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Zhang W, Xia M, Li J, Liu G, Sun Y, Chen X, Zhong J. Warburg effect and lactylation in cancer: mechanisms for chemoresistance. Mol Med 2025; 31:146. [PMID: 40264038 PMCID: PMC12016192 DOI: 10.1186/s10020-025-01205-6] [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: 02/18/2025] [Accepted: 04/09/2025] [Indexed: 04/24/2025] Open
Abstract
In the clinical management of cancers, the emergence of chemoresistance represents a profound and imperative "pain point" that requires immediate attention. Understanding the mechanisms of chemoresistance is essential for developing effective therapeutic strategies. Importantly, existing studies have demonstrated that glucose metabolic reprogramming, commonly referred to as the Warburg effect or aerobic glycolysis, is a major contributor to chemoresistance. Additionally, lactate, a byproduct of aerobic glycolysis, functions as a signaling molecule that supports lysine lactylation modification of proteins, which also plays a critical role in chemoresistance. However, it is insufficient to discuss the role of glycolysis or lactylation in chemoresistance from a single perspective. The intricate relationship between aerobic glycolysis and lactylation plays a crucial role in promoting chemoresistance. Thus, a thorough elucidation of the mechanisms underlying chemoresistance mediated by aerobic glycolysis and lactylation is essential. This review provides a comprehensive overview of these mechanisms and further outlines that glycolysis and lactylation exert synergistic effects, promoting the development of chemoresistance and creating a positive feedback loop that continues to mediate this resistance. The close link between aerobic glycolysis and lactylation suggests that the application of glycolysis-related drugs or inhibitors in cancer therapy may represent a promising anticancer strategy. Furthermore, the targeted application of lactylation, either alone or in combination with other treatments, may offer new therapeutic avenues for overcoming chemoresistance.
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Affiliation(s)
- Wenjie Zhang
- Clinical Medical Research Center, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
- Institute of Cancer Research, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Min Xia
- Clinical Medical Research Center, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
- Institute of Cancer Research, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Jiahui Li
- Clinical Medical Research Center, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
- Institute of Cancer Research, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Gaohua Liu
- Clinical Medical Research Center, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
- Institute of Cancer Research, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Yan Sun
- Clinical Medical Research Center, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
- Institute of Cancer Research, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Xisha Chen
- Clinical Medical Research Center, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
- Institute of Cancer Research, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
| | - Jing Zhong
- Clinical Medical Research Center, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
- Institute of Cancer Research, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
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Aden D, Sureka N, Zaheer S, Chaurasia JK, Zaheer S. Metabolic Reprogramming in Cancer: Implications for Immunosuppressive Microenvironment. Immunology 2025; 174:30-72. [PMID: 39462179 DOI: 10.1111/imm.13871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2024] [Revised: 10/07/2024] [Accepted: 10/09/2024] [Indexed: 10/29/2024] Open
Abstract
Cancer is a complex and heterogeneous disease characterised by uncontrolled cell growth and proliferation. One hallmark of cancer cells is their ability to undergo metabolic reprogramming, which allows them to sustain their rapid growth and survival. This metabolic reprogramming creates an immunosuppressive microenvironment that facilitates tumour progression and evasion of the immune system. In this article, we review the mechanisms underlying metabolic reprogramming in cancer cells and discuss how these metabolic alterations contribute to the establishment of an immunosuppressive microenvironment. We also explore potential therapeutic strategies targeting metabolic vulnerabilities in cancer cells to enhance immune-mediated anti-tumour responses. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02044861, NCT03163667, NCT04265534, NCT02071927, NCT02903914, NCT03314935, NCT03361228, NCT03048500, NCT03311308, NCT03800602, NCT04414540, NCT02771626, NCT03994744, NCT03229278, NCT04899921.
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Affiliation(s)
- Durre Aden
- Department of Pathology, Hamdard Institute of Medical Science and Research, New Delhi, India
| | - Niti Sureka
- Department of Pathology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India
| | - Samreen Zaheer
- Department of Radiotherapy, Jawaharlal Nehru Medical College, AMU, Aligarh, India
| | | | - Sufian Zaheer
- Department of Pathology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India
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Hao ZN, Tan XP, Zhang Q, Li J, Xia R, Ma Z. Lactate and Lactylation: Dual Regulators of T-Cell-Mediated Tumor Immunity and Immunotherapy. Biomolecules 2024; 14:1646. [PMID: 39766353 PMCID: PMC11674224 DOI: 10.3390/biom14121646] [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: 11/14/2024] [Revised: 12/14/2024] [Accepted: 12/19/2024] [Indexed: 01/11/2025] Open
Abstract
Lactate and its derivative, lactylation, play pivotal roles in modulating immune responses within the tumor microenvironment (TME), particularly in T-cell-mediated cancer immunotherapy. Elevated lactate levels, a hallmark of the Warburg effect, contribute to immune suppression through CD8+ T cell functionality and by promoting regulatory T cell (Treg) activity. Lactylation, a post-translational modification (PTM), alters histone and non-histone proteins, influencing gene expression and further reinforcing immune suppression. In the complex TME, lactate and its derivative, lactylation, are not only associated with immune suppression but can also, under certain conditions, exert immunostimulatory effects that enhance cytotoxic responses. This review describes the dual roles of lactate and lactylation in T-cell-mediated tumor immunity, analyzing how these factors contribute to immune evasion, therapeutic resistance, and immune activation. Furthermore, the article highlights emerging therapeutic strategies aimed at inhibiting lactate production or disrupting lactylation pathways to achieve a balanced regulation of these dual effects. These strategies offer new insights into overcoming tumor-induced immune suppression and hold the potential to improve the efficacy of cancer immunotherapies.
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Affiliation(s)
- Zhi-Nan Hao
- Department of Gastroenterology, First Affiliated Hospital of Yangtze University, Health Science Center, Yangtze University, Jingzhou 434023, China; (Z.-N.H.); (Q.Z.); (J.L.)
- Digestive Disease Research Institution of Yangtze University, Yangtze University, Jingzhou 434023, China;
| | - Xiao-Ping Tan
- Digestive Disease Research Institution of Yangtze University, Yangtze University, Jingzhou 434023, China;
- The Third Clinical Medical College of Yangtze University, Jingzhou Hospital of Traditional Chinese Medicine, Jingzhou 434023, China
| | - Qing Zhang
- Department of Gastroenterology, First Affiliated Hospital of Yangtze University, Health Science Center, Yangtze University, Jingzhou 434023, China; (Z.-N.H.); (Q.Z.); (J.L.)
- Digestive Disease Research Institution of Yangtze University, Yangtze University, Jingzhou 434023, China;
| | - Jie Li
- Department of Gastroenterology, First Affiliated Hospital of Yangtze University, Health Science Center, Yangtze University, Jingzhou 434023, China; (Z.-N.H.); (Q.Z.); (J.L.)
- Digestive Disease Research Institution of Yangtze University, Yangtze University, Jingzhou 434023, China;
| | - Ruohan Xia
- Department of Gastroenterology, First Affiliated Hospital of Yangtze University, Health Science Center, Yangtze University, Jingzhou 434023, China; (Z.-N.H.); (Q.Z.); (J.L.)
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, China
| | - Zhaowu Ma
- Department of Gastroenterology, First Affiliated Hospital of Yangtze University, Health Science Center, Yangtze University, Jingzhou 434023, China; (Z.-N.H.); (Q.Z.); (J.L.)
