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1
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Xiao ZW, Zeng YC, Ji LT, Yuan JT, Li L. Nitric oxide synthase 1 inhibits the progression of esophageal cancer through interacting with nitric oxide synthase 1 adaptor protein. World J Gastrointest Oncol 2025; 17:103843. [DOI: 10.4251/wjgo.v17.i4.103843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 01/22/2025] [Accepted: 02/17/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND Esophageal cancer (ESCA) is among the most prevalent and lethal tumors globally. While nitric oxide synthase 1 (NOS1) is recognized for its important involvement in various cancers, its specific function in ESCA remains unclear.
AIM To explore the potential role and underlying mechanisms of NOS1 in ESCA.
METHODS Survival rates were analyzed using GeneCards and Gene Expression Profiling Interactive Analysis. The effects and mechanisms of NOS1 on ESCA cells were evaluated via the Cell Counting Kit-8 assay, scratch assay, Transwell assay, flow cytometry, quantitative polymerase chain reaction, western blotting, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling staining. The protein interaction network was used to screen the interacting proteins of NOS1 and validate these interactions through co-immunoprecipitation and dual luciferase assays. Additionally, a nude mouse xenograft model was established to evaluate the effect of NOS1 in vivo.
RESULTS The survival rate of patients with ESCA with high NOS1 expression was higher than that of patients with low NOS1 expression. NOS1 expression in ESCA cell lines was lower than that in normal esophageal epithelial cells. Overexpression of NOS1 (oe-NOS1) inhibited proliferation, invasion, and migration abilities in ESCA cell lines, resulting in decreased autophagy levels and increased apoptosis, pyroptosis, and ferroptosis. Protein interaction studies confirmed the interaction between NOS1 and NOS1 adaptor protein (NOS1AP). Following oe-NOS1 and the silencing of NOS1AP, levels of P62 and microtubule-associated protein 1 light chain 3 beta increased both in vitro and in vivo. Furthermore, the expression levels of E-cadherin, along with the activation of phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT), were inhibited in ESCA cell lines.
CONCLUSION NOS1 and NOS1 proteins interact to suppress autophagy, activate the PI3K/AKT pathway, and exert anti-cancer effects in ESCA.
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Affiliation(s)
- Zi-Wei Xiao
- College of Medical, Hunan Normal University, Changsha 410081, Hunan Province, China
| | - Ying-Chao Zeng
- College of Medical, Hunan Normal University, Changsha 410081, Hunan Province, China
| | - Lin-Tao Ji
- College of Medical, Hunan Normal University, Changsha 410081, Hunan Province, China
| | - Jia-Tao Yuan
- College of Medical, Hunan Normal University, Changsha 410081, Hunan Province, China
| | - Lin Li
- College of Medical, Hunan Normal University, Changsha 410081, Hunan Province, China
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2
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Tang Q, Ren T, Bai P, Wang X, Zhao L, Zhong R, Sun G. Novel strategies to overcome chemoresistance in human glioblastoma. Biochem Pharmacol 2024; 230:116588. [PMID: 39461382 DOI: 10.1016/j.bcp.2024.116588] [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: 06/30/2024] [Revised: 10/16/2024] [Accepted: 10/21/2024] [Indexed: 10/29/2024]
Abstract
Temozolomide (TMZ) is currently the first-line chemotherapeutic agent for the treatment of glioblastoma multiforme (GBM). However, the inherent heterogeneity of GBM often results in suboptimal outcomes, particularly due to varying degrees of resistance to TMZ. Over the past several decades, O6-methylguanine-DNA methyltransferase (MGMT)-mediated DNA repair pathway has been extensively investigated as a target to overcome TMZ resistance. Nonetheless, the combination of small molecule covalent MGMT inhibitors with TMZ and other chemotherapeutic agents has frequently led to adverse clinical effects. Recently, additional mechanisms contributing to TMZ resistance have been identified, including epidermal growth factor receptor (EGFR) mutations, overactivation of intracellular signalling pathways, energy metabolism reprogramming or survival autophagy, and changes in tumor microenvironment (TME). These findings suggest that novel therapeutic strategies targeting these mechanisms hold promise for overcoming TMZ resistance in GBM patients. In this review, we summarize the latest advancements in understanding the mechanisms underlying intrinsic and acquired TMZ resistance. Additionally, we compile various small-molecule compounds with potential to mitigate chemoresistance in GBM. These mechanism-based compounds may enhance the sensitivity of GBM to TMZ and related chemotherapeutic agents, thereby improving overall survival rates in clinical practice.
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Affiliation(s)
- Qing Tang
- Beijing Key Laboratory of Environmental and Viral Oncology, College of Chemistry and Life Science, Beijing University of Technology, Beijing 100124, China
| | - Ting Ren
- Beijing Key Laboratory of Environmental and Viral Oncology, College of Chemistry and Life Science, Beijing University of Technology, Beijing 100124, China
| | - Peiying Bai
- Beijing Key Laboratory of Environmental and Viral Oncology, College of Chemistry and Life Science, Beijing University of Technology, Beijing 100124, China
| | - Xin Wang
- Department of Clinical Trials Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100029, China
| | - Lijiao Zhao
- Beijing Key Laboratory of Environmental and Viral Oncology, College of Chemistry and Life Science, Beijing University of Technology, Beijing 100124, China
| | - Rugang Zhong
- Beijing Key Laboratory of Environmental and Viral Oncology, College of Chemistry and Life Science, Beijing University of Technology, Beijing 100124, China
| | - Guohui Sun
- Beijing Key Laboratory of Environmental and Viral Oncology, College of Chemistry and Life Science, Beijing University of Technology, Beijing 100124, China.
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3
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Zhang X, Shao S, Song N, Yang B, Liu F, Tong Z, Wang F, Li J. Integrated omics characterization reveals reduced cancer indicators and elevated inflammatory factors after thermal ablation in non-small cell lung cancer patients. Respir Res 2024; 25:309. [PMID: 39143582 PMCID: PMC11325606 DOI: 10.1186/s12931-024-02917-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2024] [Accepted: 07/15/2024] [Indexed: 08/16/2024] Open
Abstract
BACKGROUND Thermal ablation is a minimally invasive treatment for non-small cell lung cancer (NSCLC). Aside from causing an immediate direct tumour cell injury, the effects of thermal ablation on the internal microenvironment are unknown. This study aimed to investigate the effects of thermal ablation on the plasma internal environment in patients with NSCLC. METHODS 128 plasma samples were collected from 48 NSCLC (pre [LC] and after thermal ablation [LC-T]) patients and 32 healthy controls (HCs). Olink proteomics and metabolomics were utilized to construct an integrated landscape of the cancer-related immune and inflammatory responses after ablation. RESULTS Compared with HCs, LC patients exhibited 58 differentially expressed proteins (DEPs) and 479 differentially expressed metabolites (DEMs), which might participate in tumour progression and metastasis. Moreover, 75 DEPs were identified among the HC, LC, and LC-T groups. Forty-eight highly expressed DEPs (eg, programmed death-ligand 1 [PD-L1]) in the LC group were found to be downregulated after thermal ablation. These DEPs had significant impacts on pathways such as angiogenesis, immune checkpoint blockade, and pro-tumour chemotaxis. Metabolites involved in tumour cell survival were associated with these proteins at the expression and functional levels. In contrast, 19 elevated proteins (eg, interleukin [IL]-6) were identified after thermal ablation. These proteins were mainly associated with inflammatory response pathways (NF-κB signalling and tumour necrosis factor signalling) and immune cell activation. CONCLUSIONS Thermal ablation-induced changes in the host plasma microenvironment contribute to anti-tumour immunity in NSCLC, offering new insights into tumour ablation combined with immunotherapy. Trial registration This study was registered on the Chinese Clinical Trial Registry ( https://www.chictr.org.cn/index.html ). ID: ChiCTR2300076517. Registration Date: 2023-10-11.
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Affiliation(s)
- Xinglu Zhang
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, No. 8 Gongti South Road, Beijing, 100020, Chaoyang District, China
| | - Shuai Shao
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, No. 8 Gongti South Road, Beijing, 100020, Chaoyang District, China
| | - Nan Song
- Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Baolu Yang
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, No. 8 Gongti South Road, Beijing, 100020, Chaoyang District, China
| | - Fengjiao Liu
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, No. 8 Gongti South Road, Beijing, 100020, Chaoyang District, China
| | - Zhaohui Tong
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, No. 8 Gongti South Road, Beijing, 100020, Chaoyang District, China.
- Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
| | - Feng Wang
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, No. 8 Gongti South Road, Beijing, 100020, Chaoyang District, China.
| | - Jieqiong Li
- Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
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Pathak A, Palasalava S, Knott MV, Colon B, Ciervo E, Zhou Y, Mitchell J, Pumar OT, Wong HKA, Zhang L, Susic N, Shah KH, Kay K, Chin D, Johnson S, Cheng F, Lyssiotis CA, Watson DC, Ceccarelli M, Shah A, Wahl DR, Lathia JD, Bayik D. γ-aminobutyric acid receptor B signaling drives glioblastoma in females in an immune-dependent manner. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.18.603996. [PMID: 39091833 PMCID: PMC11291093 DOI: 10.1101/2024.07.18.603996] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/04/2024]
Abstract
Sex differences in immune responses impact cancer outcomes and treatment response, including in glioblastoma (GBM). However, host factors underlying sex specific immune-cancer interactions are poorly understood. Here, we identify the neurotransmitter γ-aminobutyric acid (GABA) as a driver of GBM-promoting immune response in females. We demonstrated that GABA receptor B (GABBR) signaling enhances L-Arginine metabolism and nitric oxide synthase 2 (NOS2) expression in female granulocytic myeloid-derived suppressor cells (gMDSCs). GABBR agonist and GABA analog promoted GBM growth in females in an immune-dependent manner, while GABBR inhibition reduces gMDSC NOS2 production and extends survival only in females. Furthermore, female GBM patients have enriched GABA transcriptional signatures compared to males, and the use of GABA analogs in GBM patients is associated with worse short-term outcomes only in females. Collectively, these results highlight that GABA modulates anti-tumor immune response in a sex-specific manner, supporting future assessment of GABA pathway inhibitors as part of immunotherapy approaches.
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Affiliation(s)
- Asmita Pathak
- Department of Molecular & Cellular Pharmacology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA
| | - Sravya Palasalava
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA
| | - Maxon V Knott
- Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
- Department of Neurosurgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL
| | - Bruno Colon
- Department of Molecular & Cellular Pharmacology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Erika Ciervo
- Università degli Studi di Napoli Federico II, Napoli, ITALY
| | - Yadi Zhou
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Jonathan Mitchell
- Department of Molecular & Cellular Pharmacology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
- Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Oriana Teran Pumar
- Department of Molecular & Cellular Pharmacology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA
| | - Harrison K A Wong
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
| | - Li Zhang
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
| | - Nikola Susic
- Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
| | | | - Kristen Kay
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Diana Chin
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Sadie Johnson
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Feixiong Cheng
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- Case Comprehensive Cancer Center, Cleveland, OH, USA
| | | | - Dionysios C Watson
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA
- Department of Molecular Oncology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL
| | - Michele Ceccarelli
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA
| | - Ashish Shah
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA
- Department of Neurosurgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL
| | - Daniel R Wahl
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
| | - Justin D Lathia
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- Case Comprehensive Cancer Center, Cleveland, OH, USA
- Rose Ella Burkhardt Brain Tumor & Neuro-Oncology Center, Cleveland Clinic, Cleveland, OH, USA
| | - Defne Bayik
- Department of Molecular & Cellular Pharmacology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA
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Sun C, Wang S, Ma Z, Zhou J, Ding Z, Yuan G, Pan Y. Neutrophils in glioma microenvironment: from immune function to immunotherapy. Front Immunol 2024; 15:1393173. [PMID: 38779679 PMCID: PMC11109384 DOI: 10.3389/fimmu.2024.1393173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 04/25/2024] [Indexed: 05/25/2024] Open
Abstract
Glioma is a malignant tumor of the central nervous system (CNS). Currently, effective treatment options for gliomas are still lacking. Neutrophils, as an important member of the tumor microenvironment (TME), are widely distributed in circulation. Recently, the discovery of cranial-meningeal channels and intracranial lymphatic vessels has provided new insights into the origins of neutrophils in the CNS. Neutrophils in the brain may originate more from the skull and adjacent vertebral bone marrow. They cross the blood-brain barrier (BBB) under the action of chemokines and enter the brain parenchyma, subsequently migrating to the glioma TME and undergoing phenotypic changes upon contact with tumor cells. Under glycolytic metabolism model, neutrophils show complex and dual functions in different stages of cancer progression, including participation in the malignant progression, immune suppression, and anti-tumor effects of gliomas. Additionally, neutrophils in the TME interact with other immune cells, playing a crucial role in cancer immunotherapy. Targeting neutrophils may be a novel generation of immunotherapy and improve the efficacy of cancer treatments. This article reviews the molecular mechanisms of neutrophils infiltrating the central nervous system from the external environment, detailing the origin, functions, classifications, and targeted therapies of neutrophils in the context of glioma.
