | - Zhiyuan Zhong
- State Key Laboratory of Bioinspired Interfacial Materials Science, and Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, 215123, China.; College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.; International College of Pharmaceutical Innovation, Soochow University, Suzhou, 215222, China.
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8
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Deng C, Ye Z, Zheng CJ, Cheng H, Ge J. Iron-based nanozymes induced ferroptosis for tumor therapy. NANOSCALE 2025. [PMID: 40370315 DOI: 10.1039/d5nr00880h] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/16/2025]
Abstract
Iron-based nanozymes are an emerging class of nanomaterials demonstrating significant potential in tumor therapy by inducing ferroptosis-a regulated form of cell death marked by iron-mediated lipid peroxidation (LPO). These nanozymes exhibit unique enzymatic activities, including peroxidase, oxidase, and glutathione oxidase-like functions, enabling them to generate reactive oxygen species (ROS) and disrupt tumor microenvironment homeostasis. Leveraging Fenton chemistry, iron-based nanozymes amplify oxidative stress within tumor cells, thereby overcoming therapeutic challenges such as drug resistance and nonspecific toxicity. Despite significant advancements, the precise mechanisms by which iron-based nanozymes influence ferroptosis and their therapeutic efficacy remain underexplored. This review systematically categorizes these iron-based nanozymes, including iron oxides, single-atom enzymes, and metal-organic frameworks. We further elucidate their mechanisms in enhancing ferroptosis, focusing on their structural attributes, ROS generation pathways, and their enzymatic activities. Additionally, we summarized their biochemical applications alongside challenges in biosafety, nanozyme specificity, and advanced design and analysis approaches essential for maximizing their therapeutic efficacy.
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Affiliation(s)
- Chi Deng
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong 999077, China.
| | - Zichen Ye
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong 999077, China.
| | | | - Hongfei Cheng
- Institute of New Energy for Vehicles, School of Material Science and Engineering, Tongji University, Shanghai 201804, P.R. China
| | - Jingjie Ge
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong 999077, China.
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9
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Mansouri MM, Emami L, Rezaei Z, Khabnadideh S. Design, synthesis, biological assessments and computational studies of 3-substituted phenyl quinazolinone derivatives as promising anti-cancer agents. BMC Chem 2025; 19:125. [PMID: 40361154 PMCID: PMC12070605 DOI: 10.1186/s13065-025-01492-4] [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: 02/23/2025] [Accepted: 04/28/2025] [Indexed: 05/15/2025] Open
Abstract
A new series of 3-substituted phenyl quinazolinone derivatives were designed and synthesized as anti-cancer agents. The most potent derivative with IC50 values of 12.84 ± 0.84 and 10.90 ± 0.84 µM against MCF-7 and SW480 cell lines was comparable to Cisplatin and Erlotinib as positive controls. Cell cycle analysis showed that the most active compound could arrest at S phase in MCF-7 breast cancer cells. The apoptosis assay demonstrated the induction of apoptosis in the MCF-7 cell line, too. Molecular docking results showed better accommodation of the most active compound through hydrogen bonding interaction in the binding site of EGFR enzyme. Molecular dynamics simulations for the potent analogue demonstrated well binding stability compared to the less active analogue, with a lower RMSD, Rg and more interactions with the original active site residues. DFT calculations were performed on the active and inactive compounds, using Gaussian 09 at the M06-2X/6-31 + G(d) theoretical level. ADME (Absorption, Distribution, Metabolism, and Excretion) properties showed that most of the compounds are in acceptable range of Lipiniski rule. These findings underscore the potential of the synthesized compounds as potent cytotoxic inhibitors and provide insights for developing effective treatments for cancer therapy.
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Affiliation(s)
- Maryam Moghtader Mansouri
- Department of Medicinal Chemistry, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Leila Emami
- Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Rezaei
- Department of Medicinal Chemistry, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Soghra Khabnadideh
- Department of Medicinal Chemistry, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
- Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
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10
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Pereira AR, Pires PC, Hameed H, Lopes D, Lopes J, Sousa-Oliveira I, Babaie S, Mazzola P, Veiga F, Paiva-Santos AC. Injectable nanocomposite hydrogels for targeted intervention in cancer, wound healing, and bone and myocardial tissue engineering. Drug Deliv Transl Res 2025:10.1007/s13346-025-01864-2. [PMID: 40358831 DOI: 10.1007/s13346-025-01864-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/12/2025] [Indexed: 05/15/2025]
Abstract
Despite current medicine's fast-paced advances, many acute and chronic illnesses still lack truly effective and safe therapies. Cancer treatments often lead to off-target healthy tissue damage and poor therapeutic outcomes, wound standard treatments generally demonstrate poor healing efficacy and increased susceptibility to infection, and bone tissue engineering and myocardial tissue engineering can result in immunological rejection and limited availability. To tackle these issues, injectable hydrogels have emerged, and through the incorporation of nanoparticles, nanocomposite hydrogels have appeared as versatile platforms, offering improved biocompatibility, mechanical strength, stability, and precise controlled drug release, as well as targeted delivery with increased drug retention at the site of action, reducing systemic drug distribution to non-target sites. With the ability to deliver a diverse range of therapeutic entities, including low molecular weight drugs, proteins, antibodies, and even isolated cells, injectable nanocomposite hydrogels have revolutionized current therapies, working as multifunctional platforms capable of improving efficacy and safety in cancer treatment, including in chemotherapy, immunotherapy, photothermal therapy, magnetic hyperthermia, photodynamic therapy, chemodynamic therapy, radiotherapy, molecularly targeted therapy, and after tumor surgical removal, and in general, chronic diabetic or tumor-induced wound healing, as well as in bone tissue engineering and myocardial tissue engineering. This review provides a thorough summary and critical insight of current advances on injectable nanocomposite hydrogels as an innovative approach that could bring substantial contributions to biomedical research and clinical practice, with a focus on their applications in cancer therapy, wound healing management, and tissue engineering.
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Affiliation(s)
- Ana Rita Pereira
- Department of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, Azinhaga de Santa Comba, 3000 - 548, Coimbra, Portugal
| | - Patrícia C Pires
- Department of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, Azinhaga de Santa Comba, 3000 - 548, Coimbra, Portugal.
- REQUIMTE/LAQV, Group of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, 3000 - 548, Coimbra, Portugal.
- Department of Medical Sciences, Faculty of Health Sciences, RISE-Health, University of Beira Interior, Av. Infante D. Henrique, 6200 - 506, Covilhã, Portugal.
| | - Huma Hameed
- Faculty of Pharmaceutical Sciences, University of Central Punjab (UCP), Lahore, 54000, Pakistan
| | - Daniela Lopes
- Department of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, Azinhaga de Santa Comba, 3000 - 548, Coimbra, Portugal
- REQUIMTE/LAQV, Group of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, 3000 - 548, Coimbra, Portugal
| | - Joana Lopes
- Department of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, Azinhaga de Santa Comba, 3000 - 548, Coimbra, Portugal
- REQUIMTE/LAQV, Group of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, 3000 - 548, Coimbra, Portugal
| | - Inês Sousa-Oliveira
- Department of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, Azinhaga de Santa Comba, 3000 - 548, Coimbra, Portugal
- REQUIMTE/LAQV, Group of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, 3000 - 548, Coimbra, Portugal
| | - Soraya Babaie
- Physical Medicine and Rehabilitation Research Center, Tabriz University of Medical Sciences, Tabriz, 51368, Iran
| | - Priscila Mazzola
- Faculty of Pharmaceutical Sciences, Universidade Estadual de Campinas, Campinas, SP, 13083 - 970, Brazil
| | - Francisco Veiga
- Department of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, Azinhaga de Santa Comba, 3000 - 548, Coimbra, Portugal
- REQUIMTE/LAQV, Group of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, 3000 - 548, Coimbra, Portugal
| | - Ana Cláudia Paiva-Santos
- Department of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, Azinhaga de Santa Comba, 3000 - 548, Coimbra, Portugal.
- REQUIMTE/LAQV, Group of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, 3000 - 548, Coimbra, Portugal.
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11
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Dabo-Trubelja A. Considerations for Care of the Cancer Patient. Int Anesthesiol Clin 2025:00004311-990000000-00096. [PMID: 40353581 DOI: 10.1097/aia.0000000000000487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/14/2025]
Affiliation(s)
- Anahita Dabo-Trubelja
- Department of Anesthesiology and Critical Care, Director, Perioperative Point of Care Ultrasound, Memorial Sloan Kettering Cancer Center, New York
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12
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An Y, Song H, Qiu H, Jiang J, Shi J. Lipid Metabolism in Gastrointestinal Malignancies: Exploring Dysregulation, Biomarkers, and Treatment Strategies. Cancer Med 2025; 14:e70975. [PMID: 40391753 PMCID: PMC12090204 DOI: 10.1002/cam4.70975] [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: 01/14/2025] [Revised: 04/09/2025] [Accepted: 05/08/2025] [Indexed: 05/22/2025] Open
Abstract
BACKGROUND Gastrointestinal malignancies are a major public health concern worldwide, characterized by high incidence and mortality rates. Despite continuous advancements in existing treatment methods, overall survival rates remain low. Lipid metabolism plays a crucial role in the occurrence, progression, and treatment of gastrointestinal malignancies. Its involvement in the metabolic reprogramming of tumor cells, regulation of the tumor microenvironment, and drug response has become a research hotspot. MATERIALS & METHODS This review summarizes current research related to lipid metabolism mechanisms, biomarkers, and therapies in GI cancers, with emphasis on its interaction with the tumor microenvironment.
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Affiliation(s)
- Yan An
- Department of AnesthesiologyAffiliated Hospital of Shandong Second Medical UniversityWeifangChina
| | - Huihui Song
- Obstetrical Medicine Center, Weifang People's HospitalShandong Second Medical UniversityWeifangChina
| | - Hongyan Qiu
- Department of Endocrinology and Metabolism, School of Clinical Medicine, Affiliated Hospital of Shandong Second Medical UniversityShandong Second Medical UniversityWeifangChina
- Clinical Research CenterAffiliated Hospital of Shandong Second Medical UniversityWeifangChina
| | - Jun Jiang
- Department of AnesthesiologyAffiliated Hospital of Shandong Second Medical UniversityWeifangChina
| | - Junfeng Shi
- Department of Endocrinology and Metabolism, School of Clinical Medicine, Affiliated Hospital of Shandong Second Medical UniversityShandong Second Medical UniversityWeifangChina
- Clinical Research CenterAffiliated Hospital of Shandong Second Medical UniversityWeifangChina
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13
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Zhang MX, Liu PF, Zhang MD, Su PG, Shang HS, Zhu JT, Wang DY, Ji XY, Liao QM. Deep learning in nuclear medicine: from imaging to therapy. Ann Nucl Med 2025; 39:424-440. [PMID: 40080372 DOI: 10.1007/s12149-025-02031-w] [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: 11/25/2024] [Accepted: 02/24/2025] [Indexed: 03/15/2025]
Abstract
BACKGROUND Deep learning, a leading technology in artificial intelligence (AI), has shown remarkable potential in revolutionizing nuclear medicine. OBJECTIVE This review presents recent advancements in deep learning applications, particularly in nuclear medicine imaging, lesion detection, and radiopharmaceutical therapy. RESULTS Leveraging various neural network architectures, deep learning has significantly enhanced the accuracy of image reconstruction, lesion segmentation, and diagnosis, improving the efficiency of disease detection and treatment planning. The integration of deep learning with functional imaging techniques such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) enable more precise diagnostics, while facilitating the development of personalized treatment strategies. Despite its promising outlook, there are still some limitations and challenges, particularly in model interpretability, generalization across diverse datasets, multimodal data fusion, and the ethical and legal issues faced in its application. CONCLUSION As technological advancements continue, deep learning is poised to drive substantial changes in nuclear medicine, particularly in the areas of precision healthcare, real-time treatment monitoring, and clinical decision-making. Future research will likely focus on overcoming these challenges and further enhancing model transparency, thus improving clinical applicability.
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Affiliation(s)
- Meng-Xin Zhang
- Department of Microbiology and Immunology, Henan Provincial Research Center of Engineering Technology for Nuclear Protein Medical Detection, Zhengzhou Health College, Zhengzhou, 45000, Henan, China
- Department of Nuclear Medicine, Henan International Joint Laboratory for Nuclear Protein Regulation, The First Affiliated Hospital, Henan University College of Medicine, Ximen St, Kaifeng, 475004, Henan, China
| | - Peng-Fei Liu
- Department of Microbiology and Immunology, Henan Provincial Research Center of Engineering Technology for Nuclear Protein Medical Detection, Zhengzhou Health College, Zhengzhou, 45000, Henan, China
- Department of Nuclear Medicine, Henan International Joint Laboratory for Nuclear Protein Regulation, The First Affiliated Hospital, Henan University College of Medicine, Ximen St, Kaifeng, 475004, Henan, China
| | - Meng-Di Zhang
- Department of Microbiology and Immunology, Henan Provincial Research Center of Engineering Technology for Nuclear Protein Medical Detection, Zhengzhou Health College, Zhengzhou, 45000, Henan, China
- Department of Nuclear Medicine, Henan International Joint Laboratory for Nuclear Protein Regulation, The First Affiliated Hospital, Henan University College of Medicine, Ximen St, Kaifeng, 475004, Henan, China
| | - Pei-Gen Su
- Department of Microbiology and Immunology, Henan Provincial Research Center of Engineering Technology for Nuclear Protein Medical Detection, Zhengzhou Health College, Zhengzhou, 45000, Henan, China
- School of Medical Technology, Qiqihar Medical University, Qiqihar, 161006, Heilongjiang, China
| | - He-Shan Shang
- Department of Microbiology and Immunology, Henan Provincial Research Center of Engineering Technology for Nuclear Protein Medical Detection, Zhengzhou Health College, Zhengzhou, 45000, Henan, China
- School of Computer and Information Engineering, Henan University, Kaifeng, 475004, Henan, China
| | - Jiang-Tao Zhu
- Faculty of Basic Medical Subjects, Shu-Qing Medical College of Zhengzhou, Zhengzhou, 450064, Henan, China.
- Department of Surgery, Faculty of Clinical Medicine, Zhengzhou Shu-Qing Medical College, Gongming Rd, Mazhai Town, Zhengzhou, 450064, Henan, China.
| | - Da-Yong Wang
- Department of Microbiology and Immunology, Henan Provincial Research Center of Engineering Technology for Nuclear Protein Medical Detection, Zhengzhou Health College, Zhengzhou, 45000, Henan, China.