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, China
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Kooshan Z, Cárdenas-Piedra L, Clements J, Batra J. Glycolysis, the sweet appetite of the tumor microenvironment. Cancer Lett 2024; 600:217156. [PMID: 39127341 DOI: 10.1016/j.canlet.2024.217156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 07/17/2024] [Accepted: 08/02/2024] [Indexed: 08/12/2024]
Abstract
Cancer cells display an altered metabolic phenotype, characterised by increased glycolysis and lactate production, even in the presence of sufficient oxygen - a phenomenon known as the Warburg effect. This metabolic reprogramming is a crucial adaptation that enables cancer cells to meet their elevated energy and biosynthetic demands. Importantly, the tumor microenvironment plays a pivotal role in shaping and sustaining this metabolic shift in cancer cells. This review explores the intricate relationship between the tumor microenvironment and the Warburg effect, highlighting how communication within this niche regulates cancer cell metabolism and impacts tumor progression and therapeutic resistance. We discuss the potential of targeting the Warburg effect as a promising therapeutic strategy, with the aim of disrupting the metabolic advantage of cancer cells and enhancing our understanding of this complex interplay within the tumor microenvironment.
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Affiliation(s)
- Zeinab Kooshan
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Australia; Center for Genomics and Personalised Health, Translational Research Institute, Queensland University of Technology, Brisbane, Australia
| | - Lilibeth Cárdenas-Piedra
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Australia; Center for Genomics and Personalised Health, Translational Research Institute, Queensland University of Technology, Brisbane, Australia; ARC Training Centre for Cell & Tissue Engineering Technologies, Brisbane, Australia
| | - Judith Clements
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Australia; Center for Genomics and Personalised Health, Translational Research Institute, Queensland University of Technology, Brisbane, Australia
| | - Jyotsna Batra
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Australia; Center for Genomics and Personalised Health, Translational Research Institute, Queensland University of Technology, Brisbane, Australia; ARC Training Centre for Cell & Tissue Engineering Technologies, Brisbane, Australia.
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Zhao J, Sun H, Wang C, Shang D. Breast cancer therapy: from the perspective of glucose metabolism and glycosylation. Mol Biol Rep 2024; 51:546. [PMID: 38642246 DOI: 10.1007/s11033-024-09466-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Accepted: 03/22/2024] [Indexed: 04/22/2024]
Abstract
Breast cancer is a leading cause of mortality and the most prevalent form of malignant tumor among women worldwide. Breast cancer cells exhibit an elevated glycolysis and altered glucose metabolism. Moreover, these cells display abnormal glycosylation patterns, influencing invasion, proliferation, metastasis, and drug resistance. Consequently, targeting glycolysis and mitigating abnormal glycosylation represent key therapeutic strategies for breast cancer. This review underscores the importance of protein glycosylation and glucose metabolism alterations in breast cancer. The current research efforts in developing effective interventions targeting glycolysis and glycosylation are further discussed.
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Affiliation(s)
- Jiaqi Zhao
- Department of Pharmacy, School of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian, 116029, China
| | - Haiting Sun
- Department of Pharmacy, School of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian, 116029, China
| | - Che Wang
- Department of Pharmacy, School of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian, 116029, China.
- Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, School of Life Science, Liaoning Normal University, Dalian, 116081, China.
| | - Dejing Shang
- Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, School of Life Science, Liaoning Normal University, Dalian, 116081, China.
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Hang C, Moawad MS, Lin Z, Guo H, Xiong H, Zhang M, Lu R, Liu J, Shi D, Xie D, Liu Y, Liang D, Chen YH, Yang J. Biosafe cerium oxide nanozymes protect human pluripotent stem cells and cardiomyocytes from oxidative stress. J Nanobiotechnology 2024; 22:132. [PMID: 38532378 DOI: 10.1186/s12951-024-02383-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 03/07/2024] [Indexed: 03/28/2024] Open
Abstract
BACKGROUND Cardiovascular diseases (CVDs) have the highest mortality worldwide. Human pluripotent stem cells (hPSCs) and their cardiomyocyte derivatives (hPSC-CMs) offer a valuable resource for disease modeling, pharmacological screening, and regenerative therapy. While most CVDs are linked to significant over-production of reactive oxygen species (ROS), the effects of current antioxidants targeting excessive ROS are limited. Nanotechnology is a powerful tool to develop antioxidants with improved selectivity, solubility, and bioavailability to prevent or treat various diseases related to oxidative stress. Cerium oxide nanozymes (CeONZs) can effectively scavenge excessive ROS by mimicking the activity of endogenous antioxidant enzymes. This study aimed to assess the nanotoxicity of CeONZs and their potential antioxidant benefits in stressed human embryonic stem cells (hESCs) and their derived cardiomyocytes (hESC-CMs). RESULTS CeONZs demonstrated reliable nanosafety and biocompatibility in hESCs and hESC-CMs within a broad range of concentrations. CeONZs exhibited protective effects on the cell viability of hESCs and hESC-CMs by alleviating excessive ROS-induced oxidative stress. Moreover, CeONZs protected hESC-CMs from doxorubicin (DOX)-induced cardiotoxicity and partially ameliorated the insults from DOX in neonatal rat cardiomyocytes (NRCMs). Furthermore, during hESCs culture, CeONZs were found to reduce ROS, decrease apoptosis, and enhance cell survival without affecting their self-renewal and differentiation potential. CONCLUSIONS CeONZs displayed good safety and biocompatibility, as well as enhanced the cell viability of hESCs and hESC-CMs by shielding them from oxidative damage. These promising results suggest that CeONZs may be crucial, as a safe nanoantioxidant, to potentially improve the therapeutic efficacy of CVDs and be incorporated into regenerative medicine.
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Affiliation(s)
- Chengwen Hang
- State Key Laboratory of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Shanghai Arrhythmia Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Shanghai Frontiers Center of Nanocatalytic Medicine, Shanghai, 200092, China
| | - Mohamed S Moawad
- Department of Toxicology and Forensic Medicine, Faculty of Veterinary Medicine, Cairo University, Giza, 3725005, Egypt.
| | - Zheyi Lin
- State Key Laboratory of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Shanghai Arrhythmia Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Shanghai Frontiers Center of Nanocatalytic Medicine, Shanghai, 200092, China
- Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai, 200092, China
| | - Huixin Guo
- Department of Cardiology, The Second Hospital of Shanxi Medical University, Taiyuan, 030001, China
| | - Hui Xiong
- State Key Laboratory of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Shanghai Arrhythmia Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Shanghai Frontiers Center of Nanocatalytic Medicine, Shanghai, 200092, China
- Department of Cell Biology, Tongji University School of Medicine, Shanghai, 200092, China
| | - Mingshuai Zhang
- State Key Laboratory of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Shanghai Arrhythmia Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Shanghai Frontiers Center of Nanocatalytic Medicine, Shanghai, 200092, China
- Department of Cell Biology, Tongji University School of Medicine, Shanghai, 200092, China
| | - Renhong Lu
- State Key Laboratory of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Shanghai Arrhythmia Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Shanghai Frontiers Center of Nanocatalytic Medicine, Shanghai, 200092, China
| | - Junyang Liu
- State Key Laboratory of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Shanghai Arrhythmia Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Shanghai Frontiers Center of Nanocatalytic Medicine, Shanghai, 200092, China
- Department of Cell Biology, Tongji University School of Medicine, Shanghai, 200092, China
| | - Dan Shi
- State Key Laboratory of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Shanghai Arrhythmia Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Shanghai Frontiers Center of Nanocatalytic Medicine, Shanghai, 200092, China
| | - Duanyang Xie
- State Key Laboratory of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Shanghai Arrhythmia Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Shanghai Frontiers Center of Nanocatalytic Medicine, Shanghai, 200092, China
- Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai, 200092, China
| | - Yi Liu
- State Key Laboratory of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Shanghai Arrhythmia Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Shanghai Frontiers Center of Nanocatalytic Medicine, Shanghai, 200092, China
- Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai, 200092, China
| | - Dandan Liang
- State Key Laboratory of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Shanghai Arrhythmia Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Shanghai Frontiers Center of Nanocatalytic Medicine, Shanghai, 200092, China
- Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai, 200092, China
- Research Units of Origin and Regulation of Heart Rhythm, Chinese Academy of Medical Sciences, Shanghai, 200092, China
| | - Yi-Han Chen
- State Key Laboratory of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
- Shanghai Arrhythmia Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
- Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
- Shanghai Frontiers Center of Nanocatalytic Medicine, Shanghai, 200092, China.
- Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai, 200092, China.
- Research Units of Origin and Regulation of Heart Rhythm, Chinese Academy of Medical Sciences, Shanghai, 200092, China.
| | - Jian Yang
- State Key Laboratory of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
- Shanghai Arrhythmia Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
- Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
- Shanghai Frontiers Center of Nanocatalytic Medicine, Shanghai, 200092, China.
- Department of Cell Biology, Tongji University School of Medicine, Shanghai, 200092, China.
- Research Units of Origin and Regulation of Heart Rhythm, Chinese Academy of Medical Sciences, Shanghai, 200092, China.
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Bosso M, Haddad D, Al Madhoun A, Al-Mulla F. Targeting the Metabolic Paradigms in Cancer and Diabetes. Biomedicines 2024; 12:211. [PMID: 38255314 PMCID: PMC10813379 DOI: 10.3390/biomedicines12010211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 01/09/2024] [Accepted: 01/11/2024] [Indexed: 01/24/2024] Open
Abstract
Dysregulated metabolic dynamics are evident in both cancer and diabetes, with metabolic alterations representing a facet of the myriad changes observed in these conditions. This review delves into the commonalities in metabolism between cancer and type 2 diabetes (T2D), focusing specifically on the contrasting roles of oxidative phosphorylation (OXPHOS) and glycolysis as primary energy-generating pathways within cells. Building on earlier research, we explore how a shift towards one pathway over the other serves as a foundational aspect in the development of cancer and T2D. Unlike previous reviews, we posit that this shift may occur in seemingly opposing yet complementary directions, akin to the Yin and Yang concept. These metabolic fluctuations reveal an intricate network of underlying defective signaling pathways, orchestrating the pathogenesis and progression of each disease. The Warburg phenomenon, characterized by the prevalence of aerobic glycolysis over minimal to no OXPHOS, emerges as the predominant metabolic phenotype in cancer. Conversely, in T2D, the prevailing metabolic paradigm has traditionally been perceived in terms of discrete irregularities rather than an OXPHOS-to-glycolysis shift. Throughout T2D pathogenesis, OXPHOS remains consistently heightened due to chronic hyperglycemia or hyperinsulinemia. In advanced insulin resistance and T2D, the metabolic landscape becomes more complex, featuring differential tissue-specific alterations that affect OXPHOS. Recent findings suggest that addressing the metabolic imbalance in both cancer and diabetes could offer an effective treatment strategy. Numerous pharmaceutical and nutritional modalities exhibiting therapeutic effects in both conditions ultimately modulate the OXPHOS-glycolysis axis. Noteworthy nutritional adjuncts, such as alpha-lipoic acid, flavonoids, and glutamine, demonstrate the ability to reprogram metabolism, exerting anti-tumor and anti-diabetic effects. Similarly, pharmacological agents like metformin exhibit therapeutic efficacy in both T2D and cancer. This review discusses the molecular mechanisms underlying these metabolic shifts and explores promising therapeutic strategies aimed at reversing the metabolic imbalance in both disease scenarios.
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Affiliation(s)
- Mira Bosso
- Department of Pathology, Faculty of Medicine, Health Science Center, Kuwait University, Safat 13110, Kuwait
| | - Dania Haddad
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman 15462, Kuwait; (D.H.); (A.A.M.)
| | - Ashraf Al Madhoun
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman 15462, Kuwait; (D.H.); (A.A.M.)
- Department of Animal and Imaging Core Facilities, Dasman Diabetes Institute, Dasman 15462, Kuwait
| | - Fahd Al-Mulla
- Department of Pathology, Faculty of Medicine, Health Science Center, Kuwait University, Safat 13110, Kuwait
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman 15462, Kuwait; (D.H.); (A.A.M.)
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Tamarindo GH, Novais AA, Chuffa LGA, Zuccari DAPC. Metabolic Alterations in Canine Mammary Tumors. Animals (Basel) 2023; 13:2757. [PMID: 37685021 PMCID: PMC10487042 DOI: 10.3390/ani13172757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 08/16/2023] [Accepted: 08/25/2023] [Indexed: 09/10/2023] Open
Abstract
Canine mammary tumors (CMTs) are among the most common diseases in female dogs and share similarities with human breast cancer, which makes these animals a model for comparative oncology studies. In these tumors, metabolic reprogramming is known as a hallmark of carcinogenesis whereby cells undergo adjustments to meet the high bioenergetic and biosynthetic demands of rapidly proliferating cells. However, such alterations are also vulnerabilities that may serve as a therapeutic strategy, which has mostly been tested in human clinical trials but is poorly explored in CMTs. In this dedicated review, we compiled the metabolic changes described for CMTs, emphasizing the metabolism of carbohydrates, amino acids, lipids, and mitochondrial functions. We observed key factors associated with the presence and aggressiveness of CMTs, such as an increase in glucose uptake followed by enhanced anaerobic glycolysis via the upregulation of glycolytic enzymes, changes in glutamine catabolism due to the overexpression of glutaminases, increased fatty acid oxidation, and distinct effects depending on lipid saturation, in addition to mitochondrial DNA, which is a hotspot for mutations. Therefore, more attention should be paid to this topic given that targeting metabolic fragilities could improve the outcome of CMTs.
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Affiliation(s)
- Guilherme Henrique Tamarindo
- Department of Molecular Biology, São José do Rio Preto Faculty of Medicine, São José do Rio Preto 15090-000, SP, Brazil
- Brazilian Biosciences National Laboratory, Brazilian Center for Research in Energy and Materials (CNPEM), Campinas 13083-970, SP, Brazil
| | - Adriana Alonso Novais
- Health Sciences Institute (ICS), Mato Grosso Federal University (UFMT), Sinop 78550-728, MT, Brazil
| | - Luiz Gustavo Almeida Chuffa
- Department of Structural and Functional Biology, Institute of Biosciences, São Paulo State University (UNESP), Botucatu 18618-689, SP, Brazil
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Liu D, Wang H, Li X, Liu J, Zhang Y, Hu J. Small molecule inhibitors for cancer metabolism: promising prospects to be explored. J Cancer Res Clin Oncol 2023; 149:8051-8076. [PMID: 37002510 DOI: 10.1007/s00432-022-04501-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 11/28/2022] [Indexed: 04/03/2023]
Abstract
BACKGROUND Abnormal metabolism is the main hallmark of cancer, and cancer metabolism plays an important role in tumorigenesis, metastasis, and drug resistance. Therefore, studying the changes of tumor metabolic pathways is beneficial to find targets for the treatment of cancer diseases. The success of metabolism-targeted chemotherapy suggests that cancer metabolism research will provide potential new targets for the treatment of malignant tumors. PURPOSE The aim of this study was to systemically review recent research findings on targeted inhibitors of tumor metabolism. In addition, we summarized new insights into tumor metabolic reprogramming and discussed how to guide the exploration of new strategies for cancer-targeted therapy. CONCLUSION Cancer cells have shown various altered metabolic pathways, providing sufficient fuel for their survival. The combination of these pathways is considered to be a more useful method for screening multilateral pathways. Better understanding of the clinical research progress of small molecule inhibitors of potential targets of tumor metabolism will help to explore more effective cancer treatment strategies.
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Affiliation(s)
- Dan Liu
- Department of Pharmacy, The First Affiliated Hospital of Army Medical University, Chongqing, 400038, China
| | - HongPing Wang
- Department of Pharmacy, The First Affiliated Hospital of Army Medical University, Chongqing, 400038, China
| | - XingXing Li
- Department of Pharmacy, The First Affiliated Hospital of Army Medical University, Chongqing, 400038, China
| | - JiFang Liu
- Department of Pharmacy, The First Affiliated Hospital of Army Medical University, Chongqing, 400038, China
| | - YanLing Zhang
- Department of Pharmacy, The First Affiliated Hospital of Army Medical University, Chongqing, 400038, China
| | - Jing Hu
- Department of Pharmacy, The First Affiliated Hospital of Army Medical University, Chongqing, 400038, China.