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Affiliation(s)
- Chao Sun
- The Second Clinical Medical School, Lanzhou University, Lanzhou, China
- Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, China
- Key Laboratory of Neurology of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
| | - Siwen Wang
- The Second Clinical Medical School, Lanzhou University, Lanzhou, China
| | - Zhen Ma
- The Second Clinical Medical School, Lanzhou University, Lanzhou, China
- Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, China
- Key Laboratory of Neurology of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
| | - Jinghuan Zhou
- The Second Clinical Medical School, Lanzhou University, Lanzhou, China
- Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, China
- Key Laboratory of Neurology of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
| | - Zilin Ding
- The Second Clinical Medical School, Lanzhou University, Lanzhou, China
- Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, China
- Key Laboratory of Neurology of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
| | - Guoqiang Yuan
- The Second Clinical Medical School, Lanzhou University, Lanzhou, China
- Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, China
- Key Laboratory of Neurology of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
| | - Yawen Pan
- The Second Clinical Medical School, Lanzhou University, Lanzhou, China
- Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, China
- Key Laboratory of Neurology of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
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Wang K, Xiao Y, Zheng R, Cheng Y. Immune cell infiltration and drug response in glioblastoma multiforme: insights from oxidative stress-related genes. Cancer Cell Int 2024; 24:123. [PMID: 38566075 PMCID: PMC10986133 DOI: 10.1186/s12935-024-03316-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Accepted: 03/27/2024] [Indexed: 04/04/2024] Open
Abstract
BACKGROUND GBM, also known as glioblastoma multiforme, is the most prevalent and lethal type of brain cancer. The cell proliferation, invasion, angiogenesis, and treatment of gliomas are significantly influenced by oxidative stress. Nevertheless, the connection between ORGs and GBM remains poorly comprehended. The objective of this research is to investigate the predictive significance of ORGs in GBM and their potential as targets for therapy. METHODS We identified differentially expressed genes in glioma and ORGs from public databases. A risk model was established using LASSO regression and Cox analysis, and its performance was evaluated with ROC curves. We then performed consistent cluster analysis on the model, examining its correlation with immunity and drug response. Additionally, PCR, WB and IHC were employed to validate key genes within the prognostic model. RESULTS 9 ORGs (H6PD, BMP2, SPP1, HADHA, SLC25A20, TXNIP, ACTA1, CCND1, EEF1A1) were selected via differential expression analysis, LASSO and Cox analysis, and incorporated into the risk model with high predictive accuracy. Enrichment analyses using GSVA and GSEA focused predominantly on malignancy-associated pathways. Subtype C of GBM had the best prognosis with the lowest risk score. Furthermore, the model exhibited a strong correlation with the infiltration of immune cells and had the capability to pinpoint potential targeted therapeutic medications for GBM. Ultimately, we selected HADHA for in vitro validation. The findings indicated that GBM exhibits a significant upregulation of HADHA. Knockdown of HADHA inhibited glioma cell proliferation and diminished their migration and invasion capacities and influenced the tumor growth in vivo. CONCLUSION The risk model, built upon 9 ORGs and the identification of GBM subtypes, suggests that ORGs have a broad application prospect in the clinical immunotherapy and targeted drug treatment of GBM. HADHA significantly influences the development of gliomas, both in vivo and in vitro.
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Affiliation(s)
- Kan Wang
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin City, 150001, Heilongjiang Province, China
| | - Yifei Xiao
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin City, 150001, Heilongjiang Province, China
| | - Ruipeng Zheng
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin City, 150001, Heilongjiang Province, China
| | - Yu Cheng
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin City, 150001, Heilongjiang Province, China.
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7
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Du K, Li X, Feng F. Polymer-Drug Conjugates Codeliver a Temozolomide Intermediate and Nitric Oxide for Enhanced Chemotherapy against Glioblastoma Multiforme. ACS APPLIED BIO MATERIALS 2024; 7:1810-1819. [PMID: 38403964 DOI: 10.1021/acsabm.3c01219] [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: 02/27/2024]
Abstract
Polymer-drug conjugates (PDCs) provide possibilities for the development of multiresponsive drug delivery and release platforms utilized in cancer therapy. The delivery of Temozolomide (TMZ, a DNA methylation agent) by PDCs has been developed to improve TMZ stability under physiological conditions for the treatment of glioblastoma multiforme (GBM); however, with inefficient chemotherapeutic efficacy. In this work, we synthesized an amphiphilic triblock copolymer (P1-SNO) with four pendant functionalities, including (1) a TMZ intermediate (named MTIC) as a prodrug moiety, (2) a disulfide bond as a redox-responsive trigger to cage MTIC, (3) S-nitrosothiol as a light/heat-responsive donor of nitric oxide (NO), and (4) a poly(ethylene glycol) chain to enable self-assembly in aqueous media. P1-SNO was demonstrated to liberate MTIC in the presence of reduced glutathione and release gaseous NO upon exposure to light or heat. The in vitro results revealed a synergistic effect of released MTIC and NO on both TMZ-sensitive and TMZ-resistant GBM cells. The environment-responsive PDC system for codelivery of MTIC and NO is promising to overcome the efficacy issue in TMZ-based cancer therapy.
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Affiliation(s)
- Ke Du
- MOE Key Laboratory of High Performance Polymer Materials and Technology, and Department of Polymer Science & Engineering, School of Chemistry & Chemical Engineering, Nanjing University, Nanjing 210023, China
| | - Xiao Li
- Hunan Provincial Key Laboratory of Environmental Catalysis & Waste Regeneration, College of Materials and Chemical Engineering, Hunan Institute of Engineering, Xiangtan 411104, Hunan, China
| | - Fude Feng
- MOE Key Laboratory of High Performance Polymer Materials and Technology, and Department of Polymer Science & Engineering, School of Chemistry & Chemical Engineering, Nanjing University, Nanjing 210023, China
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Abdel-Wahab ND, Kabil MF, El-Sherbiny IM, Salama MF, El-Sayed G, El-Sherbini ES. Potential anticancer effect of free and nanoformulated Deferasirox for breast cancer treatment: in-vitro and in-vivo evaluation. Drug Dev Ind Pharm 2024; 50:223-235. [PMID: 38305197 DOI: 10.1080/03639045.2024.2314189] [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: 01/12/2024] [Accepted: 01/30/2024] [Indexed: 02/03/2024]
Abstract
BACKGROUND Breast cancer (BC) stands as the second-leading cause of mortality among women worldwide. Many chemotherapeutic treatments for BC come with significant adverse effects. Additionally, BC is recognized as one of the most resistant forms of malignancy to treatment. Consequently, there exists a critical need for innovative therapeutic agents that are both highly effective and exhibit reduced toxicity and side effects for patients. Deferasirox (DFX), an iron-chelating drug approved by the FDA for oral use, emerges as a promising contender in the fight against BC proliferation. DFX, primarily administered orally, is utilized to address chronic iron excess resulting from blood transfusions, and it is the inaugural treatment for chronic iron overload syndrome. However, DFX encounters limitations due to its poor water solubility. AIM This study aimed at incorporating DFX into lipid nanocapsules (DFX-LNCs) followed by investigating the anticancer effect of the DFX nanoform as compared to free DFX in-vitro and on an orthotopic BC mouse model in-vivo. METHODS The DFX-LNCs was prepared and imaged using TEM and also characterized in terms of particle size (PS), zeta potential (ZP), and polydispersity index (PDI) using DLS. Moreover, drug release, cytotoxicity, and anticancer effect were assessed in-vitro, and in-vivo. RESULTS The results revealed that DFX-LNCs are more cytotoxic than free DFX with IC50 of 4.417 µg/ml and 16.114 µg/ml, respectively, while the plain LNCs didn't show any cytotoxic effect on the 4T1 cell line (IC50 = 122.797 µg/ml). Besides, the apoptotic effect of DFX-LNCs was more pronounced than that of free DFX, as evidenced by Annexin V/PI staining, increased BAX expression, and decreased expression of BcL-2. Moreover, DFX-LNCs showed a superior antitumor effect in-vivo with potent antioxidant and anti-proliferative effects. CONCLUSION The newly developed DFX nanoform demonstrated a high potential as a promising therapeutic agent for BC treatment.
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Affiliation(s)
- Nadeen Diaa Abdel-Wahab
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Mansoura University, Egypt
| | - Mohamed Fawzi Kabil
- Nanomedicine Research Labs, Center for Materials Science, Zewail City of Science and Technology, Giza, Egypt
| | - Ibrahim M El-Sherbiny
- Nanomedicine Research Labs, Center for Materials Science, Zewail City of Science and Technology, Giza, Egypt
| | - Mohamed F Salama
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Mansoura University, Egypt
| | - Gehad El-Sayed
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Mansoura University, Egypt
| | - El-Said El-Sherbini
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Mansoura University, Egypt
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9
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Jia W, Gong X, Ye Z, Li N, Zhan X. Nitroproteomics is instrumental for stratification and targeted treatments of astrocytoma patients: expert recommendations for advanced 3PM approach with improved individual outcomes. EPMA J 2023; 14:673-696. [PMID: 38094577 PMCID: PMC10713973 DOI: 10.1007/s13167-023-00348-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 11/11/2023] [Indexed: 12/05/2024]
Abstract
Protein tyrosine nitration is a selectively and reversible important post-translational modification, which is closely related to oxidative stress. Astrocytoma is the most common neuroepithelial tumor with heterogeneity and complexity. In the past, the diagnosis of astrocytoma was based on the histological and clinical features, and the treatment methods were nothing more than surgery-assisted radiotherapy and chemotherapy. Obviously, traditional methods short falls an effective treatment for astrocytoma. In late 2021, the World Health Organization (WHO) adopted molecular biomarkers in the comprehensive diagnosis of astrocytoma, such as IDH-mutant and DNA methylation, which enabled the risk stratification, classification, and clinical prognosis prediction of astrocytoma to be more correct. Protein tyrosine nitration is closely related to the pathogenesis of astrocytoma. We hypothesize that nitroproteome is significantly different in astrocytoma relative to controls, which leads to establishment of nitroprotein biomarkers for patient stratification, diagnostics, and prediction of disease stages and severity grade, targeted prevention in secondary care, treatment algorithms tailored to individualized patient profile in the framework of predictive, preventive, and personalized medicine (PPPM; 3P medicine). Nitroproteomics based on gel electrophoresis and tandem mass spectrometry is an effective tool to identify the nitroproteins and effective biomarkers in human astrocytomas, clarifying the biological roles of oxidative/nitrative stress in the pathophysiology of astrocytomas, functional characteristics of nitroproteins in astrocytomas, nitration-mediated signal pathway network, and early diagnosis and treatment of astrocytomas. The results finds that these nitroproteins are enriched in mitotic cell components, which are related to transcription regulation, signal transduction, controlling subcellular organelle events, cell perception, maintaining cell homeostasis, and immune activity. Eleven statistically significant signal pathways are identified in astrocytoma, including remodeling of epithelial adherens junctions, germ cell-sertoli cell junction signaling, 14-3-3-mediated signaling, phagosome maturation, gap junction signaling, axonal guidance signaling, assembly of RNA polymerase III complex, and TREM1 signaling. Furthermore, protein tyrosine nitration is closely associated with the therapeutic effects of protein drugs, and molecular mechanism and drug targets of cancer. It provides valuable data for studying the protein nitration biomarkers, molecular mechanisms, and therapeutic targets of astrocytoma towards PPPM (3P medicine) practice. Supplementary Information The online version contains supplementary material available at 10.1007/s13167-023-00348-y.
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Affiliation(s)
- Wenshuang Jia
- Medical Science and Technology Innovation Center, Shandong Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, 440 Jiyan Road, Jinan, Shandong 250117 People’s Republic of China
| | - Xiaoxia Gong
- Medical Science and Technology Innovation Center, Shandong Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, 440 Jiyan Road, Jinan, Shandong 250117 People’s Republic of China
| | - Zhen Ye
- Medical Science and Technology Innovation Center, Shandong Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, 440 Jiyan Road, Jinan, Shandong 250117 People’s Republic of China
| | - Na Li
- Medical Science and Technology Innovation Center, Shandong Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, 440 Jiyan Road, Jinan, Shandong 250117 People’s Republic of China
| | - Xianquan Zhan
- Medical Science and Technology Innovation Center, Shandong Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, 440 Jiyan Road, Jinan, Shandong 250117 People’s Republic of China
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10
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Kruglyakov D, Ojha SK, Kartawy M, Tripathi MK, Hamoudi W, Bazbaz W, Khaliulin I, Amal H. Nitric Oxide Synthase Inhibition Prevents Cell Proliferation in Glioblastoma. J Mol Neurosci 2023; 73:875-883. [PMID: 37843719 DOI: 10.1007/s12031-023-02166-3] [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: 09/07/2023] [Accepted: 10/03/2023] [Indexed: 10/17/2023]
Abstract
Glioblastoma multiforme (GBM) is a prevalent and aggressive primary brain tumor, presenting substantial treatment challenges and high relapse rates. GBM is characterized by alterations in molecular signaling and enzyme expression within malignant cells. This tumor exhibits elevated nitric oxide (NO.) levels. NO. is a crucial signaling molecule involved in the regulation of neuronal functions, synaptic transmission, and cell proliferation. It is primarily synthesized from L-arginine by nitric oxide synthase (NOS) enzymes. The increased levels of NO. in GBM stem from dysregulated activity and expression of clinically relevant NOS isoforms, particularly inducible NOS (iNOS) and neuronal NOS (nNOS). Based on this knowledge, we hypothesize that targeted pharmacological intervention with N6-(1-iminoethyl)-L-lysine (L-NIL), an iNOS inhibitor, and 7-Nitroindazole (7-NI), an nNOS inhibitor, may suggest a promising therapeutic strategy for the treatment of GBM. To test our hypothesis, we utilized the U87-MG cell line as an in vitro model of GBM. Our results showed that treatment with L-NIL and 7-NI led to a reduction in NO. levels, NOS activity, and clonogenic proliferation in U87-MG cells. These findings suggest that NO. and NOS enzymes might be prospective therapeutic targets for GBM.