- Department of Nuclear Medicine, Henan International Joint Laboratory for Nuclear Protein Regulation, The First Affiliated Hospital, Henan University College of Medicine, Ximen St, Kaifeng, 475004, Henan, China.
| | - Xin-Ying Ji
- Department of Microbiology and Immunology, Henan Provincial Research Center of Engineering Technology for Nuclear Protein Medical Detection, Zhengzhou Health College, Zhengzhou, 45000, Henan, China.
- Department of Nuclear Medicine, Henan International Joint Laboratory for Nuclear Protein Regulation, The First Affiliated Hospital, Henan University College of Medicine, Ximen St, Kaifeng, 475004, Henan, China.
- Faculty of Basic Medical Subjects, Shu-Qing Medical College of Zhengzhou, Zhengzhou, 450064, Henan, China.
| | - Qi-Ming Liao
- Department of Medical Informatics and Computer, Shu-Qing Medical College of Zhengzhou, Gong-Ming Rd, Mazhai Town, Erqi District, Zhengzhou, 450064, Henan, China.
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14
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Shi P, Xu J, Cui H. Targeting oxygenases could be a viable anti-metastatic approach in cancer therapy. Int J Biol Macromol 2025; 310:143375. [PMID: 40268020 DOI: 10.1016/j.ijbiomac.2025.143375] [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: 02/28/2025] [Revised: 04/16/2025] [Accepted: 04/18/2025] [Indexed: 04/25/2025]
Abstract
Malignant tumors are characterized by irregular boundaries, rapid and uncontrolled cell growth, the ability to invade surrounding tissues, and the potential to spread and metastasize to other parts of the body through the bloodstream or lymphatic system. More than 90 % of cancer-related deaths are attributed to the metastasis of cancer cells. When malignant tumors metastasize, the metabolic processes within the cells undergo significant changes, with enzymes playing a crucial role in regulating metabolism and serving as key mediators in both synthesis and degradation. Oxygenases are a group of oxidative enzymes that catalyze the incorporation of oxygen atoms into various substrates. Advances in our understanding of the genome and proteome of malignant tumors have revealed that oxygenases are highly expressed in many metastatic tumor cells, where they can enhance the activity of specific proteins that regulate tumor metastasis. Furthermore, there is a growing recognition that certain drugs can specifically target oxygenases to inhibit tumor metastasis, with several of these agents are currently undergoing clinical evaluation. In this context, we summarize the mechanisms by which oxygenases influence cancer cell behavior, along with the preclinical and clinical studies related to targeted therapies involving oxygenases.
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Affiliation(s)
- Pengfei Shi
- Jinfeng Laboratory, 401329 Chongqing, China; Cancer Center, Medical Research Institute, Southwest University, 400716 Chongqing, China
| | - Jie Xu
- Jinfeng Laboratory, 401329 Chongqing, China; Cancer Center, Medical Research Institute, Southwest University, 400716 Chongqing, China
| | - Hongjuan Cui
- Jinfeng Laboratory, 401329 Chongqing, China; Cancer Center, Medical Research Institute, Southwest University, 400716 Chongqing, China.
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15
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Lizama-Muñoz A, Plaza-Diaz J. Bispecific Antibodies, Nanobodies and Extracellular Vesicles: Present and Future to Cancer Target Therapy. Biomolecules 2025; 15:639. [PMID: 40427532 PMCID: PMC12109199 DOI: 10.3390/biom15050639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2025] [Revised: 04/28/2025] [Accepted: 04/28/2025] [Indexed: 05/29/2025] Open
Abstract
Cancer remains one of the leading causes of mortality worldwide, with a growing need for precise and effective treatments. Traditional therapies such as chemotherapy and radiotherapy have limitations, including off-target effects and drug resistance. In recent years, targeted therapies have emerged as promising alternatives, aiming to improve treatment specificity and reduce systemic toxicity. Among the most innovative approaches, bispecific antibodies, nanobodies, and extracellular vesicles offer distinct and complementary mechanisms for cancer therapy. Bispecific antibodies enhance immune responses and enable dual-targeting of cancer cells, nanobodies provide superior tumor penetration due to their small size, and extracellular vesicles present a novel platform for drug and RNA delivery. This work aims to review and analyze these three approaches, assessing their current applications, advantages, challenges, and future perspectives.
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Affiliation(s)
- Asier Lizama-Muñoz
- Department of Biochemistry, Molecular Biology and Immunology III, Faculty of Medicine, University of Granada, 18016 Granada, Spain;
- Clinical Analysis and Immunology Department, University Hospital Virgen de las Nieves, 18014 Granada, Spain
| | - Julio Plaza-Diaz
- ANUT-DSM (Alimentaciò, Nutrició Desenvolupament i Salut Mental), Departament de Bioquímica i Biotecnologia, Universitat Rovira i Virgili, 43201 Reus, Spain
- School of Health Sciences, Universidad Internacional de La Rioja, Avenida de la Paz 137, 26006 Logroño, Spain
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16
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Kato R, Kamata Y, Tominaga M, Kishi R, Kaneko T, Tsujimura A, Suga Y, Takamori K. Possible Clinical Effects of Ketoconazole on Sorafenib-induced Hand-Foot Skin Reaction and Cytoprotection Mechanisms of Antifungal Agents against Multikinase Inhibitor-induced Keratinocyte Toxicity. Acta Derm Venereol 2025; 105:adv40697. [PMID: 40289816 PMCID: PMC12053523 DOI: 10.2340/actadv.v105.40697] [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: 05/02/2024] [Accepted: 03/13/2025] [Indexed: 04/30/2025] Open
Abstract
In recent years, molecular target drugs have become integral in treating malignant tumours. Multikinase inhibitors (MKIs) have been associated with serious skin disorders, including hand-foot skin reaction (HFSR), which impair patient quality of life, often disrupting activities of daily living necessitating dose reduction or discontinuation. As the pathogenic mechanisms of these skin disorders are unknown, no effective treatments have been established. Previously, by drug repurposing using an in vitro culture system, certain azole antifungal drugs (AFDs) were identified that prevented sorafenib-induced cell death of normal human epidermal keratinocytes. In this study, topical ketoconazole demonstrated clinical improvement in hyperkeratosis and pain associated with sorafenib-induced HFSR. Investigation of the mechanism using the in vitro culture system revealed sorafenib to be particularly cytotoxic among MKIs. Annexin V and TUNEL staining revealed apoptosis was mainly involved in this cytotoxicity. Antibody arrays and western blot showed increased levels of secretion of interleukin-1 receptor antagonist and macrophage migration inhibitory factor in culture supernatants. AFDs suppressed the secretion of these cytokines and reduced apoptosis in keratinocytes. This study reveals one aspect of the pathogenesis of sorafenib-induced HFSR and demonstrates that AFDs may be an effective treatment.
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Affiliation(s)
- Rui Kato
- Juntendo Itch Research Center (JIRC), Institute for Environmental and Gender-Specific Medicine, Juntendo University Graduate School of Medicine, Chiba, Japan; Department of Dermatology, Juntendo University Urayasu Hospital, Chiba, Japan
| | - Yayoi Kamata
- Juntendo Itch Research Center (JIRC), Institute for Environmental and Gender-Specific Medicine, Juntendo University Graduate School of Medicine, Chiba, Japan
| | - Mitsutoshi Tominaga
- Juntendo Itch Research Center (JIRC), Institute for Environmental and Gender-Specific Medicine, Juntendo University Graduate School of Medicine, Chiba, Japan
| | - Ryoma Kishi
- Juntendo Itch Research Center (JIRC), Institute for Environmental and Gender-Specific Medicine, Juntendo University Graduate School of Medicine, Chiba, Japan; Department of Dermatology, Juntendo University Urayasu Hospital, Chiba, Japan
| | - Takahide Kaneko
- Department of Dermatology, Juntendo University Urayasu Hospital, Chiba, Japan
| | - Akira Tsujimura
- Department of Urology, Juntendo University Urayasu Hospital, Chiba, Japan
| | - Yasushi Suga
- Department of Dermatology, Juntendo University Urayasu Hospital, Chiba, Japan
| | - Kenji Takamori
- Juntendo Itch Research Center (JIRC), Institute for Environmental and Gender-Specific Medicine, Juntendo University Graduate School of Medicine, Chiba, Japan; Department of Dermatology, Juntendo University Urayasu Hospital, Chiba, Japan.
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17
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Sankar S, Kalidass B, Indrakumar J, Kodiveri Muthukaliannan G. NSAID-encapsulated nanoparticles as a targeted therapeutic platform for modulating chronic inflammation and inhibiting cancer progression: a review. Inflammopharmacology 2025:10.1007/s10787-025-01760-8. [PMID: 40285986 DOI: 10.1007/s10787-025-01760-8] [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: 03/24/2025] [Accepted: 04/11/2025] [Indexed: 04/29/2025]
Abstract
Recent advancements in nanotechnology have significantly advanced nanocarrier-mediated drug delivery systems, promoting therapeutic outcomes in mitigating chronic inflammation and cancer. Nanomaterials offer significant advantages over traditional small-molecule drugs, including a high surface-area-to-volume ratio, tunable structural features, and extended bloodstream circulation time. Chronic inflammation is a well-established mechanism for malignant initiation, progression, and metastasis, promoting the potent strategy for cancer prevention and therapy. Numerous studies revealed that nonsteroidal anti-inflammatory drugs (NSAIDs) have the therapeutic ability to manage disease progression via amolerating angiogenesis and inducing apoptosis. However, prolonged intake of NSAIDs is often limited by adverse side-effects and systemic toxicities. The encapsulation of NSAIDs in a nanocarrier have materialized as a dynamic approach to mitigate the limitations by improving pharmacokinetics and pharmacodynamics, reducing off-target effects, and enhancing the drug stability. This review encompasses recent progress in the development of NSAID-based nanotherapeutics, focusing on pivotal mechanisms underlying nanoparticle-mediated drug delivery, such as improved tumor-specific targeting and strategies to overcome drug resistance. The ability of these nano-cargoes to accommodate anti-inflammatory strategies with advanced drug delivery platforms is critically evaluated. This review also highlights the transformative potential of NSAID-encapsulated nanoparticles as a multifaceted therapeutic venue for addressing chronic inflammation and mitigating cancer progression.
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Affiliation(s)
- Srivarshini Sankar
- Department of Biotechnology, School of Bioscience and Technology, Vellore Institute of Technology, Tamil Nadu, Vellore, 632 014, India
| | - Bharathi Kalidass
- Department of Biotechnology, School of Bioscience and Technology, Vellore Institute of Technology, Tamil Nadu, Vellore, 632 014, India
| | - Janani Indrakumar
- Department of Biotechnology, School of Bioscience and Technology, Vellore Institute of Technology, Tamil Nadu, Vellore, 632 014, India
| | - Gothandam Kodiveri Muthukaliannan
- Department of Biotechnology, School of Bioscience and Technology, Vellore Institute of Technology, Tamil Nadu, Vellore, 632 014, India.
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18
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Vágvölgyi M, Kocsis E, Tayeb BA, Zupkó I, Minorics R, Martins A, Hoyk Z, Ballai G, Szenti I, Kónya Z, Gáti T, Bogdán D, Tóth G, Hunyadi A. Ecdysteroid-Containing Squalenoylated Self-Assembling Nanoparticles Exert Tumor-Selective Sensitization to Reactive Oxygen Species (ROS)-Induced Oxidative Damage While Protecting Normal Cells: Implications for Selective Radiotherapy. J Med Chem 2025; 68:7197-7212. [PMID: 40152540 PMCID: PMC11997992 DOI: 10.1021/acs.jmedchem.4c02758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 03/04/2025] [Accepted: 03/19/2025] [Indexed: 03/29/2025]
Abstract
Central nervous system (CNS) tumors are exceptionally difficult to treat, and oxidative stress-inducing radiotherapy is an important treatment modality. In this study, we examined self-assembling pro-drug nanoconjugates of naturally derived antitumor ecdysteroids, which were designed to interfere with oxidative stress in brain tumor cells. Eight ecdysteroid-squalene conjugates were semi-synthesized and formulated into self-assembled aqueous nanosuspensions, which showed excellent stability for up to 16 weeks. The nanoassemblies demonstrated a strong dose-dependent sensitizing effect to tert-butyl hydroperoxide (tBHP)-induced oxidative damage in SH-SY5Y cells, while exerting a strong protective effect in MRC-5 fibroblast cells. In contrast, free ecdysteroids protected both cell lines from tBHP-induced damage. This suggests an important role for squalenoylation in the antitumor effect and indicates that our conjugates have potential as highly selective adjuvants in radiotherapy by sensitizing cancer cells and protecting surrounding tissues. Furthermore, our findings suggest a potential neuroprotective effect of nonconjugated ecdysteroids.