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10
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You M, Xie Z, Zhang N, Zhang Y, Xiao D, Liu S, Zhuang W, Li L, Tao Y. Signaling pathways in cancer metabolism: mechanisms and therapeutic targets. Signal Transduct Target Ther 2023; 8:196. [PMID: 37164974 PMCID: PMC10172373 DOI: 10.1038/s41392-023-01442-3] [Citation(s) in RCA: 88] [Impact Index Per Article: 44.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 03/20/2023] [Accepted: 04/17/2023] [Indexed: 05/12/2023] Open
Abstract
A wide spectrum of metabolites (mainly, the three major nutrients and their derivatives) can be sensed by specific sensors, then trigger a series of signal transduction pathways and affect the expression levels of genes in epigenetics, which is called metabolite sensing. Life body regulates metabolism, immunity, and inflammation by metabolite sensing, coordinating the pathophysiology of the host to achieve balance with the external environment. Metabolic reprogramming in cancers cause different phenotypic characteristics of cancer cell from normal cell, including cell proliferation, migration, invasion, angiogenesis, etc. Metabolic disorders in cancer cells further create a microenvironment including many kinds of oncometabolites that are conducive to the growth of cancer, thus forming a vicious circle. At the same time, exogenous metabolites can also affect the biological behavior of tumors. Here, we discuss the metabolite sensing mechanisms of the three major nutrients and their derivatives, as well as their abnormalities in the development of various cancers, and discuss the potential therapeutic targets based on metabolite-sensing signaling pathways to prevent the progression of cancer.
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Affiliation(s)
- Mengshu You
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410078, Changsha, Hunan, China
- NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute and School of Basic Medicine, Central South University, 410078, Changsha, Hunan, China
- Department of Pathology, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Xiangya Hospital, Central South University, 410078, Changsha, Hunan, China
| | - Zhuolin Xie
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410078, Changsha, Hunan, China
- NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute and School of Basic Medicine, Central South University, 410078, Changsha, Hunan, China
- Department of Pathology, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Xiangya Hospital, Central South University, 410078, Changsha, Hunan, China
| | - Nan Zhang
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410078, Changsha, Hunan, China
- NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute and School of Basic Medicine, Central South University, 410078, Changsha, Hunan, China
- Department of Pathology, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Xiangya Hospital, Central South University, 410078, Changsha, Hunan, China
| | - Yixuan Zhang
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410078, Changsha, Hunan, China
- NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute and School of Basic Medicine, Central South University, 410078, Changsha, Hunan, China
- Department of Pathology, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Xiangya Hospital, Central South University, 410078, Changsha, Hunan, China
| | - Desheng Xiao
- Department of Pathology, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China
| | - Shuang Liu
- Department of Oncology, Institute of Medical Sciences, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China
| | - Wei Zhuang
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, People's Republic of China.
| | - Lili Li
- Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Centre for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Ma Liu Shui, Hong Kong.
| | - Yongguang Tao
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410078, Changsha, Hunan, China.
- NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute and School of Basic Medicine, Central South University, 410078, Changsha, Hunan, China.
- Department of Pathology, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Xiangya Hospital, Central South University, 410078, Changsha, Hunan, China.
- Department of Thoracic Surgery, Hunan Key Laboratory of Early Diagnosis and Precision Therapy in Lung Cancer, Second Xiangya Hospital, Central South University, 410011, Changsha, China.
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11
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Nong S, Han X, Xiang Y, Qian Y, Wei Y, Zhang T, Tian K, Shen K, Yang J, Ma X. Metabolic reprogramming in cancer: Mechanisms and therapeutics. MedComm (Beijing) 2023; 4:e218. [PMID: 36994237 PMCID: PMC10041388 DOI: 10.1002/mco2.218] [Citation(s) in RCA: 43] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 01/22/2023] [Accepted: 01/30/2023] [Indexed: 03/29/2023] Open
Abstract
Cancer cells characterized by uncontrolled growth and proliferation require altered metabolic processes to maintain this characteristic. Metabolic reprogramming is a process mediated by various factors, including oncogenes, tumor suppressor genes, changes in growth factors, and tumor-host cell interactions, which help to meet the needs of cancer cell anabolism and promote tumor development. Metabolic reprogramming in tumor cells is dynamically variable, depending on the tumor type and microenvironment, and reprogramming involves multiple metabolic pathways. These metabolic pathways have complex mechanisms and involve the coordination of various signaling molecules, proteins, and enzymes, which increases the resistance of tumor cells to traditional antitumor therapies. With the development of cancer therapies, metabolic reprogramming has been recognized as a new therapeutic target for metabolic changes in tumor cells. Therefore, understanding how multiple metabolic pathways in cancer cells change can provide a reference for the development of new therapies for tumor treatment. Here, we systemically reviewed the metabolic changes and their alteration factors, together with the current tumor regulation treatments and other possible treatments that are still under investigation. Continuous efforts are needed to further explore the mechanism of cancer metabolism reprogramming and corresponding metabolic treatments.
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Affiliation(s)
- Shiqi Nong
- State Key Laboratory of Oral DiseasesWest China Hospital of StomatologyWest China School of StomatologyNational Clinical Research Center for Oral DiseasesSichuan UniversityChengduSichuanChina
| | - Xiaoyue Han
- State Key Laboratory of Oral DiseasesWest China Hospital of StomatologyWest China School of StomatologyNational Clinical Research Center for Oral DiseasesSichuan UniversityChengduSichuanChina
| | - Yu Xiang
- Department of BiotherapyCancer CenterWest China HospitalSichuan UniversityChengduSichuanChina
| | - Yuran Qian
- State Key Laboratory of Oral DiseasesWest China Hospital of StomatologyWest China School of StomatologyNational Clinical Research Center for Oral DiseasesSichuan UniversityChengduSichuanChina
| | - Yuhao Wei
- Department of Clinical MedicineWest China School of MedicineWest China HospitalSichuan UniversityChengduSichuanChina
| | - Tingyue Zhang
- State Key Laboratory of Oral DiseasesWest China Hospital of StomatologyWest China School of StomatologyNational Clinical Research Center for Oral DiseasesSichuan UniversityChengduSichuanChina
| | - Keyue Tian
- State Key Laboratory of Oral DiseasesWest China Hospital of StomatologyWest China School of StomatologyNational Clinical Research Center for Oral DiseasesSichuan UniversityChengduSichuanChina
| | - Kai Shen
- Department of OncologyFirst Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Jing Yang
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhouChina
| | - Xuelei Ma
- State Key Laboratory of Oral DiseasesWest China Hospital of StomatologyWest China School of StomatologyNational Clinical Research Center for Oral DiseasesSichuan UniversityChengduSichuanChina
- Department of Biotherapy and Cancer CenterState Key Laboratory of BiotherapyCancer CenterWest China HospitalSichuan UniversityChengduSichuanChina
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12
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Samec M, Mazurakova A, Lucansky V, Koklesova L, Pecova R, Pec M, Golubnitschaja O, Al-Ishaq RK, Caprnda M, Gaspar L, Prosecky R, Gazdikova K, Adamek M, Büsselberg D, Kruzliak P, Kubatka P. Flavonoids attenuate cancer metabolism by modulating Lipid metabolism, amino acids, ketone bodies and redox state mediated by Nrf2. Eur J Pharmacol 2023; 949:175655. [PMID: 36921709 DOI: 10.1016/j.ejphar.2023.175655] [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: 01/03/2023] [Revised: 02/20/2023] [Accepted: 03/09/2023] [Indexed: 03/14/2023]
Abstract
Metabolic reprogramming of cancer cells is a common hallmark of malignant transformation. The preference for aerobic glycolysis over oxidative phosphorylation in tumors is a well-studied phenomenon known as the Warburg effect. Importantly, metabolic transformation of cancer cells also involves alterations in signaling cascades contributing to lipid metabolism, amino acid flux and synthesis, and utilization of ketone bodies. Also, redox regulation interacts with metabolic reprogramming during malignant transformation. Flavonoids, widely distributed phytochemicals in plants, exert various beneficial effects on human health through modulating molecular cascades altered in the pathological cancer phenotype. Recent evidence has identified numerous flavonoids as modulators of critical components of cancer metabolism and associated pathways interacting with metabolic cascades such as redox balance. Flavonoids affect lipid metabolism by regulating fatty acid synthase, redox balance by modulating nuclear factor-erythroid factor 2-related factor 2 (Nrf2) activity, or amino acid flux and synthesis by phosphoglycerate mutase 1. Here, we discuss recent preclinical evidence evaluating the impact of flavonoids on cancer metabolism, focusing on lipid and amino acid metabolic cascades, redox balance, and ketone bodies.