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Affiliation(s)
- Daniel Kruglyakov
- Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Shashank Kumar Ojha
- Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Maryam Kartawy
- Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Manish Kumar Tripathi
- Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Wajeha Hamoudi
- Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Wisam Bazbaz
- Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Igor Khaliulin
- Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Haitham Amal
- Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
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11
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Vasu D, Reidl CT, Wang E, Yang S, Silverman RB. Improved synthesis and anticancer activity of a potent neuronal nitric oxide synthase inhibitor. Bioorg Med Chem Lett 2023; 90:129329. [PMID: 37196870 PMCID: PMC10330524 DOI: 10.1016/j.bmcl.2023.129329] [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: 02/21/2023] [Revised: 03/23/2023] [Accepted: 05/10/2023] [Indexed: 05/19/2023]
Abstract
An improved synthesis of 4-methyl-7-(3-((methylamino)methyl)phenethyl)quinolin-2-amine (1) is reported. A scalable, rapid, and efficient methodology was developed to access this compound with an overall yield of 35%, which is 5.9-fold higher than the previous report. The key differences in the improved synthesis are a high yielding quinoline synthesis by a Knorr reaction, a copper-mediated Sonogashira coupling to the internal alkyne in excellent yield, and a crucial deprotection of the N-acetyl and N-Boc groups achieved under acidic conditions in a single step rather than a poor yielding quinoline N-oxide strategy, basic deprotection conditions, and low yielding copper-free conditions that were reported in the previous report. Compound 1, which previously was shown to inhibit IFN-γ-induced tumor growth in a human melanoma xenograft mouse model, was found to inhibit the growth of metastatic melanoma, glioblastoma, and hepatocellular carcinoma in vitro.
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Affiliation(s)
- Dhananjayan Vasu
- Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Developmental Therapeutics, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113, United States
| | - Cory T Reidl
- Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Developmental Therapeutics, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113, United States
| | - Eric Wang
- Trabuco Hill High School, Class of 2024, Mission Viejo, CA 92691, United States
| | - Sun Yang
- Department of Pharmacy Practice, Chapman University School of Pharmacy, Irvine, CA 92618, United States
| | - Richard B Silverman
- Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Developmental Therapeutics, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113, United States; Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States.
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12
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Wu X, Shen Y, Tan S, Jiang X, Chen Z, Yu Q, Chen H, Zhuang Y, Zeng H, Fu X, Zhou H, Dou Z, Chen G, Li X. Multiscale imaging of peroxynitrite in gliomas with a blood-brain barrier permeable probe reveals its potential as a biomarker and target for glioma treatment. Biosens Bioelectron 2023; 236:115415. [PMID: 37245459 DOI: 10.1016/j.bios.2023.115415] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 05/19/2023] [Accepted: 05/19/2023] [Indexed: 05/30/2023]
Abstract
Cancer development is driven by diverse processes, and metabolic alterations are among the primary characteristics. Multiscale imaging of aberrant metabolites in cancer is critical to understand the pathology and identify new targets for treatment. While peroxynitrite (ONOO-) is reported being enriched in some tumors and plays important tumorigenic roles, whether it is upregulated in gliomas remains unexplored. To determine the levels and roles of ONOO- in gliomas, efficient tools especially those with desirable blood-brain barrier (BBB) permeability and can realize the in situ imaging of ONOO- in multiscale glioma-related samples are indispensable. Herein, we proposed a strategy of physicochemical property-guided probe design, which resulted in the development of a fluorogenic probe NOSTracker for smartly tracking ONOO-. The probe showed sufficient BBB permeability. ONOO- triggered oxidation of its arylboronate group was automatically followed by a self-immolative cleavage of a fluorescence-masking group, liberating its fluorescence signal. The probe was not only highly sensitive and selective towards ONOO-, but its fluorescence favored desirable stability in various complex biological milieus. Guaranteed by these properties, multiscale imaging of ONOO- was realized in vitro in patient-derived primary glioma cells, ex vivo in clinical glioma slices, and in vivo in the glioma of live mice. The results showed the upregulation of ONOO- in gliomas. Furthermore, a specific ONOO- scavenger uric acid (UA) was pharmaceutically used to downregulate ONOO- in glioma cell lines, and an anti-proliferative effect was observed. These results taken together imply the potential of ONOO- as a biomarker and target for glioma treatment, and propose NOSTracker as a reliable tool to further explore the role of ONOO- in glioma development.
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Affiliation(s)
- Xinyan Wu
- The Second Affiliated Hospital, Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Yikai Shen
- Institute of Drug Discovery and Design, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China; Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, 310014, China
| | - Shuyu Tan
- Institute of Drug Discovery and Design, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Xuefeng Jiang
- Institute of Drug Discovery and Design, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Zihang Chen
- The Second Affiliated Hospital, Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Qian Yu
- The Second Affiliated Hospital, Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Huaijun Chen
- The Second Affiliated Hospital, Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Yilian Zhuang
- Institute of Drug Discovery and Design, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Hanhai Zeng
- The Second Affiliated Hospital, Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Xiongjie Fu
- The Second Affiliated Hospital, Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Hang Zhou
- The Second Affiliated Hospital, Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Zhangqi Dou
- The Second Affiliated Hospital, Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Gao Chen
- The Second Affiliated Hospital, Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, School of Medicine, Zhejiang University, Hangzhou, 310058, China.
| | - Xin Li
- Institute of Drug Discovery and Design, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China; Innovation Center of Yangtze River Delta, Zhejiang University, China; Hangzhou Institute of Innovative Medicine, Zhejiang University, China.
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13
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A Novel Prognostic Pyroptosis-Related Gene Signature Correlates to Oxidative Stress and Immune-Related Features in Gliomas. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2023; 2023:4256116. [PMID: 36778205 PMCID: PMC9909087 DOI: 10.1155/2023/4256116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 10/24/2022] [Accepted: 11/24/2022] [Indexed: 02/04/2023]
Abstract
Gliomas are highly invasive and aggressive tumors having the highest incidence rate of brain cancer. Identifying effective prognostic and potential therapeutic targets is necessitated. The relationship of pyroptosis, a form of programmed cellular death, with gliomas remains elusive. We constructed and validated a prognostic model for gliomas using pyroptosis-related genes. Differentially expressed pyroptosis-related genes were screened using the "limma" package. Based on LASSO-Cox regression, nine significant genes including CASP1, CASP3, CASP6, IL32, MKI67, MYD88, PRTN3, NOS1, and VIM were employed to construct a prognostic model in the TCGA cohort; the results were validated in the CGGA cohort. According to the median risk score, the patients were classified into two risk groups, namely, high- and low-risk groups. Patients at high risk had worse prognoses relative to those at low risk evidenced by the Kaplan-Meier curve analysis. The two groups exhibited differences in immune cell infiltration and TMB scores, with high immune checkpoint levels, TMB scores, and immune cell infiltration levels in the high-risk group. KEGG and GO analyses suggested enrichment in immune-related pathways. Furthermore, we found that the genes in our signature strongly correlated with oxidative stress-related pathways and the subgroups exhibited different ssGSEA scores. Some small molecules targeted the genes in the model, and we verified their drug sensitivities between the risk groups. The scRNA-seq dataset, GSE138794, was processed using the "Seurat" package to assess the level of risk gene expression in specific cell types. Finally, the MYD88 level was lowered in the U87 glioma cell line using si-RNA constructs. Cellular proliferation was impaired, and fewer pyroptosis-related cytokines were released upon exposure to LPS. In summary, we built a pyroptosis-related gene model that accurately classified glioma patients into high- and low-risk groups. The findings suggest that the signature may be an effective prognostic predictive tool for gliomas.
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14
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Glutamine-dependent effects of nitric oxide on cancer cells subjected to hypoxia-reoxygenation. Nitric Oxide 2023; 130:22-35. [PMID: 36414197 DOI: 10.1016/j.niox.2022.11.003] [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: 07/07/2022] [Revised: 11/12/2022] [Accepted: 11/18/2022] [Indexed: 11/21/2022]
Abstract
Limited O2 availability can decrease essential processes in energy metabolism. However, cancers have developed distinct metabolic adaptations to these conditions. For example, glutaminolysis can maintain energy metabolism and hypoxia signaling. Additionally, it has been observed that nitric oxide (NO) possesses concentration-dependent, biphasic effects in cancer. NO has potent anti-tumor effects through modulating events such as angiogenesis and metastasis at low physiological concentrations and inducing cell death at higher concentrations. In this study, Ewing Sarcoma cells (A-673), MIA PaCa, and SKBR3 cells were treated with DetaNONOate (DetaNO) in a model of hypoxia (1% O2) and reoxygenation (21% O2). All 3 cell types showed NO-dependent inhibition of cellular O2 consumption which was enhanced as O2-tension decreased. L-Gln depletion suppressed the mitochondrial response to decreasing O2 tension in all 3 cell types and resulted in inhibition of Complex I activity. In A-673 cells the O2 tension dependent change in mitochondrial O2 consumption and increase in glycolysis was dependent on the presence of L-Gln. The response to hypoxia and Complex I activity were restored by α-ketoglutarate. NO exposure resulted in the A-673 cells showing greater sensitivity to decreasing O2 tension. Under conditions of L-Gln depletion, NO restored HIF-1α levels and the mitochondrial response to O2 tension possibly through the increase of 2-hydroxyglutarate. NO also resulted in suppression of cellular bioenergetics and further inhibition of Complex I which was not rescued by α-ketoglutarate. Taken together these data suggest that NO modulates the mitochondrial response to O2 differentially in the absence and presence of L-Gln. These data suggest a combination of metabolic strategies targeting glutaminolysis and Complex I in cancer cells.
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15
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Neurotransmitters: Potential Targets in Glioblastoma. Cancers (Basel) 2022; 14:cancers14163970. [PMID: 36010960 PMCID: PMC9406056 DOI: 10.3390/cancers14163970] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 08/01/2022] [Accepted: 08/12/2022] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Aiming to discover potential treatments for GBM, this review connects emerging research on the roles of neurotransmitters in the normal neural and the GBM microenvironments and sheds light on the prospects of their application in the neuropharmacology of GBM. Conventional therapy is blamed for its poor effect, especially in inhibiting tumor recurrence and invasion. Facing this dilemma, we focus on neurotransmitters that modulate GBM initiation, progression and invasion, hoping to provide novel therapy targeting GBM. By analyzing research concerning GBM therapy systematically and scientifically, we discover increasing insights into the regulatory effects of neurotransmitters, some of which have already shown great potential in research in vivo or in vitro. After that, we further summarize the potential drugs in correlation with previously published research. In summary, it is worth expecting that targeting neurotransmitters could be a promising novel pharmacological approach for GBM treatment. Abstract For decades, glioblastoma multiforme (GBM), a type of the most lethal brain tumor, has remained a formidable challenge in terms of its treatment. Recently, many novel discoveries have underlined the regulatory roles of neurotransmitters in the microenvironment both physiologically and pathologically. By targeting the receptors synaptically or non-synaptically, neurotransmitters activate multiple signaling pathways. Significantly, many ligands acting on neurotransmitter receptors have shown great potential for inhibiting GBM growth and development, requiring further research. Here, we provide an overview of the most novel advances concerning the role of neurotransmitters in the normal neural and the GBM microenvironments, and discuss potential targeted drugs used for GBM treatment.
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16
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Zhu X, Wang J, Jin X, Chen Y, Hu L, Zhao J. Construction and evaluation of a prognostic risk assessment model of gastric cancer by using hypoxia features. Mutat Res 2022; 825:111795. [PMID: 36049301 DOI: 10.1016/j.mrfmmm.2022.111795] [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: 04/07/2022] [Revised: 07/15/2022] [Accepted: 08/08/2022] [Indexed: 06/15/2023]
Abstract
In this study, mRNA expression of gastric cancer tissue and clinical data of patients in TCGA-STAD dataset were used, together with the hypoxia-related gene sets in the MsigDB database, to screen hypoxia-related differentially expressed genes (DEGs) in GC. Thereafter, univariate and multivariate Cox regression analyses were carried out on hypoxia-related DEGs. The optimal feature genes related to prognosis were obtained to construct a prognostic risk assessment model. According to the model, the riskScore of GC patients was measured, and GC samples were assigned into high- and low-risk groups in accordance with the median riskScore. Based on the Kaplan-Meier curve and Receiver operating characteristic curve, validity of the prognostic risk assessment model was measured. Gene set enrichment analysis was performed on the two risk groups through Gene set enrichment analysis software. The results revealed that in the high-risk group, 9 signaling pathways were remarkably activated in several terms, like focal adhesion, extracellular matrix receptor interaction, Cell adhesion molecules cams, Cytokine-cytokine receptor interaction, TGF-beta signaling pathway, NOD-like receptor signaling pathway, JAK-STAT signaling pathway, Toll-like receptor signaling pathway and MAPK signaling pathway. In combination with riskScore and clinical factors, univariate and multivariate Cox regression analyses verified the independence of the model. Meanwhile, a nomogram was constructed to predict the 1-, 3- and 5-year survival of GC patients. The calibration curve indicated that the survival status predicted by the nomogram fitted better with actual survival status. On the whole, the prognostic risk model of GC on the basis of hypoxia-related genes demonstrated good predictive ability. It can provide more powerful technical support for clinicians to make prognostic determination and therapeutic plans.