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Affiliation(s)
- Máté Vágvölgyi
- Institute
of Pharmacognosy, University of Szeged, Eötvös str. 6, Szeged H-6720, Hungary
| | - Endre Kocsis
- Institute
of Pharmacognosy, University of Szeged, Eötvös str. 6, Szeged H-6720, Hungary
| | - Bizhar A. Tayeb
- Institute
of Pharmacodynamics and Biopharmacy, University
of Szeged, Eötvös str. 6, Szeged H-6720, Hungary
| | - István Zupkó
- Institute
of Pharmacodynamics and Biopharmacy, University
of Szeged, Eötvös str. 6, Szeged H-6720, Hungary
| | - Renáta Minorics
- Institute
of Pharmacodynamics and Biopharmacy, University
of Szeged, Eötvös str. 6, Szeged H-6720, Hungary
| | - Ana Martins
- Institute
of Biophysics, HUN-REN Biological Research Centre, Temesvári blvd. 62, Szeged H-6726, Hungary
| | - Zsófia Hoyk
- Institute
of Biophysics, HUN-REN Biological Research Centre, Temesvári blvd. 62, Szeged H-6726, Hungary
| | - Gergő Ballai
- Department
of Applied and Environmental Chemistry, Interdisciplinary Excellence Centre, University of Szeged, Rerrich Béla sq. 1, Szeged H-6720, Hungary
| | - Imre Szenti
- Department
of Applied and Environmental Chemistry, Interdisciplinary Excellence Centre, University of Szeged, Rerrich Béla sq. 1, Szeged H-6720, Hungary
| | - Zoltán Kónya
- Department
of Applied and Environmental Chemistry, Interdisciplinary Excellence Centre, University of Szeged, Rerrich Béla sq. 1, Szeged H-6720, Hungary
- HUN-REN-SZTE
Reaction Kinetics and Surface Chemistry Research Group, University of Szeged, Rerrich Béla sq. 1, Szeged H-6720, Hungary
| | - Tamás Gáti
- Servier
Research Institute of Medicinal Chemistry (SRIMC), Záhony str. 7, Budapest H-1031, Hungary
| | - Dóra Bogdán
- Department
of Organic Chemistry, Semmelweis University, Hőgyes Endre str. 7, Budapest H-1092, Hungary
| | - Gábor Tóth
- NMR
Group, Department of Inorganic and Analytical Chemistry, Budapest University of Technology and Economics, Szt. Gellért sq. 4, Budapest H-1111, Hungary
| | - Attila Hunyadi
- Institute
of Pharmacognosy, University of Szeged, Eötvös str. 6, Szeged H-6720, Hungary
- HUN-REN-SZTE
Biologically Active Natural Products Research Group, Eötvös str. 6, H-6720 Szeged, Hungary
- Graduate
Institute of Natural Products, Shih-Chuan first Rd. 100, Kaohsiung 807, Taiwan
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19
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Wang M, An Q, Li Z, Huang Z, Huang K, Li G, Ma Q, Zhao L. The alkylglycerone phosphate synthase sustains the resistance of gastric cancer cells to ferroptosis induced by Apatinib. Gastric Cancer 2025:10.1007/s10120-025-01610-0. [PMID: 40186794 DOI: 10.1007/s10120-025-01610-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Accepted: 03/21/2025] [Indexed: 04/07/2025]
Abstract
BACKGROUND Apatinib is a targeted therapy used in the treatment of advanced gastric cancer. However, many gastric cancer patients develop resistance to Apatinib, and the mechanisms underlying this resistance remain unclear. Previous studies have shown that Apatinib can induce ferroptosis in gastric cancer cells. More recent research suggests that polyunsaturated ether phospholipids are closely associated with tumor cell sensitivity to ferroptosis, and may represent key molecules involved in the resistance of tumor cells to ferroptosis. METHODS We established Apatinib-resistant gastric cancer cell lines and assessed their tolerance to ferroptosis. We identified key enzymes responsible for the ferroptosis tolerance observed in drug-resistant cells using lipidomics and transcriptomics analysis. Molecular and biological experiments were conducted to elucidate the molecular mechanisms underlying Apatinib resistance mediated by ferroptosis tolerance in gastric cancer cells. RESULTS Apatinib resistance is closely linked to ferroptosis resistance, which is driven by a reduction in the levels of polyunsaturated ether phospholipids-phospholipids that are particularly susceptible to oxidation and induce ferroptosis. The downregulation of key enzymes involved in polyunsaturated ether phospholipid synthesis, such as AGPS, mediates tolerance to both ferroptosis and Apatinib in gastric cancer cells, both in vitro and in vivo. Mechanistically, the expression of AGPS in tumor cells is regulated by the transcription factor ELK1. Drug-resistant cells acquire Apatinib tolerance by downregulating both ELK1 and AGPS expression. CONCLUSIONS Apatinib-resistant gastric cancer cells exhibit reduced expression of the transcription factor ELK1, which regulates the expression of AGPS. This reduction contributes to the resistance and malignancy of gastric cancer cells.
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Affiliation(s)
- Minghao Wang
- Department of General Surgery and Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China
| | - Qiyuan An
- Department of Biopharmaceutics, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, 510515, China
| | - Zhiwei Li
- Department of General Surgery and Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China
| | - Zhicheng Huang
- Department of General Surgery and Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China
| | - Kaihua Huang
- Department of General Surgery and Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China
| | - Guoxin Li
- Department of General Surgery and Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China
| | - Qiang Ma
- Department of Biopharmaceutics, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, 510515, China
| | - Liying Zhao
- Department of General Surgery and Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China.
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20
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Guo X, Li S. Bone metastases of prostate cancer: Molecular mechanisms, targeted diagnosis and targeted therapy (Review). Oncol Rep 2025; 53:46. [PMID: 39981932 PMCID: PMC11865881 DOI: 10.3892/or.2025.8879] [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: 05/18/2024] [Accepted: 09/12/2024] [Indexed: 02/22/2025] Open
Abstract
Prostate cancer (PCa) is second only to lung cancer in terms of death among men worldwide. Advanced PCa frequently results in bone metastases, which occur in ~90% of patients and frequently result in severe skeleton‑related events. Currently, the treatment for this disease is limited to alleviating its clinical symptoms and cannot provide a complete cure. Therefore, the development of novel treatment strategies is particularly important. In recent years, numerous novel strategies for the diagnosis and treatment of PCa have emerged, resulting in good clinical efficacy. For example, strategies targeting prostate specific membrane antigen, poly ADP‑ribose polymerase and programmed cell death protein 1 have been applied to PCa‑induced bone metastasis, and have shown initial efficacy and great potential. Therefore, understanding the molecular mechanisms underlying the formation of bone metastases in patients with PCa is of importance for the effective management of this disease. The purpose of the present review is to comprehensively outline the roles of protein‑coding genes and non‑coding RNAs in the development of bone metastases of PCa to elucidate their significance in the management of PCa. The aim is to offer clinicians and researchers a comprehensive understanding of this topic.
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Affiliation(s)
- Xutang Guo
- Department of Urology, Gansu Province Maternity and Child Health Hospital, Lanzhou, Gansu 730000, P.R. China
| | - Shaojun Li
- Department of Urology, Gansu Province Maternity and Child Health Hospital, Lanzhou, Gansu 730000, P.R. China
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21
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Chou MY, Yang MH. Immunomodulation on tumor immune microenvironment in acquired targeted therapy resistance and implication for immunotherapy resistance. Transl Oncol 2025; 54:102353. [PMID: 40058234 PMCID: PMC11929932 DOI: 10.1016/j.tranon.2025.102353] [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: 10/20/2024] [Revised: 02/11/2025] [Accepted: 03/04/2025] [Indexed: 03/18/2025] Open
Abstract
The emergence of molecularly targeted therapies and immunotherapies has revolutionized cancer treatment, yet the optimal sequencing of these modalities remains debated. While targeted therapies often induce initial immunostimulatory effects, the development of resistance is accompanied by dynamic alterations in the tumor-immune microenvironment. These changes can promote tumor growth, hinder immune surveillance, and contribute to subsequent immunotherapy resistance. This review focuses on solid tumors and summarizes the immunomodulatory effects arising in the context of targeted therapy resistance, highlighting the challenges they pose for the subsequent immunotherapy efficacy.
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Affiliation(s)
- Ming-Yu Chou
- Department of Medical Education, Taipei Veterans General Hospital, Taipei 112201, Taiwan
| | - Muh-Hwa Yang
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, No. 155, Sec. 2, Li-Nong Street, Taipei 112304, Taiwan; Cancer and Immunology Research Center, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan; Department of Oncology, Taipei Veterans General Hospital, Taipei 112201, Taiwan.
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22
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Glomb T, Środa-Pomianek K, Palko-Łabuz A, Wesołowska O, Wikiera A, Wojtkowiak K, Jezierska A, Kochel A, Lesyk R, Świątek P. New Hydrazone Derivatives Based on Pyrazolopyridothiazine Core as Cytotoxic Agents to Colon Cancers: Design, Synthesis, Biological Evaluation, and Molecular Modeling. ChemMedChem 2025; 20:e202400687. [PMID: 39786320 DOI: 10.1002/cmdc.202400687] [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: 09/02/2024] [Revised: 12/18/2024] [Accepted: 01/08/2025] [Indexed: 01/12/2025]
Abstract
In this research, a series of novel hydrazone derivatives based on pyrazolopyridothiazinylacetohydrazide were designed, synthesized, and evaluated for their in vitro cytotoxic potency on several human colon cancer cells (HTC116, HT-29, and LoVo). After MTT and SRB assays four of the most active derivatives: hydrazide GH and hydrazones GH7, GH8, and GH11, were chosen for further investigation. Hydrazone GH11 had the highest cytotoxic activity (IC50 values of c.a. 0.5 μM). Additionally, the impact of novel derivatives on the oxidative stress level, apoptosis induction, and modulation of inflammation in colon cancer cells was examined. In all studies, the activity of the derivatives increased in order GH < GH7 < GH8 < GH11. At the same time, most of the research was conducted on compounds combined with apple pectin (PC). The most interesting observation was that all the studied derivatives applied together with PC showed significantly higher activity than observed in the case of using PC, hydrazide, or hydrazones separately. Finally, computational chemistry methods (molecular modeling and Density Functional Theory - DFT) were used to complement the experimental studies.
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Affiliation(s)
- Teresa Glomb
- Department of Medicinal Chemistry, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211, 50-556, Wroclaw, Poland
| | - Kamila Środa-Pomianek
- Department of Biophysics and Neuroscience, Faculty of Medicine, Wroclaw Medical University, Chałubińskiego 3 A, 50-368, Wroclaw, Poland
| | - Anna Palko-Łabuz
- Department of Biophysics and Neuroscience, Faculty of Medicine, Wroclaw Medical University, Chałubińskiego 3 A, 50-368, Wroclaw, Poland
| | - Olga Wesołowska
- Department of Biophysics and Neuroscience, Faculty of Medicine, Wroclaw Medical University, Chałubińskiego 3 A, 50-368, Wroclaw, Poland
| | - Agnieszka Wikiera
- Department of Medical Physiology, Faculty of Health Sciences, Jagiellonian University Medical College, Michałowskiego Kraków, 12, 31-126, Krakow, Poland
| | - Kamil Wojtkowiak
- Faculty of Chemistry, University of Wroclaw, F. Joliot-Curie 14, 50-383, Wroclaw, Poland
| | - Aneta Jezierska
- Faculty of Chemistry, University of Wroclaw, F. Joliot-Curie 14, 50-383, Wroclaw, Poland
| | - Andrzej Kochel
- Faculty of Chemistry, University of Wroclaw, F. Joliot-Curie 14, 50-383, Wroclaw, Poland
| | - Roman Lesyk
- Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, Pekarska 69, 79-010, Lviv, Ukraine
| | - Piotr Świątek
- Department of Medicinal Chemistry, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211, 50-556, Wroclaw, Poland
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23
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Zhou Y, Zhang C, Wei H, Ding S, Li H, Hao Y. Directed evolution of proteoglycan-modifying enzymes: Functional applications in cervical cancer therapy. Int J Biol Macromol 2025; 304:140659. [PMID: 39914547 DOI: 10.1016/j.ijbiomac.2025.140659] [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: 11/11/2024] [Revised: 01/18/2025] [Accepted: 02/02/2025] [Indexed: 02/11/2025]
Abstract
The study investigates the therapeutic potential of enzyme variations EP-22, DS-13, and SM-47 in cervical cancer treatment using HeLa and SiHa cell lines, focusing on their effects on cell viability, migration, and molecular targets. The MTT assay findings also show that at a concentration of 50 μg/mL, EP-22 has an IC50 value of 35 % for HeLa cells and 28 % for SiHa cells, a significant dose effect (p < 0.01). EP-22 was not less potent at a lower working concentration of 25 μg/mL and could reduce HeLa cell viability to 78 %. In this case, there were significant changes in the anti-migratory effect, as evidenced by 45 % inhibition of SiHa cell migration and a 12 % wound closure rate compared with 54 % in the untreated cells. The obtained densitometric analysis indicated that in EP-22 treated HeLa cells, syndecan-1 and perlecan protein levels were reduced by approximately 65 % and 57 %, respectively, while the MMP-2 and MMP-9 levels were reduced to about 50 % and 45 %, respectively. Annexin V staining also highlighted a 40 % enhancement in early apoptosis and 25 % in late apoptosis in EP-22 handled cells. These data suggest the potential of EP-22 and its derivatives as therapeutic molecules in cervical cancer treatment, reducing HeLa proliferation by 35 % and SiHa by 28 %, inhibiting SiHa migration by 45 %, and affecting molecular targets involved in adhesion and invasiveness. Future studies must elucidate the effectiveness of in vivo experiments and how these findings were obtained. At 50 μg/mL, EP-22 reduced HeLa and SiHa cell viability by 35 % and 28 %, respectively, with significant dose-dependent effects (p < 0.01). At 25 μg/mL, EP-22 maintained potency, reducing HeLa cell viability to 78 %. EP-22 inhibited SiHa cell migration by 45 % and reduced wound closure rates to 12 % compared to 54 % in untreated cells. This work uses the HeLa and SiHa cell lines to examine the therapeutic potential of enzyme variation EP-22 in cervical cancer. EP-22 showed significant anti-cancer effects at 50 μg/mL doses, reducing cell viability at lower concentrations and achieving an IC50 of 35 % for HeLa cells and 28 % for SiHa cells. It is worth mentioning that EP-22 considerably reduced levels of essential proteins: syndecan-1 (65 %), perlecan (57 %), MMP-2 (50 %), and MMP-9 (45 %), in addition to inhibiting SiHa cell migration by 45 %. Furthermore, annexin V staining showed that treated cells exhibited a 40 % increase in early apoptosis and a 25 % increase in late apoptosis.
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Affiliation(s)
- Yang Zhou
- Department of Obstetrics and Gynaecology, Shengjing Hospital of China Medical University, No.36, Sanhao Street, Shenyang 110004, Liaoning, China
| | - Chen Zhang
- Department of Obstetrics and Gynaecology, Shengjing Hospital of China Medical University, No.36, Sanhao Street, Shenyang 110004, Liaoning, China
| | - Heng Wei
- Department of Obstetrics and Gynaecology, Shengjing Hospital of China Medical University, No.36, Sanhao Street, Shenyang 110004, Liaoning, China
| | - Silu Ding
- Department of Radiation Oncology, The First Hospital of Chinese Medical University, China.
| | - Hui Li
- Department of Gynaecology, The First Hospital of Chinese Medica University, China.
| | - Yingying Hao
- Department of Obstetrics and Gynaecology, Shengjing Hospital of China Medical University, No.36, Sanhao Street, Shenyang 110004, Liaoning, China.