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Affiliation(s)
- Marek Samec
- Department of Pathophysiology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Alena Mazurakova
- Department of Anatomy, Comenius University in Bratislava, Martin, Slovakia
| | - Vincent Lucansky
- Biomedical Centre Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
| | - Lenka Koklesova
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01, Martin, Slovakia
| | - Renata Pecova
- Department of Pathophysiology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Martin Pec
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Olga Golubnitschaja
- Predictive, Preventive, Personalised (3P) Medicine, Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
| | | | - Martin Caprnda
- 1(st) Department of Internal Medicine, Faculty of Medicine, Comenius University and University Hospital, Bratislava, Slovakia
| | - Ludovit Gaspar
- Faculty of Health Sciences, University of Ss. Cyril and Methodius in Trnava, Trnava, Slovakia
| | - Robert Prosecky
- 2(nd) Department of Internal Medicine, Faculty of Medicine, Masaryk University and St. Anne´s University Hospital, Brno, Czech Republic; International Clinical Research Centre, St. Anne's University Hospital and Masaryk University, Brno, Czech Republic
| | - Katarina Gazdikova
- Department of Nutrition, Faculty of Nursing and Professional Health Studies, Slovak Medical University, Bratislava, Slovakia; Department of General Medicine, Faculty of Medicine, Slovak Medical University, Bratislava, Slovakia.
| | - Mariusz Adamek
- Department of Thoracic Surgery, Medical University of Silesia, Katowice, Poland
| | | | - Peter Kruzliak
- 2(nd) Department of Surgery, Faculty of Medicine, Masaryk University and St. Anne´s University Hospital, Brno, Czech Republic.
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia.
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13
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Suri GS, Kaur G, Carbone GM, Shinde D. Metabolomics in oncology. Cancer Rep (Hoboken) 2023; 6:e1795. [PMID: 36811317 PMCID: PMC10026298 DOI: 10.1002/cnr2.1795] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 01/15/2023] [Accepted: 02/10/2023] [Indexed: 02/24/2023] Open
Abstract
BACKGROUND Oncogenic transformation alters intracellular metabolism and contributes to the growth of malignant cells. Metabolomics, or the study of small molecules, can reveal insight about cancer progression that other biomarker studies cannot. Number of metabolites involved in this process have been in spotlight for cancer detection, monitoring, and therapy. RECENT FINDINGS In this review, the "Metabolomics" is defined in terms of current technology having both clinical and translational applications. Researchers have shown metabolomics can be used to discern metabolic indicators non-invasively using different analytical methods like positron emission tomography, magnetic resonance spectroscopic imaging etc. Metabolomic profiling is a powerful and technically feasible way to track changes in tumor metabolism and gauge treatment response across time. Recent studies have shown metabolomics can also predict individual metabolic changes in response to cancer treatment, measure medication efficacy, and monitor drug resistance. Its significance in cancer development and treatment is summarized in this review. CONCLUSION Although in infancy, metabolomics can be used to identify treatment options and/or predict responsiveness to cancer treatments. Technical challenges like database management, cost and methodical knowhow still persist. Overcoming these challenges in near further can help in designing new treatment régimes with increased sensitivity and specificity.
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Affiliation(s)
- Gurparsad Singh Suri
- Department of Biological Sciences, California Baptist University, Riverside, California, USA
| | - Gurleen Kaur
- Department of Biological Sciences, California Baptist University, Riverside, California, USA
| | - Giuseppina M Carbone
- Institute of Oncology Research (IOR), Universita' della Svizzera Italiana (USI), Bellinzona, Switzerland
| | - Dheeraj Shinde
- Institute of Oncology Research (IOR), Universita' della Svizzera Italiana (USI), Bellinzona, Switzerland
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14
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Chae HS, Hong ST. Overview of Cancer Metabolism and Signaling Transduction. Int J Mol Sci 2022; 24:12. [PMID: 36613455 PMCID: PMC9819818 DOI: 10.3390/ijms24010012] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 12/13/2022] [Accepted: 12/17/2022] [Indexed: 12/24/2022] Open
Abstract
Despite the remarkable progress in cancer treatment up to now, we are still far from conquering the disease. The most substantial change after the malignant transformation of normal cells into cancer cells is the alteration in their metabolism. Cancer cells reprogram their metabolism to support the elevated energy demand as well as the acquisition and maintenance of their malignancy, even in nutrient-poor environments. The metabolic alterations, even under aerobic conditions, such as the upregulation of the glucose uptake and glycolysis (the Warburg effect), increase the ROS (reactive oxygen species) and glutamine dependence, which are the prominent features of cancer metabolism. Among these metabolic alterations, high glutamine dependency has attracted serious attention in the cancer research community. In addition, the oncogenic signaling pathways of the well-known important genetic mutations play important regulatory roles, either directly or indirectly, in the central carbon metabolism. The identification of the convergent metabolic phenotypes is crucial to the targeting of cancer cells. In this review, we investigate the relationship between cancer metabolism and the signal transduction pathways, and we highlight the recent developments in anti-cancer therapy that target metabolism.
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Affiliation(s)
- Hee-Suk Chae
- Department of Obstetrics and Gynecology, Research Institute of Clinical Medicine of Jeonbuk National University, Biomedical Research Institute of Jeonbuk National University Hospital, Jeonbuk National University Medical School, Jeonju 561-712, Jeonnbuk, Republic of Korea
| | - Seong-Tshool Hong
- Department of Biomedical Sciences, Jeonbuk National University Medical School, Jeonju 561-712, Jeonnbuk, Republic of Korea
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15
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Yanar S, Kasap M, Kanli A, Akpinar G, Sarihan M. Proteomics analysis of meclofenamic acid‐treated small cell lung carcinoma cells revealed changes in cellular energy metabolism for cancer cell survival. J Biochem Mol Toxicol 2022; 37:e23289. [PMID: 36536497 DOI: 10.1002/jbt.23289] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 10/03/2022] [Accepted: 12/09/2022] [Indexed: 12/24/2022]
Abstract
Small cell lung carcinoma (SCLC) is a highly aggressive cancer with low survival rate. Although initial response to chemotherapy in SCLC patients is well-rated, the treatments applied after the disease relapses are not successful. Drug resistance is accepted to be one of the main reasons for this failure. Therefore, there is an urgent need for new treatment strategies for SCLC. Meclofenamic acid, a nonsteroidal anti-inflammatory drug, has been shown to have anticancer effects on various types of cancers via different mechanisms. The aim of this study was to investigate the alterations that meclofenamic acid caused on a SCLC cell line, DMS114 using the tools of proteomics namely two-dimensional gel electrophoresis coupled to MALDI-TOF/TOF and nHPLC coupled to LC-MS/MS. Among the proteins identified by both methods, those showing significantly altered expression levels were evaluated using bioinformatics databases, PANTHER and STRING. The key altered metabolism upon meclofenamic acid treatment appeared to the cellular energy metabolism. Glycolysis was suppressed, whereas mitochondrial activity and oxidative phosphorylation were boosted. The cells underwent metabolic reprogramming to adapt into their new environment for survival. Metabolic reprogramming is known to cause drug resistance in several cancer types including SCLC. The identified differentially regulated proteins in here associated with energy metabolism hold value as the potential targets to overcome drug resistance in SCLC treatment.