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Affiliation(s)
- Xiaoling Zhu
- Department of Oncology, Shaoxing People's Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing 312000, China
| | - Jianfang Wang
- Department of Oncology, Shaoxing People's Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing 312000, China
| | - Xueying Jin
- Department of Oncology, Shaoxing People's Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing 312000, China
| | - Yiyi Chen
- Department of Clinical Medicine, Wenzhou Medical University, Wenzhou 325035, China
| | - Liang Hu
- Assistant Researcher, Shanghai Engineering Research Center of Pharmaceutical Translation, Shanghai 200231, China
| | - Jianguo Zhao
- Department of Oncology, Shaoxing People's Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing 312000, China.
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17
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Tondepu C, Karumbaiah L. Glycomaterials to Investigate the Functional Role of Aberrant Glycosylation in Glioblastoma. Adv Healthc Mater 2022; 11:e2101956. [PMID: 34878733 PMCID: PMC9048137 DOI: 10.1002/adhm.202101956] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 11/30/2021] [Indexed: 02/03/2023]
Abstract
Glioblastoma (GBM) is a stage IV astrocytoma that carries a dismal survival rate of ≈10 months postdiagnosis and treatment. The highly invasive capacity of GBM and its ability to escape therapeutic challenges are key factors contributing to the poor overall survival rate. While current treatments aim to target the cancer cell itself, they fail to consider the significant role that the GBM tumor microenvironment (TME) plays in promoting tumor progression and therapeutic resistance. The GBM tumor glycocalyx and glycan-rich extracellular matrix (ECM), which are important constituents of the TME have received little attention as therapeutic targets. A wide array of aberrantly modified glycans in the GBM TME mediate tumor growth, invasion, therapeutic resistance, and immunosuppression. Here, an overview of the landscape of aberrant glycan modifications in GBM is provided, and the design and utility of 3D glycomaterials are discussed as a tool to evaluate glycan-mediated GBM progression and therapeutic efficacy. The development of alternative strategies to target glycans in the TME can potentially unveil broader mechanisms of restricting tumor growth and enhancing the efficacy of tumor-targeting therapeutics.
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Affiliation(s)
- Chaitanya Tondepu
- Regenerative Bioscience Science Center, University of Georgia, Athens, GA, 30602, USA
| | - Lohitash Karumbaiah
- Regenerative Bioscience Science Center, University of Georgia, Athens, GA, 30602, USA
- Division of Neuroscience, Biomedical & Translational Sciences Institute, University of Georgia, Athens, GA, 30602, USA
- Edgar L. Rhodes Center for ADS, College of Agriculture and Environmental Sciences, University of Georgia, Athens, GA, 30602, USA
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18
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Guha A, Waris S, Nabors LB, Filippova N, Gorospe M, Kwan T, King PH. The versatile role of HuR in Glioblastoma and its potential as a therapeutic target for a multi-pronged attack. Adv Drug Deliv Rev 2022; 181:114082. [PMID: 34923029 PMCID: PMC8916685 DOI: 10.1016/j.addr.2021.114082] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 10/15/2021] [Accepted: 12/12/2021] [Indexed: 02/03/2023]
Abstract
Glioblastoma (GBM) is a malignant and aggressive brain tumor with a median survival of ∼15 months. Resistance to treatment arises from the extensive cellular and molecular heterogeneity in the three major components: glioma tumor cells, glioma stem cells, and tumor-associated microglia and macrophages. Within this triad, there is a complex network of intrinsic and secreted factors that promote classic hallmarks of cancer, including angiogenesis, resistance to cell death, proliferation, and immune evasion. A regulatory node connecting these diverse pathways is at the posttranscriptional level as mRNAs encoding many of the key drivers contain adenine- and uridine rich elements (ARE) in the 3' untranslated region. Human antigen R (HuR) binds to ARE-bearing mRNAs and is a major positive regulator at this level. This review focuses on basic concepts of ARE-mediated RNA regulation and how targeting HuR with small molecule inhibitors represents a plausible strategy for a multi-pronged therapeutic attack on GBM.
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Affiliation(s)
- Abhishek Guha
- Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35294, United States
| | - Saboora Waris
- Shaheed Zulfiqar Ali Bhutto Medical University, PIMS, G-8, Islamabad, Pakistan
| | - Louis B Nabors
- Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35294, United States
| | - Natalia Filippova
- Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35294, United States
| | - Myriam Gorospe
- Laboratory of Genetics and Genomics, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, United States
| | - Thaddaeus Kwan
- Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35294, United States
| | - Peter H King
- Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35294, United States; Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, United States; Birmingham Veterans Affairs Medical Center, Birmingham, AL 35294, United States.
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19
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Harnessing oxidative stress for anti-glioma therapy. Neurochem Int 2022; 154:105281. [PMID: 35038460 DOI: 10.1016/j.neuint.2022.105281] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 12/22/2021] [Accepted: 01/10/2022] [Indexed: 02/06/2023]
Abstract
Glioma cells use intermediate levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS) for growth and invasion, and suppressing these reactive molecules thus may compromise processes that are vital for glioma survival. Increased oxidative stress has been identified in glioma cells, in particular in glioma stem-like cells. Studies have shown that these cells harbor potent antioxidant defenses, although endogenous protection against nitrosative stress remains understudied. The enhancement of oxidative or nitrosative stress offers a potential target for triggering glioma cell death, but whether oxidative and nitrosative stresses can be combined for therapeutic effects requires further research. The optimal approach of harnessing oxidative stress for anti-glioma therapy should include the induction of free radical-induced oxidative damage and the suppression of antioxidant defense mechanisms selectively in glioma cells. However, selective induction of oxidative/nitrosative stress in glioma cells remains a therapeutic challenge, and research into selective drug delivery systems is ongoing. Because of multifactorial mechanisms of glioma growth, progression, and invasion, prospective oncological therapies may include not only therapeutic oxidative/nitrosative stress but also inhibition of oncogenic kinases, antioxidant molecules, and programmed cell death mediators.
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20
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Malard E, Valable S, Bernaudin M, Pérès E, Chatre L. The Reactive Species Interactome in the Brain. Antioxid Redox Signal 2021; 35:1176-1206. [PMID: 34498917 DOI: 10.1089/ars.2020.8238] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Significance: Redox pioneer Helmut Sies attempted to explain reactive species' challenges faced by organelles, cells, tissues, and organs via three complementary definitions: (i) oxidative stress, that is, the disturbance in the prooxidant-antioxidant defense balance in favor of the prooxidants; (ii) oxidative eustress, the low physiological exposure to prooxidants; and (iii) oxidative distress, the supraphysiological exposure to prooxidants. Recent Advances: Identification, concentration, and interactions are the most important elements to improve our understanding of reactive species in physiology and pathology. In this context, the reactive species interactome (RSI) is a new multilevel redox regulatory system that identifies reactive species families, reactive oxygen species (ROS), reactive nitrogen species (RNS), and reactive sulfur species, and it integrates their interactions with their downstream biological targets. Critical Issues: We propose a united view to fully combine reactive species identification, oxidative eustress and distress, and the RSI system. In this view, we also propose including the forgotten reactive carbonyl species, an increasingly rediscovered reactive species family related to the other reactive families, and key enzymes within the RSI. We focus on brain physiology and pathology to demonstrate why this united view should be considered. Future Directions: More studies are needed for an improved understanding of the contributions of reactive species through their identification, concentration, and interactions, including in the brain. Appreciating the RSI in its entirety should unveil new molecular players and mechanisms in physiology and pathology in the brain and elsewhere.
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Affiliation(s)
- Elise Malard
- Normandie Univ, UNICAEN, CEA, CNRS, ISTCT/CERVOxy group, GIP Cyceron, Caen, France
| | - Samuel Valable
- Normandie Univ, UNICAEN, CEA, CNRS, ISTCT/CERVOxy group, GIP Cyceron, Caen, France
| | - Myriam Bernaudin
- Normandie Univ, UNICAEN, CEA, CNRS, ISTCT/CERVOxy group, GIP Cyceron, Caen, France
| | - Elodie Pérès
- Normandie Univ, UNICAEN, CEA, CNRS, ISTCT/CERVOxy group, GIP Cyceron, Caen, France
| | - Laurent Chatre
- Normandie Univ, UNICAEN, CEA, CNRS, ISTCT/CERVOxy group, GIP Cyceron, Caen, France
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21
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Mazurek M, Rola R. The implications of nitric oxide metabolism in the treatment of glial tumors. Neurochem Int 2021; 150:105172. [PMID: 34461111 DOI: 10.1016/j.neuint.2021.105172] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 08/03/2021] [Accepted: 08/21/2021] [Indexed: 12/20/2022]
Abstract
Glial tumors are the most common intracranial malignancies. Unfortunately, despite such a high prevalence, patients' prognosis is usually poor. It is related to the high invasiveness, tendency to relapse and the resistance of tumors to traditional methods of treatment. An important link in the aspect of these issues may be nitric oxide (NO) metabolism. It is a very complex mechanism with multidirectional effects on the neoplastic process. Depending on the concentration axis, it can both exert pro-tumor action as well as contribute to the inhibition of tumorigenesis. The latest observations show that the control of its metabolism can be very helpful in the development of new methods of treating gliomas, as well as in increasing the effectiveness of the agents currently used. The influence of nitric oxide and nitric oxide synthase (NOS) activity on glioma stem cells seem to be of particular importance. The use of specific inhibitors may allow the reduction of tumor growth and its tendency to relapse. Another important feature of GSCs is their conditioning of glioma resistance to traditional forms of treatment. Recent studies have shown that modulation of NO metabolism can suppress this effect, preventing the induction of radio and chemoresistance. Moreover, nitric oxide is involved in the regulation of a number of immune mechanisms. Adequate modulation of its metabolism may contribute to the induction of an anti-tumor response in the patients' immune system.
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Affiliation(s)
- Marek Mazurek
- Chair and Department of Neurosurgery and Paediatric Neurosurgery, Medical University in Lublin, Poland.
| | - Radosław Rola
- Chair and Department of Neurosurgery and Paediatric Neurosurgery, Medical University in Lublin, Poland
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22
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Li C, Guo H, Wang C, Zhan W, Tan Q, Xie C, Sharma A, Sharma HS, Chen L, Zhang Z. Network pharmacological mechanism of Cinobufotalin against glioma. PROGRESS IN BRAIN RESEARCH 2021; 265:119-137. [PMID: 34560920 DOI: 10.1016/bs.pbr.2021.06.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
OBJECTIVE Cinobufotalin was extracted from the skin of Chinese giant salamander or black sable with good clinical effect against tumor. This study aims to explore the mechanism of Cinobufotalin components and predict the target of action of Cinobufotalin on glioma. METHODS The active components of Cinobufotalin were screened by the Chinese medicine pharmacology database and analysis platform (TCMSP), PubChem database, etc. The potential molecular components and targets were identified and enrichment analysis was conducted through the construction of related networks and analysis of their characteristics. Relevant targets of glioma were searched through TTD, DRUGBANK, and other databases, and the intersection was found and the key targets were found too. RESULTS A total of 21 active components and 184 target genes of Cinobufotalin were found. According to the enrichment analysis results, the pharmacological mechanism of Cinobufotalin mainly includes inhibition of the cell cycle, promotion of cell apoptosis, and regulation of immunity. On this basis, RAC1, FOS, and NOS3 can be preliminarily predicted as potential targets of Cinobufotalin in the treatment of glioma. CONCLUSIONS The screening of active ingredients and target prediction based on network pharmacology can provide a new research idea for the multi-target treatment of glioma with Cinobufotalin.
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Affiliation(s)
- Cong Li
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Province Hospital of Chinese Medical, Guangzhou, China
| | - Hanyu Guo
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Province Hospital of Chinese Medical, Guangzhou, China
| | - Chao Wang
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Province Hospital of Chinese Medical, Guangzhou, China
| | - Wengang Zhan
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Province Hospital of Chinese Medical, Guangzhou, China
| | - Qijia Tan
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Province Hospital of Chinese Medical, Guangzhou, China
| | - Caijun Xie
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Province Hospital of Chinese Medical, Guangzhou, China
| | - Aruna Sharma
- International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden
| | - Hari Shanker Sharma
- International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden.
| | - Lin Chen
- Department of Neurosurgery, Dongzhimen Hospital of Beijing University of Traditional Chinese Medicine, Beijing, China
| | - Zhiqiang Zhang
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Province Hospital of Chinese Medical, Guangzhou, China.