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24
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Oliveira LS, Oliveira-Silva JM, Almeida-Souza HO, Martins MM, Chiminazo CB, Fonseca R, Souza CVED, Aissa AF, Bastos LM, Ionta M, Almeida Lima GDD, Castro-Gamero AM. HDAC6 inhibition through WT161 synergizes with temozolomide, induces apoptosis, reduces cell motility, and decreases β-catenin levels in glioblastoma cells. Invest New Drugs 2025; 43:223-242. [PMID: 39954199 DOI: 10.1007/s10637-025-01508-9] [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: 11/04/2024] [Accepted: 01/28/2025] [Indexed: 02/17/2025]
Abstract
Glioblastoma multiforme (GBM) accounts for 70% of all primary malignancies of the central nervous system. Current treatment strategies involve surgery followed by chemotherapy with temozolomide (TMZ); however, the median survival after treatment is approximately 15 months. Many GBM cases develop resistance to TMZ, resulting in a poor prognosis for patients, which underscores the urgent need for novel therapeutic approaches. One promising avenue is the inhibition of histone deacetylase 6 (HDAC6), an enzyme that deacetylates α-tubulin and is increasingly recognized as a potential pharmacological target in cancer. In GBM specifically, HDAC6 overexpression has been linked to poor prognosis and chemoresistance. In this study, we demonstrate that HDAC6 protein levels are elevated in GBM and evaluate the effects of the novel selective HDAC6 inhibitor, WT161, on U251, U87, and T98G cells to assess its potential to revert the malignant phenotype. Our results show a significant increase in acetylated α-tubulin levels, suppression of cell growth, cell cycle arrest at the G2/M phase, and decreased clonogenicity of 2D-cultured GBM cells. Additionally, WT161 acted synergistically with TMZ, induced apoptosis and enhanced TMZ-induced apoptosis. Notably, HDAC6 inhibition resulted in reduced cell migration and invasion, associated with decreased β-catenin levels. When cultured in 3D conditions, WT161-treated T98G spheroids were sensitized to TMZ and exhibited reduced migration. Finally, HDAC6 inhibition altered the metabolome, particularly affecting metabolites associated with lipid peroxidation. In conclusion, our data reveal, for the first time, the efficacy of the selective HDAC6 inhibitor WT161 in a preclinical GBM setting.
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Affiliation(s)
- Leilane Sales Oliveira
- Human Genetics Laboratory, Institute of Natural Sciences, Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil
- Postgraduate Program in Biosciences Applied to Health (PPGB), Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil
| | - João Marcos Oliveira-Silva
- Human Genetics Laboratory, Institute of Natural Sciences, Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil
- Postgraduate Program in Biosciences Applied to Health (PPGB), Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil
| | - Hebreia Oliveira Almeida-Souza
- Laboratory of Nanobiotechnology Prof. Dr. Luiz Ricardo Goulart, Institute of Biotechnology, Federal University of Uberlândia, Uberlândia, MG, 38400-902, Brazil
| | - Mario Machado Martins
- Laboratory of Nanobiotechnology Prof. Dr. Luiz Ricardo Goulart, Institute of Biotechnology, Federal University of Uberlândia, Uberlândia, MG, 38400-902, Brazil
| | - Carolina Berraut Chiminazo
- Human Genetics Laboratory, Institute of Natural Sciences, Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil
| | - Rafael Fonseca
- Institute of Biomedical Sciences, Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil
| | | | - Alexandre Ferro Aissa
- Division of Genetics, Department of Morphology and Genetics, Federal University of São Paulo, São Paulo, Brazil
- Postgraduate Program in Biosciences Applied to Health (PPGB), Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil
| | - Luciana Machado Bastos
- Laboratory of Nanobiotechnology Prof. Dr. Luiz Ricardo Goulart, Institute of Biotechnology, Federal University of Uberlândia, Uberlândia, MG, 38400-902, Brazil
| | - Marisa Ionta
- Institute of Biomedical Sciences, Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil
| | - Graziela Domingues de Almeida Lima
- Institute of Biomedical Sciences, Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil
- Postgraduate Program in Biosciences Applied to Health (PPGB), Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil
| | - Angel Mauricio Castro-Gamero
- Human Genetics Laboratory, Institute of Natural Sciences, Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil.
- Postgraduate Program in Biosciences Applied to Health (PPGB), Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil.
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25
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Gao Y, Chen X, Duan JA, Xiao P. A review of pharmacological mechanisms, challenges and prospects of macromolecular glycopeptides. Int J Biol Macromol 2025; 300:140294. [PMID: 39863220 DOI: 10.1016/j.ijbiomac.2025.140294] [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: 06/06/2024] [Revised: 01/13/2025] [Accepted: 01/22/2025] [Indexed: 01/27/2025]
Abstract
Macromolecular glycopeptides are natural products derived from various sources, distinguished by their structural diversity, multifaceted biological activities, and low toxicity. These compounds exhibit a wide range of biological functions, such as immunomodulation, antitumor effects, anti-inflammatory properties, antioxidant activity, and more. However, limited understanding of natural glycopeptides has hindered their development and practical application. To promote their advancement and utilization, it is crucial to thoroughly investigate the pharmacological mechanisms of glycopeptides and address the challenges in natural glycopeptide research. This review uniquely focuses on the primary biological activities and potential molecular mechanisms of glycopeptides as reported in recent literature. Moreover, we emphasize the current challenges in glycopeptide research, including extraction and isolation difficulties, purification challenges, structural analysis complexities, elucidation of structure-activity relationships, characterization of biosynthetic pathways, and ensuring bioavailability and stability. The future prospects for glycopeptide research are also explored. We argue that ongoing research into glycopeptides will significantly contribute to drug development and provide more effective therapeutic options and disease treatment alternatives for human health.
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Affiliation(s)
- Ye Gao
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing 210023, PR China
| | - Xiaoyi Chen
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing 210023, PR China
| | - Jin-Ao Duan
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing 210023, PR China.
| | - Ping Xiao
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing 210023, PR China.
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26
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Ravera F, Gilardi N, Ballestrero A, Zoppoli G. Applications, challenges and future directions of artificial intelligence in cardio-oncology. Eur J Clin Invest 2025; 55 Suppl 1:e14370. [PMID: 40191923 PMCID: PMC11973867 DOI: 10.1111/eci.14370] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 11/28/2024] [Indexed: 04/09/2025]
Abstract
BACKGROUND The management of cardiotoxicity related to cancer therapies has emerged as a significant clinical challenge, prompting the rapid growth of cardio-oncology. As cancer treatments become more complex, there is an increasing need to enhance diagnostic and therapeutic strategies for managing their cardiovascular side effects. OBJECTIVE This review investigates the potential of artificial intelligence (AI) to revolutionize cardio-oncology by integrating diverse data sources to address the challenges of cardiotoxicity management. METHODS We explore applications of AI in cardio-oncology, focusing on its ability to leverage multiple data sources, including electronic health records, electrocardiograms, imaging modalities, wearable sensors, and circulating serum biomarkers. RESULTS AI has demonstrated significant potential in improving risk stratification and longitudinal monitoring of cardiotoxicity. By optimizing the use of electrocardiograms, non-invasive imaging, and circulating biomarkers, AI facilitates earlier detection, better prediction of outcomes, and more personalized therapeutic interventions. These advancements are poised to enhance patient outcomes and streamline clinical decision-making. CONCLUSIONS AI represents a transformative opportunity in cardio-oncology by advancing diagnostic and therapeutic capabilities. However, successful implementation requires addressing practical challenges such as data integration, model interpretability, and clinician training. Continued collaboration between clinicians and AI developers will be essential to fully integrate AI into routine clinical workflows.
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Affiliation(s)
- Francesco Ravera
- Department of Internal Medicine and Medical SpecialtiesUniversity of GenoaGenoaItaly
| | - Nicolò Gilardi
- Department of Internal Medicine and Medical SpecialtiesUniversity of GenoaGenoaItaly
| | - Alberto Ballestrero
- Department of Internal Medicine and Medical SpecialtiesUniversity of GenoaGenoaItaly
- IRCCS Ospedale Policlinico San MartinoGenoaItaly
| | - Gabriele Zoppoli
- Department of Internal Medicine and Medical SpecialtiesUniversity of GenoaGenoaItaly
- IRCCS Ospedale Policlinico San MartinoGenoaItaly
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27
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Senekowitsch S, Freitag T, Dubinski D, Freiman TM, Maletzki C, Hinz B. Validation of an LC-MS/MS Method for the Simultaneous Intracellular Quantification of the CDK4/6 Inhibitor Abemaciclib and the EZH2 Inhibitors GSK126 and Tazemetostat. Pharmaceutics 2025; 17:433. [PMID: 40284428 PMCID: PMC12030624 DOI: 10.3390/pharmaceutics17040433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2025] [Revised: 03/20/2025] [Accepted: 03/24/2025] [Indexed: 04/29/2025] Open
Abstract
Background: Inhibitors of cyclin-dependent kinases (CDKs) and epigenetic modifier enhancer of zeste homolog 2 (EZH2) have emerged as promising options in the pharmacotherapy of malignant tumors. Recently, we demonstrated synergistic antitumor effects of the CDK4/6 inhibitor abemaciclib and the EZH2 inhibitors GSK126 or tazemetostat in patient-derived glioblastoma (GBM) models. Importantly, all three drugs are substrates of the two most important plasma membrane multidrug transporters ABCB1 and ABCG2, with abemaciclib and tazemetostat also being inhibitors of these proteins. Methods: To investigate whether increased intracellular accumulation of either of the two drugs used in combination could have contributed to corresponding synergisms, we developed a simple LC-MS/MS method for simultaneous detection of the three substances in cell culture lysates. The method was validated in accordance with the current International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) guideline M10 on bioanalytical method validation and study sample analysis. Results: All acceptance criteria were met. Subsequent analysis of intracellular drug concentrations confirmed increased cellular uptake of tazemetostat in the presence of abemaciclib in both GBM cell lines studied compared to single agent treatment. A comparable pattern was also observed for GSK126, but in only one of the two cell lines used. Conclusions: In conclusion, the observed synergistic antitumor effect could be partly due to increased intracellular accumulation, although this alone is certainly not sufficient to explain it. Overall, the developed method provides a valuable approach for characterizing interactions at the transport level and for predicting the efficiency of both anticancer substance classes in different cell lines.
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Affiliation(s)
- Stefan Senekowitsch
- Institute of Pharmacology and Toxicology, Rostock University Medical Center, Schillingallee 70, 18057 Rostock, Germany;
| | - Thomas Freitag
- Department of Medicine, Clinic III—Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, 18057 Rostock, Germany
- Department of Neurosurgery, Rostock University Medical Center, 18057 Rostock, Germany
| | - Daniel Dubinski
- Department of Neurosurgery, Rostock University Medical Center, 18057 Rostock, Germany
| | - Thomas M. Freiman
- Department of Neurosurgery, Rostock University Medical Center, 18057 Rostock, Germany
| | - Claudia Maletzki
- Department of Medicine, Clinic III—Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, 18057 Rostock, Germany
| | - Burkhard Hinz
- Institute of Pharmacology and Toxicology, Rostock University Medical Center, Schillingallee 70, 18057 Rostock, Germany;
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28
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Ma JJ, Zhang LF, Xu DP, Wang Z, Meng YQ. Design, synthesis and antitumor activity of pentacyclic triterpenoid ursolic acid derivatives and oleanolic acid derivatives based on multi-target. JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH 2025:1-18. [PMID: 40117208 DOI: 10.1080/10286020.2025.2473635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/24/2024] [Revised: 02/24/2025] [Accepted: 02/24/2025] [Indexed: 03/23/2025]
Abstract
Totally twelve inhibitors of Survivin and Sp1 based on ursolic acid (UA) derivatives and oleanolic acid (OA) derivatives were designed and synthesized with modification at C-2, C-3 and C-28 of UA and OA. Their structures were confirmed by HRMS,1H NMR and 13C NMR. In vitro activity assay showed that these compounds can inhibit cell proliferation of HeLa, SKOV3, BGC-823 and HT1080 cells, especially compounds IV and X showed better inhibitory activity on these tumor cells than that of the positive control drug Gefitinib and similar to Vp-16. Mechanistically, selected compound may inhibit the proliferation of SKOV3 cells and trigger apoptosis by activating Sp1 to inhibit Survivin protein expression, which may be promising leading compounds for cancer therapy.
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Affiliation(s)
- Jun-Jiao Ma
- Department of Chemical Engineering, Shenyang University of Chemical Technology, Shenyang 110142, China
| | - Liang-Feng Zhang
- Department of Chemical Engineering, Shenyang University of Chemical Technology, Shenyang 110142, China
| | - Dong-Ping Xu
- Department of Chemical Engineering, Shenyang University of Chemical Technology, Shenyang 110142, China
| | - Zan Wang
- Department of Chemical Engineering, Shenyang University of Chemical Technology, Shenyang 110142, China
| | - Yan-Qiu Meng
- Department of Chemical Engineering, Shenyang University of Chemical Technology, Shenyang 110142, China
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29
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Mardi A, Aghebati-Maleki L. Bispecific antibodies (bsAbs) directed against PD-1/PD-L1 and CTLA-4; a mini review. Hum Antibodies 2025:10932607251325751. [PMID: 40112316 DOI: 10.1177/10932607251325751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/22/2025]
Abstract
Novel approaches to tumor immunotherapy include adoptive cell immunotherapy, immune checkpoint inhibitors (ICIs), and bispecific antibodies (bsABs). bsABs are members of the antibody family that have the ability to distinguish between two distinct antigens or epitopes on a single antigen. These antibodies show better clinical results than monoclonal antibodies, suggesting that they might be a useful choice for tumor immunotherapy. Additionally, dual blockade immunotherapy targeting PD-1/PD-L1 and CTLA-4 functions at various phases of T cell activation with synergistically increasing immune responses against cancer cells, in contrast to ICI monotherapy, which sometimes displays treatment resistance and limited effectiveness. It has been shown that immune response rates and anti-tumor effects may be increased in a synergistic manner by ICI-based combination therapy. We explore the safety and effectiveness of bsABs and ICIs (especially PD1/PDL1 and CTLA-4) combination treatments in tumor immunotherapy in this study with the goal of offering evidence-based methods for clinical research and tailored tumor identification and management.
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Affiliation(s)
- Amirhossein Mardi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Science, Tabriz, Iran
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30
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Pandey P, Lakhanpal S, Mahmood D, Baldaniya L, Kang HN, Hwang S, Kang S, Choi M, Moon S, Pandey S, Chaudhary K, Khan F, Kim B. Recent Update of Natural Compounds as HIF-1α Inhibitors in Colorectal Carcinoma. Drug Des Devel Ther 2025; 19:2017-2034. [PMID: 40124557 PMCID: PMC11929541 DOI: 10.2147/dddt.s511406] [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: 12/10/2024] [Accepted: 02/08/2025] [Indexed: 03/25/2025] Open
Abstract
Hypoxia-inducible factor (HIF)-1 is a transcription factor that regulates the expression of target genes associated with oxygen homeostasis under hypoxic conditions, thereby contributing to tumor development and progression. Accumulating evidence has demonstrated that HIF-1α mediates different biological processes, including tumor angiogenesis, metastasis, metabolism, and immune evasion. Thus, overexpression of HIF-1α is strongly associated with poor prognosis in cancer patients. Natural compounds are important sources of anticancer drugs and studies have emphasized the decisive role of these mediators in modulating HIF-1α. Therefore, the pharmacological targeting of HIF-1α has emerged as a novel cancer therapeutic approach in recent years. The novelty of this review is that it summarizes natural products targeting HIF-1α in colorectal cancer that have not been presented earlier. We studied research publications related to the HIF-1α domain in cancer from 2010 to 2024. However, our main focus was to identify a better targeted approach for colorectal carcinoma management. Our review described HIF-1α role in tumor progression, summarizes the natural compounds employed as HIF-1α inhibitors, and discusses their potential in the development of natural compounds as HIF-1α inhibitors for colorectal cancer treatment.