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Affiliation(s)
- Sevinc Yanar
- Department of Medical Biology, Faculty of Medicine Kocaeli University Kocaeli Turkey
- Department of Histology and Embryology, Faculty of Medicine Sakarya University Sakarya Turkey
| | - Murat Kasap
- Department of Medical Biology, Faculty of Medicine Kocaeli University Kocaeli Turkey
| | - Aylin Kanli
- Department of Medical Biology, Faculty of Medicine Kocaeli University Kocaeli Turkey
| | - Gurler Akpinar
- Department of Medical Biology, Faculty of Medicine Kocaeli University Kocaeli Turkey
| | - Mehmet Sarihan
- Department of Medical Biology, Faculty of Medicine Kocaeli University Kocaeli Turkey
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16
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Targeting Glucose Metabolism Enzymes in Cancer Treatment: Current and Emerging Strategies. Cancers (Basel) 2022; 14:cancers14194568. [PMID: 36230492 PMCID: PMC9559313 DOI: 10.3390/cancers14194568] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 09/14/2022] [Accepted: 09/16/2022] [Indexed: 11/24/2022] Open
Abstract
Simple Summary Reprogramming of glucose metabolism is a hallmark of cancer and can be targeted by therapeutic agents. Some metabolism regulators, such as ivosidenib and enasidenib, have been approved for cancer treatment. Currently, more advanced and effective glucose metabolism enzyme-targeted anticancer drugs have been developed. Furthermore, some natural products have shown efficacy in killing tumor cells by regulating glucose metabolism, offering novel therapeutic opportunities in cancer. However, most of them have failed to be translated into clinical applications due to low selectivity, high toxicity, and side effects. Recent studies suggest that combining glucose metabolism modulators with chemotherapeutic drugs, immunotherapeutic drugs, and other conventional anticancer drugs may be a future direction for cancer treatment. Abstract Reprogramming of glucose metabolism provides sufficient energy and raw materials for the proliferation, metastasis, and immune escape of cancer cells, which is enabled by glucose metabolism-related enzymes that are abundantly expressed in a broad range of cancers. Therefore, targeting glucose metabolism enzymes has emerged as a promising strategy for anticancer drug development. Although several glucose metabolism modulators have been approved for cancer treatment in recent years, some limitations exist, such as a short half-life, poor solubility, and numerous adverse effects. With the rapid development of medicinal chemicals, more advanced and effective glucose metabolism enzyme-targeted anticancer drugs have been developed. Additionally, several studies have found that some natural products can suppress cancer progression by regulating glucose metabolism enzymes. In this review, we summarize the mechanisms underlying the reprogramming of glucose metabolism and present enzymes that could serve as therapeutic targets. In addition, we systematically review the existing drugs targeting glucose metabolism enzymes, including small-molecule modulators and natural products. Finally, the opportunities and challenges for glucose metabolism enzyme-targeted anticancer drugs are also discussed. In conclusion, combining glucose metabolism modulators with conventional anticancer drugs may be a promising cancer treatment strategy.
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17
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Sevastre AS, Manea EV, Popescu OS, Tache DE, Danoiu S, Sfredel V, Tataranu LG, Dricu A. Intracellular Pathways and Mechanisms of Colored Secondary Metabolites in Cancer Therapy. Int J Mol Sci 2022; 23:ijms23179943. [PMID: 36077338 PMCID: PMC9456420 DOI: 10.3390/ijms23179943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 08/27/2022] [Accepted: 08/29/2022] [Indexed: 12/03/2022] Open
Abstract
Despite the great advancements made in cancer treatment, there are still many unsatisfied aspects, such as the wide palette of side effects and the drug resistance. There is an obvious increasing scientific attention towards nature and what it can offer the human race. Natural products can be used to treat many diseases, of which some plant products are currently used to treat cancer. Plants produce secondary metabolites for their signaling mechanisms and natural defense. A variety of plant-derived products have shown promising anticancer properties in vitro and in vivo. Rather than recreating the natural production environment, ongoing studies are currently setting various strategies to significantly manipulate the quantity of anticancer molecules in plants. This review focuses on the recently studied secondary metabolite agents that have shown promising anticancer activity, outlining their potential mechanisms of action and pathways.
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Affiliation(s)
- Ani-Simona Sevastre
- Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova, Str. Petru Rares nr. 2-4, 200349 Craiova, Romania
| | - Elena Victoria Manea
- Department of Biochemistry, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Str. Petru Rares nr. 2-4, 200349 Craiova, Romania
| | - Oana Stefana Popescu
- Department of Biochemistry, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Str. Petru Rares nr. 2-4, 200349 Craiova, Romania
| | - Daniela Elise Tache
- Department of Biochemistry, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Str. Petru Rares nr. 2-4, 200349 Craiova, Romania
| | - Suzana Danoiu
- Department of Pathophysiology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Str. Petru Rares nr. 2-4, 200349 Craiova, Romania
| | - Veronica Sfredel
- Department of Physiology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Str. Petru Rares nr. 2-4, 200349 Craiova, Romania
| | - Ligia Gabriela Tataranu
- Neurosurgical Department, Clinical Hospital “Bagdasar-Arseni”, 041915 Bucharest, Romania
- Correspondence: ; Tel.: +40-21-334-30-25
| | - Anica Dricu
- Department of Biochemistry, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Str. Petru Rares nr. 2-4, 200349 Craiova, Romania
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18
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Kaur J, Bhattacharyya S. Cancer Stem Cells: Metabolic Characterization for Targeted Cancer Therapy. Front Oncol 2021; 11:756888. [PMID: 34804950 PMCID: PMC8602811 DOI: 10.3389/fonc.2021.756888] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 10/18/2021] [Indexed: 02/02/2023] Open
Abstract
The subpopulation of cancer stem cells (CSCs) within tumor bulk are known for tumor recurrence and metastasis. CSCs show intrinsic resistance to conventional therapies and phenotypic plasticity within the tumor, which make these a difficult target for conventional therapies. CSCs have different metabolic phenotypes based on their needs as compared to the bulk cancer cells. CSCs show metabolic plasticity and constantly alter their metabolic state between glycolysis and oxidative metabolism (OXPHOS) to adapt to scarcity of nutrients and therapeutic stress. The metabolic characteristics of CSCs are distinct compared to non-CSCs and thus provide an opportunity to devise more effective strategies to target CSCs. Mechanism for metabolic switch in CSCs is still unravelled, however existing evidence suggests that tumor microenvironment affects the metabolic phenotype of cancer cells. Understanding CSCs metabolism may help in discovering new and effective clinical targets to prevent cancer relapse and metastasis. This review summarises the current knowledge of CSCs metabolism and highlights the potential targeted treatment strategies.