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23
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Serpe C, Monaco L, Relucenti M, Iovino L, Familiari P, Scavizzi F, Raspa M, Familiari G, Civiero L, D’Agnano I, Limatola C, Catalano M. Microglia-Derived Small Extracellular Vesicles Reduce Glioma Growth by Modifying Tumor Cell Metabolism and Enhancing Glutamate Clearance through miR-124. Cells 2021; 10:2066. [PMID: 34440835 PMCID: PMC8393731 DOI: 10.3390/cells10082066] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 07/26/2021] [Accepted: 08/06/2021] [Indexed: 12/12/2022] Open
Abstract
Brain homeostasis needs continuous exchange of intercellular information among neurons, glial cells, and immune cells, namely microglial cells. Extracellular vesicles (EVs) are active players of this process. All the cells of the body, including the brain, release at least two subtypes of EVs, the medium/large EVs (m/lEVs) and small EVs (sEVs). sEVs released by microglia play an important role in brain patrolling in physio-pathological processes. One of the most common and malignant forms of brain cancer is glioblastoma. Altered intercellular communications constitute a base for the onset and the development of the disease. In this work, we used microglia-derived sEVs to assay their effects in vitro on murine glioma cells and in vivo in a glioma model on C57BL6/N mice. Our findings indicated that sEVs carry messages to cancer cells that modify glioma cell metabolism, reducing lactate, nitric oxide (NO), and glutamate (Glu) release. sEVs affect Glu homeostasis, increasing the expression of Glu transporter Glt-1 on astrocytes. We demonstrated that these effects are mediated by miR-124 contained in microglia-released sEVs. The in vivo benefit of microglia-derived sEVs results in a significantly reduced tumor mass and an increased survival of glioma-bearing mice, depending on miR-124.
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Affiliation(s)
- Carmela Serpe
- Department of Physiology and Pharmacology, Sapienza University, 00185 Rome, Italy; (C.S.); (L.M.)
| | - Lucia Monaco
- Department of Physiology and Pharmacology, Sapienza University, 00185 Rome, Italy; (C.S.); (L.M.)
| | - Michela Relucenti
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University, 00185 Rome, Italy; (M.R.); (G.F.)
| | - Ludovica Iovino
- Department of Biology, University of Padova, 35131 Padova, Italy; (L.I.); (L.C.)
| | - Pietro Familiari
- Department of Human Neurosciences, Division of Neurosurgery, Sapienza University, 00185 Rome, Italy;
| | - Ferdinando Scavizzi
- Institute of Biochemistry and Cell Biology (IBBC), CNR, 00015 Monterotond, Italy; (F.S.); (M.R.)
| | - Marcello Raspa
- Institute of Biochemistry and Cell Biology (IBBC), CNR, 00015 Monterotond, Italy; (F.S.); (M.R.)
| | - Giuseppe Familiari
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University, 00185 Rome, Italy; (M.R.); (G.F.)
| | - Laura Civiero
- Department of Biology, University of Padova, 35131 Padova, Italy; (L.I.); (L.C.)
- IRCCS San Camillo Hospital, 30126 Venice, Italy
| | - Igea D’Agnano
- Institute of Biomedical Technologies, CNR, 20054 Segrate, Italy;
| | - Cristina Limatola
- Department of Physiology and Pharmacology, Laboratory Affiliated to Istituto Pasteur Italia Fondazione Cenci Bolognetti, Sapienza University, 00185 Rome, Italy
- IRCCS Neuromed, 86077 Pozzilli, Italy
| | - Myriam Catalano
- Department of Physiology and Pharmacology, Sapienza University, 00185 Rome, Italy; (C.S.); (L.M.)
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24
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Libby CJ, Gc S, Benavides GA, Fisher JL, Williford SE, Zhang S, Tran AN, Gordon ER, Jones AB, Tuy K, Flavahan W, Gordillo J, Long A, Cooper SJ, Lasseigne BN, Augelli-Szafran CE, Darley-Usmar V, Hjelmeland AB. A role for GLUT3 in glioblastoma cell invasion that is not recapitulated by GLUT1. Cell Adh Migr 2021; 15:101-115. [PMID: 33843470 PMCID: PMC8043167 DOI: 10.1080/19336918.2021.1903684] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
The multifaceted roles of metabolism in invasion have been investigated across many cancers. The brain tumor glioblastoma (GBM) is a highly invasive and metabolically plastic tumor with an inevitable recurrence. The neuronal glucose transporter 3 (GLUT3) was previously reported to correlate with poor glioma patient survival and be upregulated in GBM cells to promote therapeutic resistance and survival under restricted glucose conditions. It has been suggested that the increased glucose uptake mediated by GLUT3 elevation promotes survival of circulating tumor cells to facilitate metastasis. Here we suggest a more direct role for GLUT3 in promoting invasion that is not dependent upon changes in cell survival or metabolism. Analysis of glioma datasets demonstrated that GLUT3, but not GLUT1, expression was elevated in invasive disease. In human xenograft derived GBM cells, GLUT3, but not GLUT1, elevation significantly increased invasion in transwell assays, but not growth or migration. Further, there were no changes in glycolytic metabolism that correlated with invasive phenotypes. We identified the GLUT3 C-terminus as mediating invasion: substituting the C-terminus of GLUT1 for that of GLUT3 reduced invasion. RNA-seq analysis indicated changes in extracellular matrix organization in GLUT3 overexpressing cells, including upregulation of osteopontin. Together, our data suggest a role for GLUT3 in increasing tumor cell invasion that is not recapitulated by GLUT1, is separate from its role in metabolism and survival as a glucose transporter, and is likely broadly applicable since GLUT3 expression correlates with metastasis in many solid tumors.
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Affiliation(s)
- Catherine J Libby
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Sajina Gc
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Gloria A Benavides
- Mitochondria Medicine Laboratory, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Jennifer L Fisher
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Sarah E Williford
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Sixue Zhang
- Chemistry Department, Drug Discovery Division, Southern Research, Birmingham, AL, USA
| | - Anh Nhat Tran
- Department of Neurosurgery, Northwestern University, Chicago, IL, USA
| | - Emily R Gordon
- HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA
| | - Amber B Jones
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Kaysaw Tuy
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - William Flavahan
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worchester, MA, USA
| | - Juan Gordillo
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Ashlee Long
- Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Sara J Cooper
- HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA
| | - Brittany N Lasseigne
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA.,O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA.,Hugh Kaul Precision Medicine Institute, University of Alabama at Birmingham, Birmingham, AL, USA.,The Center for Clinical and Translational Science, University of Alabama at Birmingham, Birmingham, AL, USA.,UAB IMPACT Fund, University of Alabama at Birmingham, Birmingham, AL, USA
| | | | - Victor Darley-Usmar
- Mitochondria Medicine Laboratory, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Anita B Hjelmeland
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA.,O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
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25
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Shi Y, Ding D, Liu L, Li Z, Zuo L, Zhou L, Du Q, Jing Z, Zhang X, Sun Z. Integrative Analysis of Metabolomic and Transcriptomic Data Reveals Metabolic Alterations in Glioma Patients. J Proteome Res 2021; 20:2206-2215. [PMID: 33764076 DOI: 10.1021/acs.jproteome.0c00697] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Glioma is a malignant brain tumor. There is growing evidence that its progression involves altered metabolism. This study's objective was to understand how those metabolic perturbations were manifested in plasma and urine. Metabolic signatures in blood and urine were characterized by liquid chromatography-tandem mass spectrometry. The results were linked to gene expression using data from the Gene Expression Omnibus database. Genes and pathways associated with the disease were thus identified. Forty metabolites were identified, which were differentially expressed in the plasma of glioma patients, and 61 were identified in their urine. Twenty-two metabolites and five disturbed pathways were found both in plasma and urine. Twelve metabolites in plasma and three in urine exhibited good diagnostic potential for glioma. Transcriptomic analyses revealed specific changes in the expression of 1437 genes associated with glioma. Seventeen differentially expressed genes were found to be correlated with four of the metabolites. Enrichment analysis indicated that dysregulation of glutamatergic synapse pathway might affect the pathology of glioma. Integration of metabolomics with transcriptomics can provide both a broad picture of novel cancer signatures and preliminary information about the molecular perturbations underlying glioma. These results may suggest promising targets for developing effective therapies.
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Affiliation(s)
- Yingying Shi
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province 450052, P. R. China.,Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, Henan Province 450052, P. R. China.,Henan Engineering Research Center of Clinical Mass Spectrometry for Precision Medicine, Zhengzhou University, Zhengzhou, Henan Province 450052, P. R. China
| | - Daling Ding
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province 450052, P. R. China
| | - Liwei Liu
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province 450052, P. R. China.,Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, Henan Province 450052, P. R. China.,Henan Engineering Research Center of Clinical Mass Spectrometry for Precision Medicine, Zhengzhou University, Zhengzhou, Henan Province 450052, P. R. China
| | - Zhuolun Li
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province 450052, P. R. China.,Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, Henan Province 450052, P. R. China.,Henan Engineering Research Center of Clinical Mass Spectrometry for Precision Medicine, Zhengzhou University, Zhengzhou, Henan Province 450052, P. R. China
| | - Lihua Zuo
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province 450052, P. R. China.,Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, Henan Province 450052, P. R. China.,Henan Engineering Research Center of Clinical Mass Spectrometry for Precision Medicine, Zhengzhou University, Zhengzhou, Henan Province 450052, P. R. China
| | - Lin Zhou
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province 450052, P. R. China.,Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, Henan Province 450052, P. R. China.,Henan Engineering Research Center of Clinical Mass Spectrometry for Precision Medicine, Zhengzhou University, Zhengzhou, Henan Province 450052, P. R. China
| | - Qiuzheng Du
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province 450052, P. R. China.,Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, Henan Province 450052, P. R. China.,Henan Engineering Research Center of Clinical Mass Spectrometry for Precision Medicine, Zhengzhou University, Zhengzhou, Henan Province 450052, P. R. China
| | - Ziwei Jing
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province 450052, P. R. China.,Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, Henan Province 450052, P. R. China.,Henan Engineering Research Center of Clinical Mass Spectrometry for Precision Medicine, Zhengzhou University, Zhengzhou, Henan Province 450052, P. R. China
| | - Xiaojian Zhang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province 450052, P. R. China.,Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, Henan Province 450052, P. R. China.,Henan Engineering Research Center of Clinical Mass Spectrometry for Precision Medicine, Zhengzhou University, Zhengzhou, Henan Province 450052, P. R. China
| | - Zhi Sun
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province 450052, P. R. China.,Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, Henan Province 450052, P. R. China.,Henan Engineering Research Center of Clinical Mass Spectrometry for Precision Medicine, Zhengzhou University, Zhengzhou, Henan Province 450052, P. R. China
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26
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Afshari AR, Mollazadeh H, Mohtashami E, Soltani A, Soukhtanloo M, Hosseini A, Jalili-Nik M, Vahedi MM, Roshan MK, Sahebkar A. Protective Role of Natural Products in Glioblastoma Multiforme: A Focus on Nitric Oxide Pathway. Curr Med Chem 2021; 28:377-400. [PMID: 32000638 DOI: 10.2174/0929867327666200130104757] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 11/07/2019] [Accepted: 11/14/2019] [Indexed: 11/22/2022]
Abstract
In spite of therapeutic modalities such as surgical resection, chemotherapy, and radiotherapy, Glioblastoma Multiforme (GBM) remains an incurable fatal disease. This necessitates further therapeutic options that could enhance the efficacy of existing modalities. Nitric Oxide (NO), a short-lived small molecule, has been revealed to play a crucial role in the pathophysiology of GBM. Several studies have demonstrated that NO is involved in apoptosis, metastasis, cellular proliferation, angiogenesis, invasion, and many other processes implicated in GBM pathobiology. Herein, we elaborate on the role of NO as a therapeutic target in GBM and discuss some natural products affecting the NO signaling pathway.
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Affiliation(s)
- Amir R Afshari
- Department of Physiology and Pharmacology, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Hamid Mollazadeh
- Department of Physiology and Pharmacology, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Elmira Mohtashami
- Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Arash Soltani
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Soukhtanloo
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Azar Hosseini
- Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Jalili-Nik
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Mahdi Vahedi
- Department of Pharmacology, Faculty of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Mostafa Karimi Roshan
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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27
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Current Progress of Phytomedicine in Glioblastoma Therapy. Curr Med Sci 2021; 40:1067-1074. [PMID: 33428134 DOI: 10.1007/s11596-020-2288-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Accepted: 10/20/2020] [Indexed: 01/13/2023]
Abstract
Glioblastoma multiforme, an intrusive brain cancer, has the lowest survival rate of all brain cancers. The chemotherapy utilized to prevent their proliferation and propagation is limited due to modulation of complex cancer signalling pathways. These complex pathways provide infiltrative and drug evading properties leading to the development of chemotherapy resistance. Therefore, the development and discovery of such interventions or therapies that can bypass all these resistive barriers to ameliorate glioma prognosis and survival is of profound importance. Medicinal plants are comprised of an exorbitant range of phytochemicals that have the broad-spectrum capability to target intrusive brain cancers, modulate anti-cancer pathways and immunological responses to facilitate their eradication, and induce apoptosis. These phytocompounds also interfere with several oncogenic proteins that promote cancer invasiveness and metastasis, chemotherapy resistance and angiogenesis. These plants are extremely vital for promising anti-glioma therapy to avert glioma proliferation and recurrence. In this review, we acquired recent literature on medicinal plants whose extracts/bioactive ingredients are newly exploited in glioma therapeutics, and also highlighted their mode of action and pharmacological profile.