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Affiliation(s)
- Pratibha Pandey
- Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, Punjab, 140401, India
- Chitkara Centre for Research and Development, Chitkara University, Baddi, Himanchal Pradesh, 174103, India
| | - Sorabh Lakhanpal
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India
| | - Danish Mahmood
- Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraydah, 51452, Saudi Arabia
| | - Lalji Baldaniya
- Marwadi University Research Center, Department of Pharmaceutical Sciences, Faculty of Health Sciences, Marwadi University, Rajkot, Gujarat, 360003, India
| | - Han Na Kang
- KM Convergence Research Division, Korea Institute of Oriental Medicine, Daejeon, Republic of Korea
| | - Sungho Hwang
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemungu, Seoul, 05253, Republic of Korea
| | - Sojin Kang
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemungu, Seoul, 05253, Republic of Korea
| | - Min Choi
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemungu, Seoul, 05253, Republic of Korea
| | - Seungjoon Moon
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemungu, Seoul, 05253, Republic of Korea
| | - Shivam Pandey
- School of Applied and Life Sciences, Uttaranchal University, Dehradun, Uttarakhand, 248007, India
| | - Kamlesh Chaudhary
- Department of Neurology, National Institute of Medical Sciences, NIMS University Rajasthan, Jaipur, Rajasthan, India
| | - Fahad Khan
- Center for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, India
| | - Bonglee Kim
- KM Convergence Research Division, Korea Institute of Oriental Medicine, Daejeon, Republic of Korea
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemungu, Seoul, 05253, Republic of Korea
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Stojchevski R, Sutanto EA, Sutanto R, Hadzi-Petrushev N, Mladenov M, Singh SR, Sinha JK, Ghosh S, Yarlagadda B, Singh KK, Verma P, Sengupta S, Bhaskar R, Avtanski D. Translational Advances in Oncogene and Tumor-Suppressor Gene Research. Cancers (Basel) 2025; 17:1008. [PMID: 40149342 PMCID: PMC11940485 DOI: 10.3390/cancers17061008] [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: 02/10/2025] [Revised: 03/10/2025] [Accepted: 03/15/2025] [Indexed: 03/29/2025] Open
Abstract
Cancer, characterized by the uncontrolled proliferation of cells, is one of the leading causes of death globally, with approximately one in five people developing the disease in their lifetime. While many driver genes were identified decades ago, and most cancers can be classified based on morphology and progression, there is still a significant gap in knowledge about genetic aberrations and nuclear DNA damage. The study of two critical groups of genes-tumor suppressors, which inhibit proliferation and promote apoptosis, and oncogenes, which regulate proliferation and survival-can help to understand the genomic causes behind tumorigenesis, leading to more personalized approaches to diagnosis and treatment. Aberration of tumor suppressors, which undergo two-hit and loss-of-function mutations, and oncogenes, activated forms of proto-oncogenes that experience one-hit and gain-of-function mutations, are responsible for the dysregulation of key signaling pathways that regulate cell division, such as p53, Rb, Ras/Raf/ERK/MAPK, PI3K/AKT, and Wnt/β-catenin. Modern breakthroughs in genomics research, like next-generation sequencing, have provided efficient strategies for mapping unique genomic changes that contribute to tumor heterogeneity. Novel therapeutic approaches have enabled personalized medicine, helping address genetic variability in tumor suppressors and oncogenes. This comprehensive review examines the molecular mechanisms behind tumor-suppressor genes and oncogenes, the key signaling pathways they regulate, epigenetic modifications, tumor heterogeneity, and the drug resistance mechanisms that drive carcinogenesis. Moreover, the review explores the clinical application of sequencing techniques, multiomics, diagnostic procedures, pharmacogenomics, and personalized treatment and prevention options, discussing future directions for emerging technologies.
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Affiliation(s)
- Radoslav Stojchevski
- Friedman Diabetes Institute, Lenox Hill Hospital, Northwell Health, New York, NY 10022, USA;
- Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA
| | - Edward Agus Sutanto
- CUNY School of Medicine, The City College of New York, 160 Convent Avenue, New York, NY 10031, USA;
| | - Rinni Sutanto
- New York Institute of Technology College of Osteopathic Medicine, Glen Head, NY 11545, USA;
| | - Nikola Hadzi-Petrushev
- Faculty of Natural Sciences and Mathematics, Institute of Biology, Ss. Cyril and Methodius University, 1000 Skopje, North Macedonia; (N.H.-P.)
| | - Mitko Mladenov
- Faculty of Natural Sciences and Mathematics, Institute of Biology, Ss. Cyril and Methodius University, 1000 Skopje, North Macedonia; (N.H.-P.)
| | - Sajal Raj Singh
- GloNeuro, Sector 107, Vishwakarma Road, Noida 201301, Uttar Pradesh, India (J.K.S.)
| | - Jitendra Kumar Sinha
- GloNeuro, Sector 107, Vishwakarma Road, Noida 201301, Uttar Pradesh, India (J.K.S.)
| | - Shampa Ghosh
- GloNeuro, Sector 107, Vishwakarma Road, Noida 201301, Uttar Pradesh, India (J.K.S.)
| | | | - Krishna Kumar Singh
- Symbiosis Centre for Information Technology (SCIT), Rajiv Gandhi InfoTech Park, Hinjawadi, Pune 411057, Maharashtra, India;
| | - Prashant Verma
- School of Management, BML Munjal University, NH8, Sidhrawali, Gurugram 122413, Haryana, India
| | - Sonali Sengupta
- Department of Gastroenterology, All India Institute of Medical Sciences (AIIMS), New Delhi 110029, India
| | - Rakesh Bhaskar
- School of Chemical Engineering, Yeungnam University, Gyeongsan 38541, Republic of Korea
- Research Institute of Cell Culture, Yeungnam University, Gyeongsan 38541, Republic of Korea
| | - Dimiter Avtanski
- Friedman Diabetes Institute, Lenox Hill Hospital, Northwell Health, New York, NY 10022, USA;
- Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA
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32
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Su JX, Zhou HX, Zhang ZJ, Zhou XF, Zou QM, Li SJ, Zhuang XS, Lai JQ, Yang SY, Cui K, Liu YQ, Yuan RJ, Pan HX, Li ZS, Tu HY, Cheng M, Yan Y, Qi Q, Zhang YB. Gracillin suppresses cancer progression through inducing Merlin/LATS protein-protein interaction and activating Hippo signaling pathway. Acta Pharmacol Sin 2025:10.1038/s41401-025-01514-w. [PMID: 40055528 DOI: 10.1038/s41401-025-01514-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Accepted: 02/13/2025] [Indexed: 03/12/2025]
Abstract
Gene therapy, epigenetic therapies, natural compounds targeted therapy, photodynamic therapy, nanoparticles, and precision medicines are becoming available to diagnose and treat cancer. Gracillin, a natural steroidal saponin extracted from herbs, has shown potent efficacy against a range of malignancies. In this study, we investigated the molecular anticancer mechanisms of gracillin. We showed that gracillin dose-dependently suppressed proliferation, migration, and invasion in breast cancer, liver cancer, and glioblastoma cells with IC50 values around 1 μM, which were associated with MST-independent activation of Hippo signaling pathway and subsequent decreased YAP activity. We demonstrated that gracillin activated the Hippo signaling by inducing Merlin/LATS protein-protein interaction (PPI). A competitive inhibitory peptide (SP) derived from the binding interface of the PPI, disrupted the interaction, abolishing the anticancer activity of gracillin. In nude mice bearing MDA-MB-231, HCCLM3, or U87MG xenograft tumor, administration of gracillin (5, 10 mg·kg-1·d-1, i.g. for 21 days) dose-dependently suppressed the tumor growth, associated with the induced Merlin/LATS PPI, activated Hippo signaling, as well as decreased YAP activity in tumor tissues. Our data demonstrate that gracillin is an efficacious therapeutic agent for cancer treatment, induction of Merlin/LATS PPI might provide proof-of-concept in developing therapeutic agent for cancer treatment.
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Affiliation(s)
- Jin-Xuan Su
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Hai-Xia Zhou
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Zhi-Jing Zhang
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510632, China
| | - Xiao-Feng Zhou
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Qiu-Ming Zou
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Si-Jia Li
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Xiao-Song Zhuang
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Jian-Qin Lai
- Department of Colorectal & Anal Surgery, Guangzhou First People's Hospital, Guangzhou, 510632, China
| | - Si-Yu Yang
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Kai Cui
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Yong-Qi Liu
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China
- Department of Respiratory and Critical Care, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Rui-Jie Yuan
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Heng-Xin Pan
- Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia
| | - Zi-Sheng Li
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Han-Yun Tu
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Mei Cheng
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China.
| | - Yu Yan
- Functional Experimental Teaching Center, School of Medicine, Jinan University, Guangzhou, 510632, China.
| | - Qi Qi
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China.
| | - Yu-Bo Zhang
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China.
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Li X, Hu H, Wang H, Liu J, Jiang W, Zhou F, Zhang J. DNA nanotechnology-based strategies for minimising hybridisation-dependent off-target effects in oligonucleotide therapies. MATERIALS HORIZONS 2025; 12:1388-1412. [PMID: 39692461 DOI: 10.1039/d4mh01158a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2024]
Abstract
Targeted therapy has emerged as a transformative breakthrough in modern medicine. Oligonucleotide drugs, such as antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), have made significant advancements in targeted therapy. Other oligonucleotide-based therapeutics like clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein (Cas) systems are also leading a revolution in targeted gene therapy. However, hybridisation-dependent off-target effects, arising from imperfect base pairing, remain a significant and growing concern for the clinical translation of oligonucleotide-based therapeutics. These mismatches in base pairing can lead to unintended steric blocking or cleavage events in non-pathological genes, affecting the efficacy and safety of the oligonucleotide drugs. In this review, we examine recent developments in oligonucleotide-based targeted therapeutics, explore the factors influencing sequence-dependent targeting specificity, and discuss the current approaches employed to reduce the off-target side effects. The existing strategies, such as chemical modifications and oligonucleotide length optimisation, often require a trade-off between specificity and binding affinity. To further address the challenge of hybridisation-dependent off-target effects, we discuss DNA nanotechnology-based strategies that leverage the collaborative effects of nucleic acid assembly in the design of oligonucleotide-based therapies. In DNA nanotechnology, collaborative effects refer to the cooperative interactions between individual strands or nanostructures, where multiple bindings result in more stable and specific hybridisation behaviour. By requiring multiple complementary interactions to occur simultaneously, the likelihood of unintended partially complementary binding events in nucleic acid hybridisation should be reduced. And thus, with the aid of collaborative effects, DNA nanotechnology has great promise in achieving both high binding affinity and high specificity to minimise the hybridisation-dependent off-target effects of oligonucleotide-based therapeutics.
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Affiliation(s)
- Xiaoyu Li
- Laboratory of Advanced Theranostic Materials and Technology, Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo, China.
- Ningbo Cixi Institute of Biomedical Engineering, Ningbo, China
| | - Huanhuan Hu
- Laboratory of Advanced Theranostic Materials and Technology, Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo, China.
- Ningbo Cixi Institute of Biomedical Engineering, Ningbo, China
| | - Hailong Wang
- Laboratory of Advanced Theranostic Materials and Technology, Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo, China.
- Ningbo Cixi Institute of Biomedical Engineering, Ningbo, China
- School of Materials Science and Chemical Engineering, Ningbo University, Ningbo, China
| | - Jia Liu
- Laboratory of Advanced Theranostic Materials and Technology, Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo, China.
- Ningbo Cixi Institute of Biomedical Engineering, Ningbo, China
| | - Wenting Jiang
- Laboratory of Advanced Theranostic Materials and Technology, Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo, China.
- Ningbo Cixi Institute of Biomedical Engineering, Ningbo, China
- Cixi Biomedical Research Institute, Wenzhou Medical University, Zhejiang, China
| | - Feng Zhou
- Laboratory of Advanced Theranostic Materials and Technology, Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo, China.
- Ningbo Cixi Institute of Biomedical Engineering, Ningbo, China
| | - Jiantao Zhang
- Laboratory of Advanced Theranostic Materials and Technology, Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo, China.
- Ningbo Cixi Institute of Biomedical Engineering, Ningbo, China
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Mohammadi S, Mortazavi M, Poustforoosh A, Moosavi F, Saso L, Edraki N, Firuzi O. Novel spiroisatin-pyranopyrazole hybrids as anticancer agents with TrkC inhibitory potential. J Biomol Struct Dyn 2025:1-14. [PMID: 40025803 DOI: 10.1080/07391102.2025.2472404] [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: 10/30/2023] [Accepted: 04/06/2024] [Indexed: 03/04/2025]
Abstract
Cancer still represents a global health concern due to its high mortality and morbidity rates. Isatin-and pyrazole-based compounds have recently garnered interest as novel anticancer agents. A series of 15 novel spiroisatin pyranopyrazole derivatives were synthesized. Anticancer potential of synthesized agents against EBC-1, HT-29, A549, and AsPC-1 cell lines, representing cancers of the lung, colon, and pancreas, were evaluated using the MTT assay. The possible molecular mechanism contributing to antiproliferative activities of the most potent compounds was further investigated in silico by using SuperPred web server, a ligand-based tool. Docking and molecular dynamics (MD) simulation studies were carried out to investigate the binding affinity and key interactions of the agents with their predicted target. Among the tested compounds, four cyanide-containing derivatives 6c, 6d, 6f, and 6g with bromobenzyl, chlorobenzyl, p-tButyl benzyl and methylbenzyl moieties on the isatin ring, respectively, displayed the highest antiproliferative effects against all four cell lines. These compounds were particularly effective against EBC-1, and HT-29 cells with IC50 values of 3.3-7.1 and 7.3-10.2 μΜ, respectively, while relatively sparing non-cancer cells. The obtained target prediction results suggested that the growth inhibitory activity of the analyzed analogues could be related to tropomyosin receptor kinase C (TrkC) inhibition. The outcomes of molecular docking and MD simulation demonstrated that the most active agents may interact closely with the active site of the suggested target, further confirming target prediction findings. The findings of this study suggest the potential of spiroisatin pyranopyrazole analogues for further exploration as novel targeted anticancer agents.