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Affiliation(s)
- Jasmeet Kaur
- Department of Biophysics, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Shalmoli Bhattacharyya
- Department of Biophysics, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
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19
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Zeng X, Li Z, Zhu C, Xu L, Sun Y, Han S. Research progress of nanocarriers for gene therapy targeting abnormal glucose and lipid metabolism in tumors. Drug Deliv 2021; 28:2329-2347. [PMID: 34730054 PMCID: PMC8567922 DOI: 10.1080/10717544.2021.1995081] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
In recent years, the incidence of various types of tumors has gradually increased, and it has also been found that there is a certain correlation between abnormal glucose and lipid metabolism and tumors. Glycolipid metabolism can promote tumor progression through multiple pathways, and the expression of related genes also directly or indirectly affects tumor metabolism, metastasis, invasion, and apoptosis. There has been much research on targeted drug delivery systems designed for abnormal glucose and lipid metabolism due to their accuracy and efficiency when used for tumor therapy. In addition, gene mutations have become an important factor in tumorigenesis. For this reason, gene therapy consisting of drugs designed for certain specifically expressed genes have been transfected into target cells to express or silence the corresponding proteins. Targeted gene drug vectors that achieve their corresponding therapeutic purposes are also rapidly developing. The genes related to glucose and lipid metabolism are considered as the target, and a corresponding gene drug carrier is constructed to influence and interfere with the expression of related genes, so as to block the tumorigenesis process and inhibit tumor growth. Designing drugs that target genes related to glucose and lipid metabolism within tumors is considered to be a promising strategy for the treatment of tumor diseases. This article summarizes the chemical drugs/gene drug delivery systems and the corresponding methods used in recent years for the treatment of abnormal glucose and lipid metabolism of tumors, and provides a theoretical basis for the development of glucolipid metabolism related therapeutic methods.
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Affiliation(s)
- Xianhu Zeng
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao, China
| | - Zhipeng Li
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao, China
| | - Chunrong Zhu
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao, China
| | - Lisa Xu
- School of Public Health, Qingdao University, Qingdao, China
| | - Yong Sun
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao, China
| | - Shangcong Han
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao, China
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20
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Coronel-Hernández J, Pérez-Yépez EA, Delgado-Waldo I, Contreras-Romero C, Jacobo-Herrera N, Cantú-De León D, Pérez-Plasencia C. Aberrant Metabolism as Inductor of Epigenetic Changes in Breast Cancer: Therapeutic Opportunities. Front Oncol 2021; 11:676562. [PMID: 34692471 PMCID: PMC8531643 DOI: 10.3389/fonc.2021.676562] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 09/08/2021] [Indexed: 12/23/2022] Open
Abstract
Aberrant metabolism is arising interest in the scientific community not only because of the role it plays in the development and establishment of the tumor mass but also the possibility of drug poisoning of key enzymes overexpressed in tumor cells. Moreover, tumor metabolism provides key molecules to maintain the epigenetic changes that are also an undisputed characteristic of each tumor type. This metabolic change includes the Warburg effect and alterations in key pathways involved in glutaminolysis, pentose phosphate, and unsaturated fatty acid biosynthesis. Modifications in all these pathways have consequences that impact genetics and epigenetics processes such as DNA methylation patterns, histone post-translational modifications, triggering oncogenes activation, and loss in tumor suppressor gene expression to lead the tumor establishment. In this review, we describe the metabolic rearrangement and its association with epigenetic regulation in breast cancer, as well as its implication in biological processes involved in cancer progression. A better understanding of these processes could help to find new targets for the diagnosis, prognosis, and treatment of this human health problem.
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Affiliation(s)
| | - Eloy Andrés Pérez-Yépez
- Laboratorio de Genómica, Instituto Nacional de Cancerología, Mexico City, Mexico.,Cátedra-CONACYT, Dirección de Cátedras, Consejo Nacional de Ciencia y Tecnología (CONACYT), Mexico City, Mexico
| | | | | | - Nadia Jacobo-Herrera
- Unidad de Bioquímica, Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubirán, Mexico City, Mexico
| | - David Cantú-De León
- Unidad de Investigación en Cáncer, Instituto Nacional de Cancerología , Mexico City, Mexico
| | - Carlos Pérez-Plasencia
- Laboratorio de Genómica, Instituto Nacional de Cancerología, Mexico City, Mexico.,Laboratorio de Genómica Funcional, Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Mexico City, Mexico
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21
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Sun X, Peng Y, Zhao J, Xie Z, Lei X, Tang G. Discovery and development of tumor glycolysis rate-limiting enzyme inhibitors. Bioorg Chem 2021; 112:104891. [PMID: 33940446 DOI: 10.1016/j.bioorg.2021.104891] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 04/02/2021] [Accepted: 04/03/2021] [Indexed: 12/13/2022]
Abstract
Tumor cells mainly provide necessary energy and substances for rapid cell growth through aerobic perglycolysis rather than oxidative phosphorylation. This phenomenon is called the "Warburg effect". The mechanism of glycolysis in tumor cells is more complicated, which is caused by the comprehensive regulation of multiple factors. Abnormal enzyme metabolism is one of the main influencing factors and inhibiting the three main rate-limiting enzymes in glycolysis is thought to be important strategy for cancer treatment. Therefore, numerous inhibitors of glycolysis rate-limiting enzyme have been developed in recent years, such as the latest HKII inhibitor and PKM2 inhibitor Pachymic acid (PA) and N-(4-(3-(3-(methylamino)-3-oxopropyl)-5-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1H-pyrazol-1-yl)phenyl)propiolamide. The review focuses on source, structure-activity relationship, bioecological activity and mechanism of the three main rate-limiting enzymes inhibitors, and hopes to guide the future research on the design and synthesis of rate-limiting enzyme inhibitors.
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Affiliation(s)
- Xueyan Sun
- Institute of Pharmacy and Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang City, PR China
| | - Yijiao Peng
- Institute of Pharmacy and Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang City, PR China
| | - Jingduo Zhao
- Institute of Pharmacy and Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang City, PR China
| | - Zhizhong Xie
- Hunan Provincial Key Laboratory of tumor microenvironment responsive drug research, Hengyang City, Hunan Province, PR China
| | - Xiaoyong Lei
- Hunan Provincial Key Laboratory of tumor microenvironment responsive drug research, Hengyang City, Hunan Province, PR China
| | - Guotao Tang
- Institute of Pharmacy and Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang City, PR China; Hunan Provincial Key Laboratory of tumor microenvironment responsive drug research, Hengyang City, Hunan Province, PR China.
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22
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Khan A, Siddiqui S, Husain SA, Mazurek S, Iqbal MA. Phytocompounds Targeting Metabolic Reprogramming in Cancer: An Assessment of Role, Mechanisms, Pathways, and Therapeutic Relevance. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2021; 69:6897-6928. [PMID: 34133161 DOI: 10.1021/acs.jafc.1c01173] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
The metabolism of cancer is remarkably different from that of normal cells and confers a variety of benefits, including the promotion of other cancer hallmarks. As the rewired metabolism is a near-universal property of cancer cells, efforts are underway to exploit metabolic vulnerabilities for therapeutic benefits. In the continued search for safer and effective ways of cancer treatment, structurally diverse plant-based compounds have gained substantial attention. Here, we present an extensive assessment of the role of phytocompounds in modulating cancer metabolism and attempt to make a case for the use of plant-based compounds in targeting metabolic vulnerabilities of cancer. We discuss the pharmacological interactions of phytocompounds with major metabolic pathways and evaluate the role of phytocompounds in the regulation of growth signaling and transcriptional programs involved in the metabolic transformation of cancer. Lastly, we examine the potential of these compounds in the clinical management of cancer along with limitations and challenges.