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28
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Girotti AW, Fahey JM, Korytowski W. Negative effects of tumor cell nitric oxide on anti-glioblastoma photodynamic therapy. JOURNAL OF CANCER METASTASIS AND TREATMENT 2020; 6:52. [PMID: 33564720 PMCID: PMC7869587 DOI: 10.20517/2394-4722.2020.107] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Glioblastomas are highly aggressive brain tumors that can persist after exposure to conventional chemotherapy or radiotherapy. Nitric oxide (NO) produced by inducible NO synthase (iNOS/NOS2) in these tumors is known to foster malignant cell proliferation, migration, and invasion as well as resistance to chemo- and radiotherapy. Minimally invasive photodynamic therapy (PDT) sensitized by 5-aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) is a highly effective anti-glioblastoma modality, but it is also subject to NO-mediated resistance. Studies by the authors have revealed that glioblastoma U87 and U251 cells use endogenous iNOS/NO to not only resist photokilling after an ALA/light challenge, but also to promote proliferation and migration/invasion of surviving cells. Stress-upregulated iNOS/NO was found to play a major role in these negative responses to PDT-like treatment. Our studies have revealed a tight network of upstream signaling events leading to iNOS induction in photostressed cells and transition to a more aggressive phenotype. These events include activation or upregulation of pro-survival/ pro-expansion effector proteins such as NF-κB, phosphoinositide-3-kinase (PI3K), protein kinase-B (Akt), p300, Survivin, and Brd4. In addition to this upstream signaling and its regulation, pharmacologic approaches for directly suppressing iNOS at its activity vs. transcriptional level are discussed. One highly effective agent in the latter category is bromodomain and extra-terminal (BET) inhibitor, JQ1, which was found to minimize iNOS upregulation in photostressed U87 cells. By acting similarly at the clinical level, a BET inhibitor such as JQ1 should markedly improve the efficacy of anti-glioblastoma PDT.
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Affiliation(s)
- Albert W. Girotti
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, United States
| | - Jonathan M. Fahey
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, United States
| | - Witold Korytowski
- Department of Biophysics, Jagiellonian University, Krakow 30-387, Poland
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29
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Girotti AW, Fahey JM, Korytowski W. Nitric oxide-elicited resistance to anti-glioblastoma photodynamic therapy. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2020; 3:401-414. [PMID: 33073206 PMCID: PMC7558220 DOI: 10.20517/cdr.2020.25] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 06/23/2020] [Accepted: 07/14/2020] [Indexed: 12/22/2022]
Abstract
Glioblastoma multiforme is a highly aggressive primary brain malignancy that resists most conventional chemoand radiotherapeutic interventions. Nitric oxide (NO), a short lived free radical molecule produced by inducible NO synthase (iNOS) in glioblastomas and other tumors, is known to play a key role in tumor persistence, progression, and chemo/radiotherapy resistance. Site-specific and minimally invasive photodynamic therapy (PDT), based on oxidative damage resulting from non-ionizing photoactivation of a sensitizing agent, is highly effective against glioblastoma, but resistance also exists in this case. Studies in the authors' laboratory have shown that much of the latter is mediated by iNOS/NO. For example, when glioblastoma U87 or U251 cells sensitized in mitochondria with 5-aminolevulinic acid -induced protoporphyrin IX were exposed to a moderate dose of visible light, the observed apoptosis was strongly enhanced by an iNOS activity inhibitor or NO scavenger, indicating that iNOS/NO had increased cell resistance to photokilling. Moreover, cells that survived the photochallenge proliferated, migrated, and invaded more aggressively than controls, and these responses were also driven predominantly by iNOS/NO. Photostress-upregulated iNOS rather than basal enzyme was found to be responsible for all the negative effects described. Recognition of NO-mediated hyper-resistance/hyper-aggression in PDT-stressed glioblastoma has stimulated interest in how these responses can be prevented or at least minimized by pharmacologic adjuvants such as inhibitors of iNOS activity or transcription. Recent developments along these lines and their clinical potential for improving anti-glioblastoma PDT are discussed.
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Affiliation(s)
- Albert W. Girotti
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Jonathan M. Fahey
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Witold Korytowski
- Department of Biophysics, Jagiellonian University, Krakow 31-008, Poland
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30
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Mishra D, Patel V, Banerjee D. Nitric Oxide and S-Nitrosylation in Cancers: Emphasis on Breast Cancer. BREAST CANCER-BASIC AND CLINICAL RESEARCH 2020; 14:1178223419882688. [PMID: 32030066 PMCID: PMC6977095 DOI: 10.1177/1178223419882688] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Accepted: 09/16/2019] [Indexed: 12/12/2022]
Abstract
Nitric oxide (NO) is a ubiquitous, endogenously produced, water-soluble signaling molecule playing critical roles in physiological processes. Nitric oxide plays pleiotropic roles in cancer and, depending on its local concentration, may lead to either tumor progression or tumor suppression. Addition of NO group to a cysteine residue within a protein, termed as S-nitrosylation, plays diverse regulatory roles and affects processes such as metabolism, apoptosis, protein phosphorylation, and regulation of transcription factors. The process of S-nitrosylation has been associated with development of different cancers, including breast cancer. The present review discusses different mechanisms through which NO acts, with special emphasis on breast cancers, and provides detailed insights into reactive nitrogen species, posttranslational modifications of proteins mediated by NO, dual nature of NO in cancers, and the implications of S-nitrosylation in cancers. Our review will generate interest in exploring molecular regulation by NO in different cancers and will have significant therapeutic implications in the management and treatment of breast cancer.
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Affiliation(s)
- Deepshikha Mishra
- Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Vaibhav Patel
- Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.,School of Graduate Studies, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Debabrata Banerjee
- Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.,School of Graduate Studies, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
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31
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Zhang L. Glioma characterization based on magnetic resonance imaging: Challenge overview and future perspective. GLIOMA 2020. [DOI: 10.4103/glioma.glioma_9_20] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Basati G, Khaksarian M, Abbaszadeh S, Lashgarian HE, Marzban A. Cancer stem cells and nanotechnological approaches for eradication. Stem Cell Investig 2019; 6:38. [PMID: 31853454 DOI: 10.21037/sci.2019.10.07] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Accepted: 10/08/2019] [Indexed: 12/12/2022]
Abstract
Cancer stem cells (CSCs) are currently known as the main cause of tumor recurrence. After chemotherapy is completed, CSCs proliferate and then differentiate to generate new tumor tissues. Similar to normal stem cells, this non-uniformly distributed cell population in the tumor tissue has self-renewal capacity and is responsible for survival of the tumor and difference in its genetic and metabolic characteristics. Followed by gene instability in CSCs, new phenotypic markers are aberrantly expressed in CSCs subpopulation. Hence, some of the surface markers and metabolic pathways that are upregulated in CSCs may be applied as specific targets for development of diagnostic and therapeutic approaches. In this review article, the distinctive properties of CSCs including signal pathways implicated in self-renewal and surface markers were discussed. Moreover, targeting CSCs based on their specific properties using nanodrugs was reviewed.
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Affiliation(s)
- Gholam Basati
- Clinical Microbiology Research Center, Ilam University of Medical Sciences, Ilam, Iran
| | - Mojtaba Khaksarian
- Razi Herbal Medicine Research Center & Department of Physiology, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Saber Abbaszadeh
- Student Research Committee, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Hamed Esmaeil Lashgarian
- Department of Biotechnology, School of Medicine, Hepatitis Research Center, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Abdolrazagh Marzban
- Razi Herbal Medicines Research Center, Lorestan University of Medical Sciences, Khorramabad, Iran
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33
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Affiliation(s)
- Korneel Grauwet
- Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - E Antonio Chiocca
- Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
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Tran AN, Dussaq AM, Kennell T, Willey CD, Hjelmeland AB. HPAanalyze: an R package that facilitates the retrieval and analysis of the Human Protein Atlas data. BMC Bioinformatics 2019; 20:463. [PMID: 31500569 PMCID: PMC6734269 DOI: 10.1186/s12859-019-3059-z] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Accepted: 08/27/2019] [Indexed: 02/07/2023] Open
Abstract
Background The Human Protein Atlas (HPA) aims to map human proteins via multiple technologies including imaging, proteomics and transcriptomics. Access of the HPA data is mainly via web-based interface allowing views of individual proteins, which may not be optimal for data analysis of a gene set, or automatic retrieval of original images. Results HPAanalyze is an R package for retrieving and performing exploratory analysis of data from HPA. HPAanalyze provides functionality for importing data tables and xml files from HPA, exporting and visualizing data, as well as downloading all staining images of interest. The package is free, open source, and available via Bioconductor and GitHub. We provide examples of the use of HPAanalyze to investigate proteins altered in the deadly brain tumor glioblastoma. For example, we confirm Epidermal Growth Factor Receptor elevation and Phosphatase and Tensin Homolog loss and suggest the importance of the GTP Cyclohydrolase I/Tetrahydrobiopterin pathway. Additionally, we provide an interactive website for non-programmers to explore and visualize data without the use of R. Conclusions HPAanalyze integrates into the R workflow with the tidyverse framework, and it can be used in combination with Bioconductor packages for easy analysis of HPA data. Electronic supplementary material The online version of this article (10.1186/s12859-019-3059-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Anh Nhat Tran
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, THT 948, 1900 University Blvd, Birmingham, AL, 35294, USA.
| | - Alex M Dussaq
- Department of Pathology, University of Alabama at Birmingham, 121 Shelby Biomedical Research Building, Birmingham, AL, 35294, USA
| | - Timothy Kennell
- Department of Genetics, University of Alabama at Birmingham, 121 Shelby Biomedical Research Building, Birmingham, AL, 35294, USA
| | - Christopher D Willey
- Department of Radiation Oncology, University of Alabama at Birmingham, 176 Facility Building, Birmingham, AL, 35294, USA
| | - Anita B Hjelmeland
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, THT 948, 1900 University Blvd, Birmingham, AL, 35294, USA.
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Lu E, Li C, Wang J, Zhang C. Inflammation and angiogenesis in the corpus luteum. J Obstet Gynaecol Res 2019; 45:1967-1974. [PMID: 31373134 DOI: 10.1111/jog.14076] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Accepted: 07/15/2019] [Indexed: 12/15/2022]
Abstract
Angiogenesis is a very important process that helps establish and maintain the normal structure and function of the corpus luteum (CL). Early luteal development can be considered a kind of physiological injury with an inflammatory response; therefore, the inflammatory response may play an important role in the luteal angiogenesis. The inflammatory response is companied by activated leukocytes and their mediators. For luteal tissue, numerous activated leukocytes such as macrophages, neutrophils and eosinophils are present in the early luteal phase and are widely involved in neovascularization. The objective of this review is to describe the role of the inflammatory factors in the angiogenesis and to discuss their mechanism. Knowledge of action and mechanism of these inflammatory factors on angiogenic activity will be beneficial for the understanding of luteal function.
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Affiliation(s)
- Enhang Lu
- Joint Programme of Nanchang University and Queen Mary University of London, School of Medicine, Nanchang University, Nanchang, China
| | - Chunjie Li
- Forth Clinical College, School of Medicine, Nanchang University, Nanchang, China
| | - Jing Wang
- Department of Microbiology, School of Medicine, Nanchang University, Nanchang, China
| | - Chunping Zhang
- Department of Cell Biology, School of Medicine, Nanchang University, Nanchang, China
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Tang X, Li Z, Zhang W, Yao Z. Nitric oxide might be an inducing factor in cognitive impairment in Alzheimer's disease via downregulating the monocarboxylate transporter 1. Nitric Oxide 2019; 91:35-41. [PMID: 31326499 DOI: 10.1016/j.niox.2019.07.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 05/08/2019] [Accepted: 07/17/2019] [Indexed: 12/20/2022]
Abstract
Alzheimer's disease (AD) is a typical neurodegenerative disease in central nervous system (CNS). Generally speaking, patients with severe AD are often accompanied with cognitive impairment. Oligodendrocytes (OLs) are myelin-forming cells in CNS, and myelin injury potentially has something to do with the cognitive impairment in AD. Based on the previous experimental studies, it has been recognized that nitric oxide (NO), as a signaling molecule, might have an influence on the axon and myelin by affecting the energy transport mechanism of OLs through monocarboxylate transporter 1 (MCT1). Interestingly, a novel model of cell signaling----axo-myelinic synapse (AMS) has been put forward. In the context of this model, chances are that a new way is established in which NO can influence the pathogenesis of AD by down-regulating the expression of MCT1. As a consequence, it may provide attractive prospective and underlying drug targeting effects for the treatment of AD.