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Affiliation(s)
- Somayeh Mohammadi
- Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Motahareh Mortazavi
- Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Alireza Poustforoosh
- Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Fatemeh Moosavi
- Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Luciano Saso
- Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University of Rome, Rome, Italy
| | - Najmeh Edraki
- Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Omidreza Firuzi
- Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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Ren X, Chen W, Liu Y, Chen Z, Wang X, Sun X. TRPV4 as a Novel Regulator of Ferroptosis in Colon Adenocarcinoma: Implications for Prognosis and Therapeutic Targeting. Dig Dis Sci 2025; 70:1064-1077. [PMID: 39826064 DOI: 10.1007/s10620-025-08843-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Accepted: 01/02/2025] [Indexed: 01/20/2025]
Abstract
BACKGROUND Colon adenocarcinoma (COAD) is a leading cause of cancer-related mortality worldwide. Transient receptor potential vanilloid 4 (TRPV4), a calcium-permeable non-selective cation channel, has been implicated in various cancers, including COAD. This study investigates the role of TRPV4 in colon adenocarcinoma and elucidates its potential mechanism via the ferroptosis pathway. MATERIALS AND METHODS Gene expression profiles and clinical data were obtained from The Cancer Genome Atlas (TCGA), encompassing 647 colon adenocarcinoma tissue samples and 51 normal colorectal tissue samples. Ferroptosis-related genes were retrieved from the FerrDb database. Differential expression analysis, survival analysis, and Cox proportional hazards regression were performed to assess the prognostic significance of TRPV4. Protein-protein interaction networks and gene enrichment analyses (GO and KEGG) were conducted to explore functional associations. In vitro experiments were carried out using HT-29 and SW480 colon cancer cell lines. TRPV4 was knocked down using siRNA, and cell viability was assessed via hematoxylin and eosin (HE) staining. Immunofluorescence assays evaluated the expression of ferroptosis-related proteins (SLC3A2, GPX4) and proliferation markers (KI67, SRC, CTNNB1, COL1). RESULTS TRPV4 expression was significantly elevated in colon adenocarcinoma tissues compared to normal tissues (p < 0.05), demonstrating high diagnostic accuracy (AUC = 0.848). High TRPV4 expression correlated with poorer overall survival (OS) and disease-specific survival (DSS), particularly in patients over 65 years old and those in clinical stage II. Cox regression analysis confirmed TRPV4 as an independent prognostic factor (HR = 1.395, p = 0.074). Bioinformatics analyses revealed that TRPV4 is closely associated with ferroptosis-related genes, participating in key biological processes such as responses to external stimuli, oxidative stress, and cell adhesion. In vitro, TRPV4 knockdown significantly reduced cell viability (p < 0.05) and decreased expression levels of SLC3A2, GPX4, KI67, SRC, and COL1 (p < 0.05). The addition of the ferroptosis inhibitor FER-1 did not restore cell viability in TRPV4 knockdown cells, suggesting that TRPV4 modulates cell survival through the ferroptosis pathway. DISCUSSION The bioinformation and in vitro experiments inTRPV4 and ferroptosis-related genes support the hypothesis that TRPV4 influences tumor cell survival via the ferroptosis pathway. The inability of FER-1 to rescue viability in TRPV4-deficient cells further confirms this mechanism. These findings provide novel insights into the molecular mechanisms of COAD and highlight TRPV4 as a potential therapeutic target. CONCLUSION TRPV4 is significantly upregulated in COAD and is associated with unfavorable patient outcomes. It appears to promote tumor progression by regulating the ferroptosis pathway, affecting the expression of key ferroptosis-related genes and proliferation markers. Targeting TRPV4 may offer a new therapeutic approach for COAD, and further research is warranted to explore its role in other cancers and to develop TRPV4-based therapies.
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Affiliation(s)
- Xiangshun Ren
- Huaian Hospital of Huaian City, Huaian Block, Shanyang Avenue No.19, Huaian City, 223001, JiangSu Province, People's Republic of China
| | - Wancheng Chen
- Nanjing University of Chinese Medicine, Xianlin Avenue No. 138, Qixia District, Nanjing City, 210046, Jiangsu Province, People's Republic of China
| | - Yuxing Liu
- Ningxia Medical University, Xing Qing Block, Shengli Street No.1160, Yin Chuan City, 750004, Ningxia Province, People's Republic of China
| | - Zijie Chen
- Ningxia Medical University, Xing Qing Block, Shengli Street No.1160, Yin Chuan City, 750004, Ningxia Province, People's Republic of China
| | - Xing Wang
- China Rehabilitation Research Center & Beijing Boai Hospital, Beijing, 100068, People's Republic of China
| | - Xiaojiao Sun
- Ningxia Medical University, Xing Qing Block, Shengli Street No.1160, Yin Chuan City, 750004, Ningxia Province, People's Republic of China.
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Wu H, Liao X, Huang W, Hu H, Lan L, Yang Q, An Y. Examining the prognostic and clinicopathological significance of GPX4 in human cancers: a meta-analysis. Free Radic Res 2025; 59:239-249. [PMID: 40034003 DOI: 10.1080/10715762.2025.2475153] [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: 08/30/2024] [Revised: 11/13/2024] [Accepted: 12/10/2024] [Indexed: 03/05/2025]
Abstract
Elevated levels of the enzyme GPX4 have been detected in tumor tissues, which may play a role in cancer progression. We did a meta-analysis of eight studies encompassing 1180 individuals to evaluate the importance of GPX4 in cancer, particularly in terms of prognosis and clinicopathological characteristics. Research results indicate that higher levels of GPX4 were linked to worse overall survival (OS) (HR = 1.47 [95%CI = 1.18-1.76], p < .001). Elevated levels of GPX4 were linked to lymph node invasion (OR.69 [95% CI.44-1.10], p =.12), metastasis (OR 1.58 [95% CI.97-2.55], p =.06, p <.0001), and advanced clinical stage III-IV (OR.82 [95% CI.70-.96], p =.001). A sensitivity study revealed that the general findings were constant across all levels of impact intensity. The findings of this meta-analysis suggest that increased GPX4 levels are not only correlated with reduced overall survival rates for patients with tumors but it also offers valuable insights regarding the clinical traits of tumor malignancy and metastasis. Based on these connections, GPX4 has the potential to serve as a biomarker for tumor detection, prognosis, and targeted therapy.
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Affiliation(s)
- Hao Wu
- Department of Toxicology, School of Public Health, Jiangsu Key Laboratory of Preventive and Translational Medicine for Major Chronic Non-communicable Diseases, MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Xiting Liao
- Department of Toxicology, School of Public Health, Jiangsu Key Laboratory of Preventive and Translational Medicine for Major Chronic Non-communicable Diseases, MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Wusixian Huang
- Department of Toxicology, School of Public Health, Jiangsu Key Laboratory of Preventive and Translational Medicine for Major Chronic Non-communicable Diseases, MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Huai Hu
- Department of Toxicology, School of Public Health, Jiangsu Key Laboratory of Preventive and Translational Medicine for Major Chronic Non-communicable Diseases, MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Lan Lan
- Department of Toxicology, School of Public Health, Jiangsu Key Laboratory of Preventive and Translational Medicine for Major Chronic Non-communicable Diseases, MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Qianlei Yang
- Department of Toxicology, School of Public Health, Jiangsu Key Laboratory of Preventive and Translational Medicine for Major Chronic Non-communicable Diseases, MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Yan An
- Department of Toxicology, School of Public Health, Jiangsu Key Laboratory of Preventive and Translational Medicine for Major Chronic Non-communicable Diseases, MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China
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Huang T, Ren K, Ling X, Li Z, Chen L. Transcription factor Yin Yang 1 enhances epithelial-mesenchymal transition, migration, and stemness of non-small cell lung cancer cells by targeting sonic hedgehog. Mol Cell Biochem 2025; 480:1831-1843. [PMID: 39261409 DOI: 10.1007/s11010-024-05104-y] [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: 03/28/2024] [Accepted: 08/21/2024] [Indexed: 09/13/2024]
Abstract
Non-small cell lung cancer (NSCLC) is a frequent type of lung cancer. Transcription factor Yin Yang 1 (YY1), an endogenous transcription factor containing zinc finger structure, can accelerate NSCLC progression. However, the impact of YY1 on the stemness of NSCLC cells and the mechanism of promoting NSCLC cell progression is unclear. YY1 and Sonic hedgehog (Shh) expressions were monitored by RT-qPCR, western blot, and immunohistochemistry. Overall survival was tested through Kaplan-Meier analysis. The interaction between YY1 and Shh was confirmed. Then, cell migration, stemness, and epithelial-mesenchymal transition (EMT) were assessed with functional experiments in vitro and in vivo. YY1 and Shh were highly expressed in NSCLC tissues and positively correlated with the poor OS of NSCLC patients. Functional experiments denoted that YY1 or Shh overexpression could accelerate EMT, migration, and stemness of NSCLC cells, and YY1 or Shh knockdown played the opposite role to its overexpression. Mechanism analysis disclosed that Shh, as a target gene of YY1, was positively related to YY1. The rescued experiment manifested that Shh silencing could reverse the induction effect of YY1 overexpression on EMT, migration, and stemness of NSCLC cells. In vivo experiments also confirmed that YY1 could accelerate tumor growth and EMT and weaken apoptosis. YY1 promotes NSCLC EMT, migration, and stemness by Shh, which might be novel diagnostic markers and therapeutic targets for NSCLC therapy.
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Affiliation(s)
- Tonghai Huang
- Department of Thoracic Surgery, Shenzhen People's Hospital, 1st Affiliated Hospital of Southern University of Science and Technology, 2, Clinical Medical College of Jinan University, No.1017, East Gate Rd, Shenzhen, 518020, Guangdong, China.
| | - Kangqi Ren
- Department of Thoracic Surgery, Shenzhen People's Hospital, 1st Affiliated Hospital of Southern University of Science and Technology, 2, Clinical Medical College of Jinan University, No.1017, East Gate Rd, Shenzhen, 518020, Guangdong, China
| | - Xiean Ling
- Department of Thoracic Surgery, Shenzhen People's Hospital, 1st Affiliated Hospital of Southern University of Science and Technology, 2, Clinical Medical College of Jinan University, No.1017, East Gate Rd, Shenzhen, 518020, Guangdong, China
| | - Zeyao Li
- Department of Thoracic Surgery, Shenzhen People's Hospital, 1st Affiliated Hospital of Southern University of Science and Technology, 2, Clinical Medical College of Jinan University, No.1017, East Gate Rd, Shenzhen, 518020, Guangdong, China
| | - Lin Chen
- Department of Thoracic Surgery, Shenzhen People's Hospital, 1st Affiliated Hospital of Southern University of Science and Technology, 2, Clinical Medical College of Jinan University, No.1017, East Gate Rd, Shenzhen, 518020, Guangdong, China
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Guo Y, Li Y, Li J, Cai H, Liu K, Duan D, Zhang W, Han G, Zhao Y. Controlled Inflammation Drives Neutrophil-Mediated Precision Drug Delivery in Heterogeneous Tumors. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2411307. [PMID: 39799561 PMCID: PMC11923894 DOI: 10.1002/advs.202411307] [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: 09/16/2024] [Revised: 12/05/2024] [Indexed: 01/15/2025]
Abstract
Tumor heterogeneity remains a formidable obstacle in targeted cancer therapy, often leading to suboptimal treatment outcomes. This study presents an innovative approach that harnesses controlled inflammation to guide neutrophil-mediated drug delivery, effectively overcoming the limitations imposed by tumor heterogeneity. By inducing localized inflammation within tumors using lipopolysaccharide, it significantly amplify the recruitment of drug-laden neutrophils to tumor sites, irrespective of specific tumor markers. This strategy not only enhances targeted drug delivery but also triggers the release of neutrophil extracellular traps, further potentiating the anti-tumor effect. Crucially, this study demonstrates that potential systemic inflammatory responses can be effectively mitigated through neutrophil transfusion, ensuring the safety and clinical viability of this approach. In a murine breast cancer model, the method significantly impedes tumor growth compared to conventional treatments. This work offers a versatile strategy for precise drug delivery across diverse tumor types. The findings pave the way for more effective and broadly applicable cancer treatments, potentially addressing the long-standing challenge of tumor heterogeneity.
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Affiliation(s)
- Yunfei Guo
- Department of RadiologyThe Second Hospital of Tianjin Medical UniversityTianjin300211P. R. China
| | - Yiming Li
- Department of RadiologyThe Second Hospital of Tianjin Medical UniversityTianjin300211P. R. China
| | - Jianmin Li
- Tianjin Institute of UrologyThe Second Hospital of Tianjin Medical UniversityTianjin300211P. R. China
| | - Haoran Cai
- Department of RadiologyThe Second Hospital of Tianjin Medical UniversityTianjin300211P. R. China
| | - Kangkang Liu
- Tianjin Institute of UrologyThe Second Hospital of Tianjin Medical UniversityTianjin300211P. R. China
| | - Dengyi Duan
- Department of RadiologyThe Second Hospital of Tianjin Medical UniversityTianjin300211P. R. China
| | - Wenyi Zhang
- Department of RadiologyThe Second Hospital of Tianjin Medical UniversityTianjin300211P. R. China
| | - Gang Han
- Biochemistry and Molecular BiotechnologyUniversity of Massachusetts Chan Medical SchoolWorcesterMA01605USA
| | - Yang Zhao
- Department of RadiologyThe Second Hospital of Tianjin Medical UniversityTianjin300211P. R. China
- Tianjin Institute of UrologyThe Second Hospital of Tianjin Medical UniversityTianjin300211P. R. China
- Biochemistry and Molecular BiotechnologyUniversity of Massachusetts Chan Medical SchoolWorcesterMA01605USA
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Zhao Y, Yuan C, Shi Y, Liu X, Luo L, Zhang L, Pešić M, Yao H, Li L. Drug screening approaches for small-molecule compounds in cancer-targeted therapy. J Drug Target 2025; 33:368-383. [PMID: 39575843 DOI: 10.1080/1061186x.2024.2427185] [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: 05/30/2024] [Revised: 09/30/2024] [Accepted: 10/27/2024] [Indexed: 02/08/2025]
Abstract
Small-molecule compounds exhibit distinct pharmacological properties and clinical effectiveness. Over the past decade, advances in covalent drug discovery have led to successful small-molecule drugs, such as EGFR, BTK, and KRAS (G12C) inhibitors, for cancer therapy. Researchers are paying more attention to refining drug screening methods aiming for high throughput, fast speed, high specificity, and accuracy. Therefore, the discovery and development of small-molecule drugs has been facilitated by significantly reducing screening time and financial resources, and increasing promising lead compounds compared with traditional methods. This review aims to introduce classical and emerging methods for screening small-molecule compounds in targeted cancer therapy. It includes classification, principles, advantages, disadvantages, and successful applications, serving as valuable references for subsequent researchers.