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Affiliation(s)
- Xiaoyi Tang
- Department of Physiology, Army Medical University (Third Military Medical University), Chongqing, 400038, China; Luliang Military Airport Hospital, Yunnan, 655699, China
| | - Zhuang Li
- Luliang Military Airport Hospital, Yunnan, 655699, China
| | - Weiwei Zhang
- Department of Physiology, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Zhongxiang Yao
- Department of Physiology, Army Medical University (Third Military Medical University), Chongqing, 400038, China.
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Fahey JM, Korytowski W, Girotti AW. Upstream signaling events leading to elevated production of pro-survival nitric oxide in photodynamically-challenged glioblastoma cells. Free Radic Biol Med 2019; 137:37-45. [PMID: 30991141 PMCID: PMC6526063 DOI: 10.1016/j.freeradbiomed.2019.04.013] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Revised: 03/15/2019] [Accepted: 04/10/2019] [Indexed: 12/19/2022]
Abstract
Nitric oxide (NO) generated endogenously by inducible nitric oxide synthase (iNOS) promotes growth and migration/invasion of glioblastoma cells and also fosters resistance to chemotherapy and ionizing radiotherapy. Our recent studies revealed that glioblastoma cell iNOS/NO also opposes the cytotoxic effects of non-ionizing photodynamic therapy (PDT), and moreover stimulates growth/migration aggressiveness of surviving cells. These negative responses, which depended on PI3K/Akt/NF-κB activation, were strongly suppressed by blocking iNOS transcription with JQ1, a BET bromodomain inhibitor. In the present study, we sought to identify additional molecular events that precede iNOS transcriptional upregulation. Akt activation, iNOS induction, and viability loss in PDT-challenged glioblastoma U87 cells were all strongly inhibited by added l-histidine, consistent with primary involvement of photogenerated singlet oxygen (1O2). Transacetylase p300 not only underwent greater Akt-dependent activation after PDT, but greater interaction with NF-κB subunit p65, which in turn exhibited greater K310 acetylation. In addition, PDT promoted intramolecular disulfide formation and inactivation of tumor suppressor PTEN, thereby favoring Akt and p300 activation leading to iNOS upregulation. Importantly, deacetylase Sirt1 was down-regulated by PDT stress, consistent with the observed increase in p65-acK310 level, which fostered iNOS transcription. This study provides new mechanistic insights into how glioblastoma tumors can exploit iNOS/NO to not only resist PDT, but to attain a more aggressive survival phenotype.
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Affiliation(s)
- Jonathan M Fahey
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, 53226-3548, USA
| | | | - Albert W Girotti
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, 53226-3548, USA.
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38
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The role of microglia and P2X7 receptors in gliomas. J Neuroimmunol 2019; 332:138-146. [PMID: 31031209 DOI: 10.1016/j.jneuroim.2019.04.010] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Revised: 04/18/2019] [Accepted: 04/18/2019] [Indexed: 02/06/2023]
Abstract
Gliomas are the most prevalent tumours of the central nervous system and present with high morbidity and mortality. The most common and most aggressive form of glioma is glioblastoma multiforme, of which patients have a median survival time of only 12 to 15 months. Current treatment options are limited and have a small impact on clinical outcome and prognosis. There is accumulating evidence that microglia, the immunocompetent cells of the central nervous system, and the purinergic P2X7 receptor (P2X7R) may contribute to tumour progression and pathology. Importantly, P2X7R on both tumour cells and infiltrating microglia is overexpressed in animal and human glioma cultures. Factors released by glioma cells and P2X7R activation recruit microglia into the largely immunosuppressive tumour microenvironment where they have been demonstrated to contribute to either tumour proliferation or tumour suppression. It is likely that P2X7R mediates a range of microglia effector functions in the glioma setting, potentially increasing tumour growth and proliferation. This review evaluates current evidence on the roles of microglia and P2X7R in glioma pathogenesis. Understanding the nature, mechanisms and outcomes of microglia and P2X7R activation in gliomas is necessary for the development of more therapies with increased efficacy and specificity.
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Wang J, Hjelmeland AB, Nabors LB, King PH. Anti-cancer effects of the HuR inhibitor, MS-444, in malignant glioma cells. Cancer Biol Ther 2019; 20:979-988. [PMID: 30991885 DOI: 10.1080/15384047.2019.1591673] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Glioblastoma is a highly malignant and typically fatal tumor of the central nervous system. The tumor is characterized by marked cellular and molecular heterogeneity, including a subpopulation of brain tumor initiating cells (BTICs) that are highly resistant to radiation and chemotherapy. We previously reported that the RNA-binding protein HuR is: (1) overexpressed in glioblastoma, (2) necessary for tumor growth in vivo, and (3) a positive regulator of tumor-promoting genes in glioblastoma. These findings provide strong evidence that HuR might be a viable therapeutic target in glioblastoma. In this report, we investigated the effects of MS-444, a small molecule inhibitor of HuR, in xenograft-derived human glioblastoma cells and BTICs. We found that MS-444 treatment of glioblastoma cells resulted in loss of viability and induction of apoptosis, with evidence implicating death receptor 5. BTICs were particularly sensitive to MS-444. At sub-lethal doses, MS-444 attenuated invasion of glioblastoma cells and BTICs in a transwell model. At the molecular level, MS-444 treatment led to an attenuation of mRNAs in different tumor promoting pathways including angiogenesis, immune evasion and suppression of apoptosis. Although cytoplasmic HuR was reduced with MS-444 treatment, the attenuation of mRNAs could not be explained by RNA destabilization. In summary, this report provides proof of concept that small molecule inhibition of HuR could be a viable approach for treatment of glioblastoma.
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Affiliation(s)
- Jiping Wang
- a Departments of Neurology , University of Alabama , Birmingham , AL
| | - Anita B Hjelmeland
- b Cell, Developmental, and Integrative Biology , University of Alabama , Birmingham , AL
| | - L Burt Nabors
- a Departments of Neurology , University of Alabama , Birmingham , AL
| | - Peter H King
- a Departments of Neurology , University of Alabama , Birmingham , AL.,b Cell, Developmental, and Integrative Biology , University of Alabama , Birmingham , AL.,c Birmingham Veterans Affairs Medical Center , Birmingham , AL
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Fahey JM, Girotti AW. Nitric Oxide Antagonism to Anti-Glioblastoma Photodynamic Therapy: Mitigation by Inhibitors of Nitric Oxide Generation. Cancers (Basel) 2019; 11:E231. [PMID: 30781428 PMCID: PMC6406633 DOI: 10.3390/cancers11020231] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 01/25/2019] [Accepted: 02/09/2019] [Indexed: 12/14/2022] Open
Abstract
Many studies have shown that low flux nitric oxide (NO) produced by inducible NO synthase (iNOS/NOS2) in various tumors, including glioblastomas, can promote angiogenesis, cell proliferation, and migration/invasion. Minimally invasive, site-specific photodynamic therapy (PDT) is a highly promising anti-glioblastoma modality. Recent research in the authors' laboratory has revealed that iNOS-derived NO in glioblastoma cells elicits resistance to 5-aminolevulinic acid (ALA)-based PDT, and moreover endows PDT-surviving cells with greater proliferation and migration/invasion aggressiveness. In this contribution, we discuss iNOS/NO antagonism to glioblastoma PDT and how this can be overcome by judicious use of pharmacologic inhibitors of iNOS activity or transcription.
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Affiliation(s)
- Jonathan M Fahey
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
| | - Albert W Girotti
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
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41
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Gaseous signaling molecules and their application in resistant cancer treatment: from invisible to visible. Future Med Chem 2019; 11:323-336. [PMID: 30802141 DOI: 10.4155/fmc-2018-0403] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Multidrug resistance (MDR) in cancer remains a critical obstacle for efficient chemotherapy. Many MDR reversal agents have been discovered but failed in clinical trials due to severe toxic effects. Gaseous signaling molecules (GSMs), such as oxygen, nitric oxide, hydrogen sulfide and carbon monoxide, play key roles in regulating cell biological function and MDR. Compared with other toxic chemosensitizing agents, GSMs are endogenous and biocompatible molecules with little side effects. Research show that GSM modulators, including pharmaceutical formulations of GSMs (combined with conventional chemotherapeutic drugs) and GSM-donors (small molecules with GSMs releasing property), can overcome or reverse MDR. This review discusses the roles of these four GSMs in modulating MDR, and summarizes GSMs modulators in treating cancers with drug resistance.
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Lan M, Tang X, Zhang J, Yao Z. Insights in pathogenesis of multiple sclerosis: nitric oxide may induce mitochondrial dysfunction of oligodendrocytes. Rev Neurosci 2018; 29:39-53. [PMID: 28822986 DOI: 10.1515/revneuro-2017-0033] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Accepted: 06/15/2017] [Indexed: 01/01/2023]
Abstract
Demyelinating diseases, such as multiple sclerosis (MS), are kinds of common diseases in the central nervous system (CNS), and originated from myelin loss and axonal damage. Oligodendrocyte dysfunction is the direct reason of demyelinating lesions in the CNS. Nitric oxide (NO) plays an important role in the pathological process of demyelinating diseases. Although the neurotoxicity of NO is more likely mediated by peroxynitrite rather than NO itself, NO can impair oligodendrocyte energy metabolism through mediating the damaging of mitochondrial DNA, mitochondrial membrane and mitochondrial respiratory chain complexes. In the progression of MS, NO can mainly mediate demyelination, axonal degeneration and cell death. Hence, in this review, we extensively discuss endangerments of NO in oligodendrocytes (OLs), which is suggested to be the main mediator in demyelinating diseases, e.g. MS. We hypothesize that NO takes part in MS through impairing the function of monocarboxylate transporter 1, especially causing axonal degeneration. Then, it further provides a new insight that NO for OLs may be a reliable therapeutic target to ameliorate the course of demyelinating diseases.
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Affiliation(s)
- Minghong Lan
- Department of Physiology, Third Military Medical University, Chongqing 400038, China
| | - Xiaoyi Tang
- Department of Physiology, Third Military Medical University, Chongqing 400038, China
| | - Jie Zhang
- Department of Physiology, Third Military Medical University, Chongqing 400038, China
| | - Zhongxiang Yao
- Department of Physiology, Third Military Medical University, Chongqing 400038, China
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Palumbo P, Lombardi F, Siragusa G, Dehcordi SR, Luzzi S, Cimini A, Cifone MG, Cinque B. Involvement of NOS2 Activity on Human Glioma Cell Growth, Clonogenic Potential, and Neurosphere Generation. Int J Mol Sci 2018; 19:ijms19092801. [PMID: 30227679 PMCID: PMC6165034 DOI: 10.3390/ijms19092801] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Revised: 09/13/2018] [Accepted: 09/14/2018] [Indexed: 12/12/2022] Open
Abstract
Aberrant nitric oxide synthase 2 (NOS2) expression has been suggested as an interesting therapeutic target that is being implicated as a component of the molecular profile of several human malignant tumors, including glioblastoma, which is the most aggressive brain tumor with limited therapeutic options and poor prognosis. The aim of the present work was to evaluate the effect of 1400W, a specific NOS2 inhibitor, on human glioma cells in terms of clonogenic potential, proliferation, migration rate, and neurosphere generation ability. NOS2 expression was determined by Western blotting. Nitric oxide (NO) production was measured through nitrite level determination. The trypan blue exclusion test and the plate colony formation assay were performed to evaluate cell proliferation and clonogenic potential. Cell proliferation and migration ability was assessed by the in vitro wound-healing assay. Neurosphere generation in a specific stemcell medium was investigated. NOS2 was confirmed to be expressed in both the glioma cell line and a human glioma primary culture, and overexpressed in relative derived neurospheres. Experiments that aimed to evaluate the influence of 1400W on U-87 MG, T98G (glioblastoma cell lines) and primary glioma cells sustained the crucial role played by NOS2 in proliferation, colony formation, migration, and neurosphere generation, thus supporting the emerging relevance of a NOS2/NO system as a prognostic factor for glioma malignancy and recurrence.
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Affiliation(s)
- Paola Palumbo
- Department of Life, Health & Environmental Sciences, University of L'Aquila, Building Delta 6, Coppito, 67100 L'Aquila, Italy.
| | - Francesca Lombardi
- Department of Life, Health & Environmental Sciences, University of L'Aquila, Building Delta 6, Coppito, 67100 L'Aquila, Italy.
| | - Giuseppe Siragusa
- Department of Life, Health & Environmental Sciences, University of L'Aquila, Building Delta 6, Coppito, 67100 L'Aquila, Italy.
| | | | - Sabino Luzzi
- Operative Unit of Neurosurgery, San Salvatore Hospital, 67100 L'Aquila, Italy.
| | - AnnaMaria Cimini
- Department of Life, Health & Environmental Sciences, University of L'Aquila, Building Delta 6, Coppito, 67100 L'Aquila, Italy.
- Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology, Temple University, Philadelphia, PA 19122, USA.
| | - Maria Grazia Cifone
- Department of Life, Health & Environmental Sciences, University of L'Aquila, Building Delta 6, Coppito, 67100 L'Aquila, Italy.
| | - Benedetta Cinque
- Department of Life, Health & Environmental Sciences, University of L'Aquila, Building Delta 6, Coppito, 67100 L'Aquila, Italy.
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Tran AN, Walker K, Harrison DG, Chen W, Mobley J, Hocevar L, Hackney JR, Sedaka RS, Pollock JS, Goldberg MS, Hambardzumyan D, Cooper SJ, Gillespie Y, Hjelmeland AB. Reactive species balance via GTP cyclohydrolase I regulates glioblastoma growth and tumor initiating cell maintenance. Neuro Oncol 2018; 20:1055-1067. [PMID: 29409010 PMCID: PMC6280150 DOI: 10.1093/neuonc/noy012] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Background Depending on the level, differentiation state, and tumor stage, reactive nitrogen and oxygen species inhibit or increase cancer growth and tumor initiating cell maintenance. The rate-limiting enzyme in a pathway that can regulate reactive species production but has not been thoroughly investigated in glioblastoma (GBM; grade IV astrocytoma) is guanosine triphosphate (GTP) cyclohydrolase 1 (GCH1). We sought to define the role of GCH1 in the regulation of GBM growth and brain tumor initiating cell (BTIC) maintenance. Methods We examined GCH1 mRNA and protein expression in patient-derived xenografts, clinical samples, and glioma gene expression datasets. GCH1 levels were modulated using lentiviral expression systems, and effects on cell growth, self-renewal, reactive species production, and survival in orthotopic patient-derived xenograft models were determined. Results GCH1 was expressed in GBMs with elevated but not exclusive RNA and protein levels in BTICs in comparison to non-BTICs. Overexpression of GCH1 in GBM cells increased cell growth in vitro and decreased survival in an intracranial GBM mouse model. In converse experiments, GCH1 knockdown with short hairpin RNA led to GBM cell growth inhibition and reduced self-renewal in association with decreased CD44 expression. GCH1 was critical for controlling reactive species balance, including suppressing reactive oxygen species production, which mediated GCH1 cell growth effects. In silico analyses demonstrated that higher GCH1 levels in glioma patients correlate with higher glioma grade, recurrence, and worse survival. Conclusions GCH1 expression in established GBMs is pro-tumorigenic, causing increased growth due, in part, to promotion of BTIC maintenance and suppression of reactive oxygen species.
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Affiliation(s)
- Anh Nhat Tran
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Kiera Walker
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama
| | - David G Harrison
- Division of Clinical Pharmacology, Vanderbilt University, Nashville, Tennessee
| | - Wei Chen
- Division of Clinical Pharmacology, Vanderbilt University, Nashville, Tennessee
| | - James Mobley
- Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama
| | - Lauren Hocevar
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama
| | - James R Hackney
- Division of Neuropathology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Randee S Sedaka
- Division of Nephrology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Jennifer S Pollock
- Division of Nephrology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Matthew S Goldberg
- Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama
| | | | - Sara J Cooper
- HudsonAlpha Institute for Biotechnology, Huntsville, Alabama
| | - Yancey Gillespie
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama
| | - Anita B Hjelmeland
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama
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Hira VV, Aderetti DA, van Noorden CJ. Glioma Stem Cell Niches in Human Glioblastoma Are Periarteriolar. J Histochem Cytochem 2018; 66:349-358. [PMID: 29328867 PMCID: PMC5958355 DOI: 10.1369/0022155417752676] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Accepted: 12/11/2017] [Indexed: 12/22/2022] Open
Abstract
Survival of primary brain tumor (glioblastoma) patients is seriously hampered by glioma stem cells (GSCs) that are distinct therapy-resistant self-replicating pluripotent cancer cells. GSCs reside in GSC niches, which are specific protective microenvironments in glioblastoma tumors. We have recently found that GSC niches are hypoxic periarteriolar, whereas in most studies, GSC niches are identified as hypoxic perivascular. The aim of this review is to critically evaluate the literature on perivascular GSC niches to establish whether these are periarteriolar, pericapillary, perivenular, and/or perilymphatic. We found six publications showing images of human glioblastoma tissue containing perivascular GSC niches without any specification of the vessel type. However, it is frequently assumed that these vessels are capillaries which are exchange vessels, whereas arterioles and venules are transport vessels. Closer inspection of the figures of these publications showed vessels that were not capillaries. Whether these vessels were arterioles or venules was difficult to determine in one case, but in the other cases, these were clearly arterioles and their perivascular niches were similar to the periarteriolar niches we have found. Therefore, we conclude that in human glioblastoma tumors, GSC niches are hypoxic periarteriolar and are structurally and functionally look-alikes of hematopoietic stem cell niches in the bone marrow.
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Affiliation(s)
- Vashendriya V.V. Hira
- Cancer Center Amsterdam, Department of Medical Biology at the Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Diana A. Aderetti
- Cancer Center Amsterdam, Department of Medical Biology at the Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Cornelis J.F. van Noorden
- Cancer Center Amsterdam, Department of Medical Biology at the Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
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Endothelial Ca 2+ Signaling and the Resistance to Anticancer Treatments: Partners in Crime. Int J Mol Sci 2018; 19:ijms19010217. [PMID: 29324706 PMCID: PMC5796166 DOI: 10.3390/ijms19010217] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Revised: 01/08/2018] [Accepted: 01/10/2018] [Indexed: 02/06/2023] Open
Abstract
Intracellular Ca2+ signaling drives angiogenesis and vasculogenesis by stimulating proliferation, migration, and tube formation in both vascular endothelial cells and endothelial colony forming cells (ECFCs), which represent the only endothelial precursor truly belonging to the endothelial phenotype. In addition, local Ca2+ signals at the endoplasmic reticulum (ER)-mitochondria interface regulate endothelial cell fate by stimulating survival or apoptosis depending on the extent of the mitochondrial Ca2+ increase. The present article aims at describing how remodeling of the endothelial Ca2+ toolkit contributes to establish intrinsic or acquired resistance to standard anti-cancer therapies. The endothelial Ca2+ toolkit undergoes a major alteration in tumor endothelial cells and tumor-associated ECFCs. These include changes in TRPV4 expression and increase in the expression of P2X7 receptors, Piezo2, Stim1, Orai1, TRPC1, TRPC5, Connexin 40 and dysregulation of the ER Ca2+ handling machinery. Additionally, remodeling of the endothelial Ca2+ toolkit could involve nicotinic acetylcholine receptors, gasotransmitters-gated channels, two-pore channels and Na⁺/H⁺ exchanger. Targeting the endothelial Ca2+ toolkit could represent an alternative adjuvant therapy to circumvent patients' resistance to current anti-cancer treatments.
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Cholia RP, Kumari S, Kumar S, Kaur M, Kaur M, Kumar R, Dhiman M, Mantha AK. An in vitro study ascertaining the role of H 2O 2 and glucose oxidase in modulation of antioxidant potential and cancer cell survival mechanisms in glioblastoma U-87 MG cells. Metab Brain Dis 2017; 32:1705-1716. [PMID: 28676971 DOI: 10.1007/s11011-017-0057-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Accepted: 06/16/2017] [Indexed: 12/15/2022]
Abstract
Glial cells protect themselves from the elevated reactive oxygen species (ROS) via developing unusual mechanisms to maintain the genomic stability, and reprogramming of the cellular antioxidant system to cope with the adverse effects. In the present study non-cytotoxic dose of oxidants, H2O2 (100 μM) and GO (10 μU/ml) was used to induce moderate oxidative stress via generating ROS in human glioblastoma cell line U-87 MG cells, which showed a marked increase in the antioxidant capacity as studied by measuring the modulation in expression levels and activities of superoxide dismutase (SOD1 and SOD2) and catalase (CAT) enzymes, and the GSH content. However, pretreatment (3 h) of Curcumin and Quercetin (10 μM) followed by the treatment of oxidants enhanced the cell survival, and the levels/activities of the antioxidants studied. Oxidative stress also resulted in an increase in the nitrite levels in the culture supernatants, and further analysis by immunocytochemistry showed an increase in iNOS expression. In addition, phytochemical pretreatment decreased the nitrite level in the culture supernatants of oxidatively stressed U-87 MG cells. Elevated ROS also increased the expression of COX-2 and APE1 enzymes and pretreatment of Curcumin and Quercetin decreased COX-2 expression and increased APE1 expression in the oxidatively stressed U-87 MG cells. The immunocytochemistry also indicates for APE1 enhanced stress-dependent subcellular localization to the nuclear compartment, which advocates for enhanced DNA repair and redox functions of APE1 towards survival of U-87 MG cells. It can be concluded that intracellular oxidants activate the key enzymes involved in antioxidant mechanisms, NO-dependent survival mechanisms, and also in the DNA repair pathways for glial cell survival in oxidative-stress micro-environment.
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Affiliation(s)
- Ravi P Cholia
- Center for Animal Sciences, School of Basic and Applied Sciences, Central University of Punjab, Bathinda, Punjab, 151 001, India
| | - Sanju Kumari
- Center for Biosciences, School of Basic and Applied Sciences, Central University of Punjab, Bathinda, Punjab, India
| | - Saurabh Kumar
- Center for Biosciences, School of Basic and Applied Sciences, Central University of Punjab, Bathinda, Punjab, India
| | - Manpreet Kaur
- Center for Biosciences, School of Basic and Applied Sciences, Central University of Punjab, Bathinda, Punjab, India
| | - Manbir Kaur
- Center for Biosciences, School of Basic and Applied Sciences, Central University of Punjab, Bathinda, Punjab, India
| | - Raj Kumar
- Center for Pharmaceutical Sciences and Natural Products, School of Basic and Applied Sciences, Central University of Punjab, Bathinda, Punjab, India
| | - Monisha Dhiman
- Center for Biochemistry and Microbial Sciences, School of Basic and Applied Sciences, Central University of Punjab, Bathinda, Punjab, India
| | - Anil K Mantha
- Center for Animal Sciences, School of Basic and Applied Sciences, Central University of Punjab, Bathinda, Punjab, 151 001, India.
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Palumbo P, Miconi G, Cinque B, Lombardi F, Torre CL, Dehcordi SR, Galzio R, Cimini A, Giordano A, Cifone MG. NOS2 expression in glioma cell lines and glioma primary cell cultures: correlation with neurosphere generation and SOX-2 expression. Oncotarget 2017; 8:25582-25598. [PMID: 28424427 PMCID: PMC5421953 DOI: 10.18632/oncotarget.16106] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Accepted: 02/15/2017] [Indexed: 01/14/2023] Open
Abstract
Nitric oxide has been implicated in biology and progression of glioblastoma (GBM) being able to influence the cellular signal depending on the concentration and duration of cell exposure. NOS2 (inducible nitric oxide synthase) have been proposed as a component of molecular profile of several tumors, including glioma, one of the most aggressive primary brain tumor featuring local cancer stem cells responsible for enhanced resistance to therapies and for tumor recurrence. Here, we investigated the NOS2 mRNA expression by reverse transcription-PCR in human glioma primary cultures at several grade of malignancy and glioma stem cell (GSC) derived neurospheres. Glioma cell lines were used as positive controls both in terms of stemness marker expression that of capacity of generating neurospheres. NOS2 expression was detected at basal levels in cell lines and primary cultures and appeared significantly up-regulated in cultures kept in the specific medium for neurospheres. The immunofluorescence analysis of all cell cultures to evaluate the levels of SOX-2, a stemness marker aberrantly up-regulated in GBM, was also performed. The potential correlation between NOS2 expression and ability to generate neurospheres and between NOS2 and SOX-2 levels was also verified. The results show that the higher NOS2 expression is detected in all primary cultures able to arise neurosphere. A high and significant correlation between NOS2 expression and SOX-2 positive cells (%) in all cell cultures maintained in standard conditions has been observed. The results shed light on the potential relevance of NOS2 as a prognostic factor for glioma malignancy and recurrence.
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Affiliation(s)
- Paola Palumbo
- Department of Life, Health and Environmental Sciences, University of L’Aquila, L’Aquila, Italy
| | - Gianfranca Miconi
- Department of Life, Health and Environmental Sciences, University of L’Aquila, L’Aquila, Italy
| | - Benedetta Cinque
- Department of Life, Health and Environmental Sciences, University of L’Aquila, L’Aquila, Italy
| | - Francesca Lombardi
- Department of Life, Health and Environmental Sciences, University of L’Aquila, L’Aquila, Italy
| | - Cristina La Torre
- Department of Life, Health and Environmental Sciences, University of L’Aquila, L’Aquila, Italy
| | - Soheila Raysi Dehcordi
- Department of Life, Health and Environmental Sciences, University of L’Aquila, L’Aquila, Italy
- Department of Surgery, Operative Unit of Neurosurgery, San Salvatore Hospital, L’Aquila, Italy
| | - Renato Galzio
- Department of Life, Health and Environmental Sciences, University of L’Aquila, L’Aquila, Italy
- Department of Surgery, Operative Unit of Neurosurgery, San Salvatore Hospital, L’Aquila, Italy
| | - Annamaria Cimini
- Department of Life, Health and Environmental Sciences, University of L’Aquila, L’Aquila, Italy
- Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology, Temple University, Philadelphia, PA, USA
- National Institute for Nuclear Physics (INFN), Gran Sasso National Laboratory (LNGS), Assergi, Italy
| | - Antonio Giordano
- Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology, Temple University, Philadelphia, PA, USA
- Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy
| | - Maria Grazia Cifone
- Department of Life, Health and Environmental Sciences, University of L’Aquila, L’Aquila, Italy
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