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Affiliation(s)
- Yelin Zhao
- State Key Laboratory of Respiratory Health and Multimorbidity, NHC Key Laboratory of Biotechnology for Microbial Drugs, Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chenyu Yuan
- State Key Laboratory of Respiratory Health and Multimorbidity, NHC Key Laboratory of Biotechnology for Microbial Drugs, Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuchen Shi
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Xiaohong Liu
- Guang'anmen Hospital, Chinese Academy of Chinese Medical Sciences, Xicheng District, Beijing, China
| | - Liaoxin Luo
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China
| | - Li Zhang
- State Key Laboratory of Respiratory Health and Multimorbidity, NHC Key Laboratory of Biotechnology for Microbial Drugs, Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Milica Pešić
- Department of Neurobiology, Institute for Biological Research, 'Siniša Stanković'- National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Hongjuan Yao
- State Key Laboratory of Respiratory Health and Multimorbidity, NHC Key Laboratory of Biotechnology for Microbial Drugs, Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Liang Li
- State Key Laboratory of Respiratory Health and Multimorbidity, NHC Key Laboratory of Biotechnology for Microbial Drugs, Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Zhang J, He S, Ying H. RETRACTED: Refining molecular subtypes and risk stratification of ovarian cancer through multi-omics consensus portfolio and machine learning. ENVIRONMENTAL TOXICOLOGY 2025; 40:E1-E16. [PMID: 38480676 DOI: 10.1002/tox.24222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 02/13/2024] [Accepted: 03/04/2024] [Indexed: 01/23/2025]
Abstract
Ovarian cancer (OC), known for its pronounced heterogeneity, has long evaded a unified classification system despite extensive research efforts. This study integrated five distinct multi-omics datasets from eight multicentric cohorts, applying a combination of ten clustering algorithms and ninety-nine machine learning models. This methodology has enabled us to refine the molecular subtyping of OC, leading to the development of a novel Consensus Machine Learning-driven Signature (CMLS). Our analysis delineated two prognostically significant cancer subtypes (CS), each marked by unique genetic and immunological signatures. Notably, CS1 is associated with an adverse prognosis. Leveraging a subtype classifier, we identified five key genes (CTHRC1, SPEF1, SCGB3A1, FOXJ1, and C1orf194) instrumental in constructing the CMLS. Patients classified within the high CMLS group exhibited a poorer prognosis and were characterized by a "cold tumor" phenotype, indicative of an immunosuppressive microenvironment rich in MDSCs, CAFs, and Tregs. Intriguingly, this group also presented higher levels of tumor mutation burden (TMB) and tumor neoantigen burden (TNB), factors that correlated with a more favorable response to immunotherapy compared to their low CMLS counterparts. In contrast, the low CMLS group, despite also displaying a "cold tumor" phenotype, showed a favorable prognosis and a heightened responsiveness to chemotherapy. This study's findings underscore the potential of targeting immune-suppressive cells, particularly in patients with high CMLS, as a strategic approach to enhance OC prognosis. Furthermore, the redefined molecular subtypes and risk stratification, achieved through sophisticated multi-omics analysis, provide a framework for the selection of therapeutic agents.
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Affiliation(s)
- Jing Zhang
- Department of Obstetrics and Gynecology, The Ningbo Women and Children's Hospital, Ningbo, China
| | - Shanshan He
- Department of Obstetrics and Gynecology, The Ningbo Women and Children's Hospital, Ningbo, China
| | - Hongjun Ying
- Department of Obstetrics and Gynecology, The Ningbo Women and Children's Hospital, Ningbo, China
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Wang S, Luo X. A First-Principles Study of Graphene and Graphene Oxide as Potential Tamoxifen Drug Delivery Vehicles for Breast Cancer. ACS OMEGA 2025; 10:5593-5600. [PMID: 39989753 PMCID: PMC11840592 DOI: 10.1021/acsomega.4c08517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Revised: 01/19/2025] [Accepted: 01/22/2025] [Indexed: 02/25/2025]
Abstract
Targeted therapy with tamoxifen is an effective method to treat breast cancer. This method requires competent drug delivery vehicles to ensure successful therapeutic practices. The stable adsorption between the drug and delivery vehicle is one of the essential components. Using first-principles calculations, the adsorption behaviors of tamoxifen on reduced graphene and graphene oxide were studied based on density functional theory. The results indicated that tamoxifen was weakly adsorbed on pristine graphene, while it was relatively strongly adsorbed on reduced graphene oxides. Our results concluded that among the systems of reduced graphene oxide with an oxygen concentration of 0%, 3.125%, and 12.5%, graphene sheets with oxygen were potential candidates for tamoxifen delivery vehicles for breast cancer targeted therapy, and graphene oxide with an oxygen concentration of 12.5% was the most promising one compared to other carbon-based vehicles.
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Affiliation(s)
- Suri Wang
- National Graphene Research
and Development Center, Springfield, Virginia 22151, United States
| | - Xuan Luo
- National Graphene Research
and Development Center, Springfield, Virginia 22151, United States
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Hua X, Xiang K, Liang A, Chang M, Jia S, Shang Z, Jiang Y, Liu X, Mao C. A novel peptide CP29L, selected from the phage displayed cyclic random heptapeptide library, demonstrates its potent inhibitory effects to liver cancer HCCLM3 cells by targeting FOXM1. Eur J Pharmacol 2025; 989:177246. [PMID: 39755244 DOI: 10.1016/j.ejphar.2024.177246] [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: 08/09/2024] [Revised: 12/24/2024] [Accepted: 12/30/2024] [Indexed: 01/06/2025]
Abstract
FOXM1 is the "Achilles' heel" of cancers and hence the potential therapeutic target for anticancer drug discovery. In this work, we selected high affinity peptides against the protein of human DNA binding domain of FOXM1 (FOXM1-DBD) from the disulfide-constrained, phage displayed random cyclic heptapeptide library Ph.D.-C7C. We obtained a novel peptide, 9 R-CP29L, which was identified to be a potent anticancer peptide with IC50 values of 9.0 and 11.1 μM at 24 h for HCCLM3 and MD-MBA-231 cells respectively. Molecular docking, CETSA, ITC and immunoblot assays demonstrated that 9 R-CP29L can potentially specifically bind to FOXM1-DBD with a Kd value of 1.25 μM and reduced the expression of FOXM1. In addition, Annexin V/PI flow cytometry, AO/EB staining, PI flow cytometry, clone formation and Transwell assays revealed that 9 R-CP29L also induced cell apoptosis and cell cycle arrest while inhibited the proliferation and migration of HCCLM3 cells. The findings were further supported by the results of qRT-PCR and immunoblot assays for the associated gene (CMYC, CDC25B, BAX, CASPASE3 and MMP2, etc) expression in HCCLM3 cells. Finally, in vivo experiment showed that 9 R-CP29 significantly reduced the tumor growth and downregulated the expression of FOXM1 in HCCLM3 xenograft nude mouse models. Taking together, our work provides a novel FOXM1 targeted peptide which has potential in both anticancer drug development and scientific researches.
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Affiliation(s)
- Xinyi Hua
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, Sichuan province, PR China; School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, Sichuan, PR China
| | - Kun Xiang
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, Sichuan province, PR China
| | - Anping Liang
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, Sichuan province, PR China; School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, Sichuan, PR China
| | - Miao Chang
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, Sichuan province, PR China
| | - Shijie Jia
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, Sichuan province, PR China
| | - Zhixian Shang
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, Sichuan province, PR China
| | - Yuhong Jiang
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, Sichuan province, PR China
| | - Xinrong Liu
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, Sichuan province, PR China
| | - Canquan Mao
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, Sichuan province, PR China.
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Lian Y, Sun J, Yang L, Yu W. A bibliometric and visualization analysis of the role of traditional Chinese medicine in cancer immunotherapy. Front Immunol 2025; 16:1499026. [PMID: 40028340 PMCID: PMC11868050 DOI: 10.3389/fimmu.2025.1499026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Accepted: 01/27/2025] [Indexed: 03/05/2025] Open
Abstract
Objective Traditional Chinese medicine (TCM) is used as a complementary treatment for patients with cancer, especially in immunotherapy. Although extensive clinical and basic research has been conducted on TCM in cancer immunotherapy, a comprehensive bibliometric analysis of this field has not yet been performed. This study aimed to investigate the progress and status of TCM, and the research focused on cancer immunotherapy. Methods We collected 1,657 articles on TCM in cancer immunotherapy from 1994 to 2024 from the Web of Science Core Collection database. VOSviewer, CiteSpace, and the Bibliometrix R package were used to analyze countries, institutions, journals, authors, references, and keywords to predict future trends in cancer immunotherapy with TCM. Results The publication rate of TCM in cancer immunotherapy research steadily increased from 1994 to 2018, with a swift growth from 2018 to 2023. China and TCM universities have achieved the most research advancements in this field. The most studied types of cancer are liver, lung, and colorectal cancers. However, few studies exist on upper respiratory tract tumors, cervical cancer, and melanoma, which deserve more attention. The study trend has gradually shifted from in vivo and in vitro models to clinical efficacy. Simultaneously, the focus of research transitioned from compound TCM preparations or classes of ingredients to specific pharmacodynamic ingredients, and the corresponding targets transitioned from cytokines to immune checkpoints. In general, molecular docking combined with multi-omics analysis is a popular and trending research method in TCM for cancer immunotherapy, helping researchers understand the mechanisms of TCM in cancer immunotherapy more comprehensively and accurately. By analyzing the literature, it is evident that TCM-based immunotherapy should contribute to effective maintenance or adjuvant therapy throughout the entire course of cancer rather than only in the late stages. Conclusion This study comprehensively summarized and identified research frontiers providing a reference for promoting the development of TCM immunotherapy preparations and guiding clinical practice. Consequently, more patients with cancer can benefit from immunotherapy.
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Affiliation(s)
- Yixiao Lian
- Department of Library, Peking University People’s Hospital, Beijing, China
| | - Jie Sun
- Department of Central Laboratory and Institute of Clinical Molecular Biology, Peking University People’s Hospital, Beijing, China
| | - Lin Yang
- Department of Library, Peking University People’s Hospital, Beijing, China
| | - Weidong Yu
- Department of Central Laboratory and Institute of Clinical Molecular Biology, Peking University People’s Hospital, Beijing, China
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Obst CS, Seifert R. Updated analysis of the prescription and evaluation of protein kinase inhibitors for oncology in Germany. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:1799-1813. [PMID: 39177786 PMCID: PMC11825581 DOI: 10.1007/s00210-024-03377-0] [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: 05/10/2024] [Accepted: 08/12/2024] [Indexed: 08/24/2024]
Abstract
A recent analysis from our group ( https://pubmed.ncbi.nlm.nih.gov/37014400/ ) has shown that the immense costs of the 20 protein kinase inhibitors for oncology approved from 2015 to 2019 are largely caused by drugs whose additional benefit has not been proven. We updated our analysis by adding the newly approved protein kinase inhibitors of the years 2020 and 2021. Based on the 2021 and 2022 Arzneiverordnungsreport (AVR), we expanded our analysis to include a total of nine protein kinase inhibitors newly approved by the European Medicines Agency (EMA) in 2020 and 2021. As a result, 29 protein kinase inhibitors were identified for an update of our analysis. For these 29 drugs, all additional benefit assessments published by the Gemeinsamer Bundesausschuss (GBA) were analyzed. The additional benefit assessments of the GBA were compared with the corresponding assessments of the European Society for Medical Oncology (ESMO), the Deutsche Gesellschaft für Hämatologie und Onkologie (DGHO, German Society for Hematology and Oncology) and the Arzneimittelkommission der deutschen Ärzteschaft (AkdÄ, Drug Commission of the German Medical Association). In addition, a total number of 91 drug advertisements published in the journal Oncology Research and Treatment in 2022 were analyzed. The number of protein kinase inhibitors for which no additional benefit can be found by the GBA is increasing, whereas the number of drugs for which a considerable additional benefit can be found is decreasing. Thus, in the current 2022 (re)assessment of additional benefit by the GBA, no additional benefit was identified for 50% of the drugs (2020, 46%). Nineteen percent were assessed with a minor additional benefit (2020, 18%) and also 19% with a considerable additional benefit (2020, 27%). For 12% of the drugs, the additional benefit could not be quantified by the GBA (2020, 9%). The benefit assessments by other medical societies often differ significantly from those of the GBA, mainly due to different evaluations of various endpoint parameters. In addition, more and more protein kinase inhibitors are being approved as orphan drugs. However, their additional benefit cannot be quantified by the GBA in most cases (78%). In 38% of the advertisements of an oncology journal, protein kinase inhibitors are promoted, which shows the pharmacoeconomic importance of these drugs. In summary, the current additional benefit assessment procedure in Germany is very questionable, and reforms are urgently needed to maintain the stability of the German healthcare system, which is being undermined by the high cost of medicines, particularly for drugs whose additional benefits have not been proven.
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Affiliation(s)
- Caecilia S Obst
- Institute of Pharmacology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany
| | - Roland Seifert
- Institute of Pharmacology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
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Andrysik Z, Espinosa JM. Harnessing p53 for targeted cancer therapy: new advances and future directions. Transcription 2025; 16:3-46. [PMID: 40031988 PMCID: PMC11970777 DOI: 10.1080/21541264.2025.2452711] [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: 11/28/2024] [Revised: 01/07/2025] [Accepted: 01/08/2025] [Indexed: 03/05/2025] Open
Abstract
The transcription factor p53 is the most frequently impaired tumor suppressor in human cancers. In response to various stress stimuli, p53 activates transcription of genes that mediate its tumor-suppressive functions. Distinctive characteristics of p53 outlined here enable a well-defined program of genes involved in cell cycle arrest, apoptosis, senescence, differentiation, metabolism, autophagy, DNA repair, anti-viral response, and anti-metastatic functions, as well as facilitating autoregulation within the p53 network. This versatile, anti-cancer network governed chiefly by a single protein represents an immense opportunity for targeted cancer treatment, since about half of human tumors retain unmutated p53. During the last two decades, numerous compounds have been developed to block the interaction of p53 with the main negative regulator MDM2. However, small molecule inhibitors of MDM2 only induce a therapeutically desirable apoptotic response in a limited number of cancer types. Moreover, clinical trials of the MDM2 inhibitors as monotherapies have not met expectations and have revealed hematological toxicity as a characteristic adverse effect across this drug class. Currently, combination treatments are the leading strategy for enhancing efficacy and reducing adverse effects of MDM2 inhibitors. This review summarizes efforts to identify and test therapeutics that work synergistically with MDM2 inhibitors. Two main types of drugs have emerged among compounds used in the following combination treatments: first, modulators of the p53-regulated transcriptome (including chromatin modifiers), translatome, and proteome, and second, drugs targeting the downstream pathways such as apoptosis, cell cycle arrest, DNA repair, metabolic stress response, immune response, ferroptosis, and growth factor signaling. Here, we review the current literature in this field, while also highlighting overarching principles that could guide target selection in future combination treatments.
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Affiliation(s)
- Zdenek Andrysik
- Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Joaquin M. Espinosa
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
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Karami Fath M, Najafiyan B, Morovatshoar R, Khorsandi M, Dashtizadeh A, Kiani A, Farzam F, Kazemi KS, Nabi Afjadi M. Potential promising of synthetic lethality in cancer research and treatment. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:1403-1431. [PMID: 39305329 DOI: 10.1007/s00210-024-03444-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Accepted: 09/08/2024] [Indexed: 02/14/2025]
Abstract
Cancer is a complex disease driven by multiple genetic changes, including mutations in oncogenes, tumor suppressor genes, DNA repair genes, and genes involved in cancer metabolism. Synthetic lethality (SL) is a promising approach in cancer research and treatment, where the simultaneous dysfunction of specific genes or pathways causes cell death. By targeting vulnerabilities created by these dysfunctions, SL therapies selectively kill cancer cells while sparing normal cells. SL therapies, such as PARP inhibitors, WEE1 inhibitors, ATR and ATM inhibitors, and DNA-PK inhibitors, offer a distinct approach to cancer treatment compared to conventional targeted therapies. Instead of directly inhibiting specific molecules or pathways, SL therapies exploit genetic or molecular vulnerabilities in cancer cells to induce selective cell death, offering benefits such as targeted therapy, enhanced treatment efficacy, and minimized harm to healthy tissues. SL therapies can be personalized based on each patient's unique genetic profile and combined with other treatment modalities to potentially achieve synergistic effects. They also broaden the effectiveness of treatment across different cancer types, potentially overcoming drug resistance and improving patient outcomes. This review offers an overview of the current understanding of SL mechanisms, advancements, and challenges, as well as the preclinical and clinical development of SL. It also discusses new directions and opportunities for utilizing SL in targeted therapy for anticancer treatment.
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Affiliation(s)
- Mohsen Karami Fath
- Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Behnam Najafiyan
- Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Morovatshoar
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Mahdieh Khorsandi
- Department of Biotechnology, Faculty of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Arash Kiani
- Student Research Committee, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Farnoosh Farzam
- Department of Biochemistry, Faculty of Biological Science, Tarbiat Modares University, Tehran, Iran
| | - Kimia Sadat Kazemi
- Faculty of Dentistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Mohsen Nabi Afjadi
- Department of Biochemistry, Faculty of Biological Science, Tarbiat Modares University, Tehran, Iran.
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Zhou CH, Zhang T, Yu J, Yu G, Cheng S, Wu H, Xu BX, Luo H, Tian XB. MMP13 as an effective target of an active trifluoromethyl quinazoline compound against osteosarcoma. Toxicol Appl Pharmacol 2025; 495:117204. [PMID: 39674349 DOI: 10.1016/j.taap.2024.117204] [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: 04/09/2024] [Revised: 12/01/2024] [Accepted: 12/10/2024] [Indexed: 12/16/2024]
Abstract
Osteosarcoma (OS) is a highly fatal malignant tumor with a high metastatic rate and poor prognosis. Matrix metalloproteinase-13 (MMP13) is involved in OS metastasis. Its increased expression is closely related to distant metastasis and poor prognosis. The trifluoromethyl quinazoline compound KZL-201 was designed and synthesized, and its inhibitory effect on the progression of OS cells was investigated. The aim of this study was to investigate the underlying mechanism of action of KZL-201 in OS using a combination of bioinformatics analysis, molecular biology, cytology, and zoology. The in vitro experiments showed that KZL-201 inhibited OS cell proliferation, invasion, and migration; KZL-201 induced apoptosis and arrested the cell cycle at the G2/M phase. The results of molecular docking, the cellular thermal shift assay, and gene silencing experiments showed that KZL-201 had a strong affinity for MMP13. KZL-201 inhibited the progression of 143B cells by regulating the TGF-β1/Smad2/3 pathway. Thus, MMP13 is an important target gene of KZL-201 in inhibiting 143B cell progression. The in vivo experiments showed that KZL-201 inhibited the growth of OS tissues and the expression of MMP13 in OS tissues. In summary, KZL-201 targeted MMP13 and inhibited its expression, consequently suppressing the progression of OS by regulating the TGF-β1/Smad2/3 pathway.
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Affiliation(s)
- Chang-Hua Zhou
- Department of Orthopedics, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China; State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; Clinical College of Guizhou Medical University, Guiyang 550004, China
| | - Ting Zhang
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; Clinical College of Guizhou Medical University, Guiyang 550004, China
| | - Jia Yu
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; Guizhou Natural Products Research Center, Guiyang 550014, China
| | - Gang Yu
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; Guizhou Natural Products Research Center, Guiyang 550014, China
| | - Sha Cheng
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; Guizhou Natural Products Research Center, Guiyang 550014, China
| | - Hui Wu
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; Guizhou Natural Products Research Center, Guiyang 550014, China
| | - Bi-Xue Xu
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; Guizhou Natural Products Research Center, Guiyang 550014, China.
| | - Heng Luo
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; Guizhou Natural Products Research Center, Guiyang 550014, China.
| | - Xiao-Bin Tian
- Department of Orthopedics, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China; Clinical College of Guizhou Medical University, Guiyang 550004, China.
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48
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Pérez-Navarro Y, Salinas-Vera YM, López-Camarillo C, Figueroa-Angulo EE, Alvarez-Sánchez ME. The role of long non-coding RNA NORAD in digestive system tumors. Noncoding RNA Res 2025; 10:55-62. [PMID: 39296642 PMCID: PMC11406672 DOI: 10.1016/j.ncrna.2024.09.002] [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: 07/18/2024] [Revised: 08/28/2024] [Accepted: 09/01/2024] [Indexed: 09/21/2024] Open
Abstract
In recent years, it has been discovered that the expression of long non-coding RNAs is highly deregulated in several types of cancer and contributes to its progression and development. Recently, it has been described that in tumors of the digestive system, such as colorectal cancer, pancreatic cancer, and gastric cancer, DNA damage-activated lncRNA (NORAD) was frequently up-regulated. The purpose of this review is to elucidate the functions of NORAD in tumors of the digestive system, emphasizing its involvement in important cellular processes such as invasion, metastasis, proliferation, and apoptosis. NORAD acts as a ceRNA (competitive endogenous RNA) that sponges microRNAs and regulates the expression of target genes involved in tumorigenesis. Thus, the mechanisms underlying the effects of NORAD are complex and involve multiple signaling pathways. This review consolidates current knowledge on the role of NORAD in digestive cancers and highlights the need for further research to explore its potential as a therapeutic target. Understanding the intricate functions of NORAD could elucidate the way for innovative approaches to cancer treatment.
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Affiliation(s)
- Yussel Pérez-Navarro
- Posgrado en Ciencias Genómicas, Laboratorio de Patogénesis Celular y Molecular Humana y Veterinaria, Universidad Autónoma de la Ciudad de México, Ciudad de México, CDMX, Mexico
| | - Yarely M. Salinas-Vera
- Centro Nacional de Identificación Humana, Comisión Nacional de Búsqueda, Secretaría de Gobernación, Camino a Santa Teresa No 1679, Jardines del Pedregal, Ciudad de México, Mexico
| | - Cesar López-Camarillo
- Posgrado en Ciencias Genómicas, Laboratorio de Oncogenómica y Proteómica del cáncer, Universidad Autónoma de la Ciudad de México, Ciudad de México, Mexico
| | - Elisa Elvira Figueroa-Angulo
- Licenciatura en Ciencias Genómicas, Laboratorio de Patogénesis Celular y Molecular Humana y Veterinaria, Universidad Autónoma de la Ciudad de México, Mexico
| | - María Elizbeth Alvarez-Sánchez
- Posgrado en Ciencias Genómicas, Laboratorio de Patogénesis Celular y Molecular Humana y Veterinaria, Universidad Autónoma de la Ciudad de México, Ciudad de México, CDMX, Mexico
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49
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Miranda-Vera C, Hernández ÁP, García-García P, Díez D, García PA, Castro MÁ. Bioconjugation of Podophyllotoxin and Nanosystems: Approaches for Boosting Its Biopharmaceutical and Antitumoral Profile. Pharmaceuticals (Basel) 2025; 18:169. [PMID: 40005983 PMCID: PMC11859694 DOI: 10.3390/ph18020169] [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: 12/10/2024] [Revised: 01/19/2025] [Accepted: 01/22/2025] [Indexed: 02/27/2025] Open
Abstract
Podophyllotoxin is a natural compound belonging to the lignan family and is well-known for its great antitumor activity. However, it shows several limitations, such as severe side effects and some pharmacokinetics problems, including low water solubility, which hinders its application as an anticancer agent. Over the past few years, antitumor research has been focused on developing nanotechnology-based medicines or nanomedicines which allow researchers to improve the pharmacokinetic properties of anticancer compounds. Following this trend, podophyllotoxin nanoconjugates have been obtained to overcome its biopharmaceutical drawbacks and to enhance its antitumor properties. The objective of this review is to highlight the advances made over the past few years (2017-2023) regarding the inclusion of podophyllotoxin in different nanosystems. Among the huge variety of nanoconjugates of diverse nature, drug delivery systems bearing podophyllotoxin as cytotoxic payload are organic nanoparticles mainly based on polymer carriers, micelles, and liposomes. Along with the description of their pharmacological properties as antitumorals and the advantages compared to the free drug in terms of biocompatibility, solubility, and selectivity, we also provide insight into the synthetic procedures developed to obtain those podophyllotoxin-nanocarriers. Typical procedures in this regard are self-assembly techniques, nanoprecipitations, or ionic gelation methods among others. This comprehensive perspective aims to enlighten the medicinal chemistry community about the tendencies followed in the design of new podophyllotoxin-based drug delivery systems, their features and applications.
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Affiliation(s)
- Carolina Miranda-Vera
- Laboratorio de Química Farmacéutica, Departamento de Ciencias Farmacéuticas, CIETUS, IBSAL, Facultad de Farmacia, Campus Miguel de Unamuno, Universidad de Salamanca, 37007 Salamanca, Spain; (C.M.-V.); (Á.-P.H.); (P.G.-G.); (P.A.G.)
| | - Ángela-Patricia Hernández
- Laboratorio de Química Farmacéutica, Departamento de Ciencias Farmacéuticas, CIETUS, IBSAL, Facultad de Farmacia, Campus Miguel de Unamuno, Universidad de Salamanca, 37007 Salamanca, Spain; (C.M.-V.); (Á.-P.H.); (P.G.-G.); (P.A.G.)
| | - Pilar García-García
- Laboratorio de Química Farmacéutica, Departamento de Ciencias Farmacéuticas, CIETUS, IBSAL, Facultad de Farmacia, Campus Miguel de Unamuno, Universidad de Salamanca, 37007 Salamanca, Spain; (C.M.-V.); (Á.-P.H.); (P.G.-G.); (P.A.G.)
| | - David Díez
- Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad de Salamanca, 37008 Salamanca, Spain;
| | - Pablo A. García
- Laboratorio de Química Farmacéutica, Departamento de Ciencias Farmacéuticas, CIETUS, IBSAL, Facultad de Farmacia, Campus Miguel de Unamuno, Universidad de Salamanca, 37007 Salamanca, Spain; (C.M.-V.); (Á.-P.H.); (P.G.-G.); (P.A.G.)
| | - María Ángeles Castro
- Laboratorio de Química Farmacéutica, Departamento de Ciencias Farmacéuticas, CIETUS, IBSAL, Facultad de Farmacia, Campus Miguel de Unamuno, Universidad de Salamanca, 37007 Salamanca, Spain; (C.M.-V.); (Á.-P.H.); (P.G.-G.); (P.A.G.)
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50
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Yang Y, Zheng W, Zhang J, Guo J, Liu Q, Wang H, Xu F, Bao Z. Integrating Photothermal, Photodynamic, and Chemodynamic Therapies: The Innovative Design Based on Copper Sulfide Nanoparticles for Enhanced Tumor Therapy. ACS APPLIED BIO MATERIALS 2025; 8:676-687. [PMID: 39829270 DOI: 10.1021/acsabm.4c01538] [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: 01/22/2025]
Abstract
A multifunctional nanoplatform integrating multiple therapeutic functions may be an effective strategy to realize satisfactory therapeutic efficacy in the treatment of tumors. However, there is still a certain challenge in integrating multiple therapeutic agents into a single formulation using a simple method due to variations in their properties. In this work, multifunctional CuS-ICG@PDA-FA nanoparticles (CIPF NPs) with excellent ability to produce reactive oxygen species and photothermal conversion performance are fabricated by a simple and gentle method. Hollow mesoporous copper sulfide nanoparticles (HMCuS NPs) not only have excellent loading and photothermal conversion performance but also can cause a highly efficient Fenton-like reaction for chemodynamic therapy (CDT). The loaded photosensitizer indocyanine green (ICG) imparts excellent photodynamic properties to the NPs, which in turn enhances the stability of ICG. The polydopamine (PDA) coating improves the stability and biocompatibility of the NPs and creates the conditions for surface modification of folic acid. The FA-coated NPs show precise targeting of tumor cells. The results of the cellular uptake assay demonstrate that CIPF NPs enter tumor cells through an endocytic pathway. Lysosome colocalization and escape experiments prove that CIPF NPs possess good lysosomal escape ability under irradiation of NIR. Both in vitro and in vivo antitumor studies of CIPF NPs reveal excellent efficacy in photothermal/photodynamic/chemodynamic therapy. The construction of high-performance CIPF NPs offers valuable insights into the design of a multifunctional copper sulfide-based nanoplatform for combined cancer treatment and precise theranostics.
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Affiliation(s)
- Yue Yang
- School of Pharmacy, Shenyang Key Laboratory of Functional Drug Carrier Materials, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Wen Zheng
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Jiabao Zhang
- School of Pharmacy, Shenyang Key Laboratory of Functional Drug Carrier Materials, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Jiangxue Guo
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Qian Liu
- School of Pharmacy, Shenyang Key Laboratory of Functional Drug Carrier Materials, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Hanyang Wang
- School of Pharmacy, Shenyang Key Laboratory of Functional Drug Carrier Materials, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Fanxing Xu
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Zhihong Bao
- School of Pharmacy, Shenyang Key Laboratory of Functional Drug Carrier Materials, Shenyang Pharmaceutical University, Shenyang 110016, China
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