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Affiliation(s)
- Asifa Khan
- Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia (A Central University), New Delhi 110025, India
- Department of Biosciences, Faculty of Natural Sciences, Jamia Millia Islamia (A Central University), New Delhi 110025, India
| | - Shumaila Siddiqui
- Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia (A Central University), New Delhi 110025, India
| | - Syed Akhtar Husain
- Department of Biosciences, Faculty of Natural Sciences, Jamia Millia Islamia (A Central University), New Delhi 110025, India
| | - Sybille Mazurek
- Institute of Veterinary-Physiology and Biochemistry, University of Giessen, Giessen 35392, Germany
| | - Mohammad Askandar Iqbal
- Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia (A Central University), New Delhi 110025, India
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23
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Ingram DK, Roth GS. Glycolytic inhibition: an effective strategy for developing calorie restriction mimetics. GeroScience 2021; 43:1159-1169. [PMID: 33184758 PMCID: PMC8190254 DOI: 10.1007/s11357-020-00298-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 11/05/2020] [Indexed: 12/20/2022] Open
Abstract
Calorie restriction mimetics encompass a growing research field directed toward developing treatments that mimic the anti-aging effects of long-term calorie restriction without requiring a change in eating habits. A wide range of approaches have been identified that include (1) intestinal inhibitors of fat and carbohydrate metabolism; (2) inhibitors of intracellular glycolysis; (3) stimulators of the AMPK pathway; (4) sirtuin activators; (5) inhibitors of the mTOR pathway, and (6) polyamines. Several biotech companies have been formed to pursue several of these strategies. The objective of this review is to describe the approaches directed toward glycolytic inhibition. This upstream strategy is considered an effective means to invoke a wide range of anti-aging mechanisms induced by CR. Anti-cancer and anti-obesity effects are important considerations in early development efforts. Although many dozens of candidates could be discussed, the compounds selected to be reviewed are the following: 2-deoxyglucose, 3-bromopyruvate, chrysin, genistein, astragalin, resveratrol, glucosamine, mannoheptulose, and D-allulose. Some candidates have been investigated extensively with both positive and negative results, while others are only beginning to be studied.
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Affiliation(s)
- Donald K. Ingram
- Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Road, Baton Rouge, LA 70809 USA
| | - George S. Roth
- GeroScience, Inc., 1124 Ridge Road, Pylesville, MD 21132 USA
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24
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Schiliro C, Firestein BL. Mechanisms of Metabolic Reprogramming in Cancer Cells Supporting Enhanced Growth and Proliferation. Cells 2021; 10:cells10051056. [PMID: 33946927 PMCID: PMC8146072 DOI: 10.3390/cells10051056] [Citation(s) in RCA: 270] [Impact Index Per Article: 67.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 04/27/2021] [Accepted: 04/28/2021] [Indexed: 02/07/2023] Open
Abstract
Cancer cells alter metabolic processes to sustain their characteristic uncontrolled growth and proliferation. These metabolic alterations include (1) a shift from oxidative phosphorylation to aerobic glycolysis to support the increased need for ATP, (2) increased glutaminolysis for NADPH regeneration, (3) altered flux through the pentose phosphate pathway and the tricarboxylic acid cycle for macromolecule generation, (4) increased lipid uptake, lipogenesis, and cholesterol synthesis, (5) upregulation of one-carbon metabolism for the production of ATP, NADH/NADPH, nucleotides, and glutathione, (6) altered amino acid metabolism, (7) metabolism-based regulation of apoptosis, and (8) the utilization of alternative substrates, such as lactate and acetate. Altered metabolic flux in cancer is controlled by tumor-host cell interactions, key oncogenes, tumor suppressors, and other regulatory molecules, including non-coding RNAs. Changes to metabolic pathways in cancer are dynamic, exhibit plasticity, and are often dependent on the type of tumor and the tumor microenvironment, leading in a shift of thought from the Warburg Effect and the “reverse Warburg Effect” to metabolic plasticity. Understanding the complex nature of altered flux through these multiple pathways in cancer cells can support the development of new therapies.
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Affiliation(s)
- Chelsea Schiliro
- Cell and Developmental Biology Graduate Program and Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, 604 Allison Road, Piscataway, NJ 08854, USA;
| | - Bonnie L. Firestein
- Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, 604 Allison Road, Piscataway, NJ 08854, USA
- Correspondence: ; Tel.: +1-848-445-8045
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25
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Samec M, Liskova A, Koklesova L, Mersakova S, Strnadel J, Kajo K, Pec M, Zhai K, Smejkal K, Mirzaei S, Hushmandi K, Ashrafizadeh M, Saso L, Brockmueller A, Shakibaei M, Büsselberg D, Kubatka P. Flavonoids Targeting HIF-1: Implications on Cancer Metabolism. Cancers (Basel) 2021; 13:E130. [PMID: 33401572 PMCID: PMC7794792 DOI: 10.3390/cancers13010130] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 12/24/2020] [Accepted: 12/29/2020] [Indexed: 12/24/2022] Open
Abstract
Tumor hypoxia is described as an oxygen deprivation in malignant tissue. The hypoxic condition is a consequence of an imbalance between rapidly proliferating cells and a vascularization that leads to lower oxygen levels in tumors. Hypoxia-inducible factor 1 (HIF-1) is an essential transcription factor contributing to the regulation of hypoxia-associated genes. Some of these genes modulate molecular cascades associated with the Warburg effect and its accompanying pathways and, therefore, represent promising targets for cancer treatment. Current progress in the development of therapeutic approaches brings several promising inhibitors of HIF-1. Flavonoids, widely occurring in various plants, exert a broad spectrum of beneficial effects on human health, and are potentially powerful therapeutic tools against cancer. Recent evidences identified numerous natural flavonoids and their derivatives as inhibitors of HIF-1, associated with the regulation of critical glycolytic components in cancer cells, including pyruvate kinase M2(PKM2), lactate dehydrogenase (LDHA), glucose transporters (GLUTs), hexokinase II (HKII), phosphofructokinase-1 (PFK-1), and pyruvate dehydrogenase kinase (PDK). Here, we discuss the results of most recent studies evaluating the impact of flavonoids on HIF-1 accompanied by the regulation of critical enzymes contributing to the Warburg phenotype. Besides, flavonoid effects on glucose metabolism via regulation of HIF-1 activity represent a promising avenue in cancer-related research. At the same time, only more-in depth investigations can further elucidate the mechanistic and clinical connections between HIF-1 and cancer metabolism.
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Affiliation(s)
- Marek Samec
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia; (M.S.); (A.L.); (L.K.)
| | - Alena Liskova
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia; (M.S.); (A.L.); (L.K.)
| | - Lenka Koklesova
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia; (M.S.); (A.L.); (L.K.)
| | - Sandra Mersakova
- Biomedical Centre Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Mala Hora 4D, 03601 Martin, Slovakia; (S.M.); (J.S.)
| | - Jan Strnadel
- Biomedical Centre Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Mala Hora 4D, 03601 Martin, Slovakia; (S.M.); (J.S.)
| | - Karol Kajo
- Department of Pathology, St. Elizabeth Cancer Institute Hospital, 81250 Bratislava, Slovakia;
| | - Martin Pec
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia;
| | - Kevin Zhai
- Department of Physiology and Biophysics, Weill Cornell Medicine in Qatar, Education City, Qatar Foundation, Doha 24144, Qatar;
| | - Karel Smejkal
- Department of Natural Drugs, Faculty of Pharmacy, Masaryk University, Palackého třída 1946/1, 61200 Brno, Czech Republic;
| | - Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, 1477893855 Tehran, Iran;
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology, Faculty of Veterinary Medicine, University of Tehran, 1419963114 Tehran, Iran;
| | - Milad Ashrafizadeh
- Faculty of Engineering and Natural Sciences, Sabanci University, Orta Mahalle, Üniversite Caddesi No. 27, Orhanlı, Tuzla, 34956 Istanbul, Turkey;
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, 34956 Istanbul, Turkey
| | - Luciano Saso
- Department of Physiology and Pharmacology “Vittorio Erspamer”, Faculty of Pharmacy and Medicine, Sapienza University, 00185 Rome, Italy;
| | - Aranka Brockmueller
- Musculoskeletal Research Group and Tumor Biology, Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilian-University Munich, D-80336 Munich, Germany; (A.B.); (M.S.)
| | - Mehdi Shakibaei
- Musculoskeletal Research Group and Tumor Biology, Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilian-University Munich, D-80336 Munich, Germany; (A.B.); (M.S.)
| | - Dietrich Büsselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine in Qatar, Education City, Qatar Foundation, Doha 24144, Qatar;
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia;
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26
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Hollenberg AM, Smith CO, Shum LC, Awad H, Eliseev RA. Lactate Dehydrogenase Inhibition With Oxamate Exerts Bone Anabolic Effect. J Bone Miner Res 2020; 35:2432-2443. [PMID: 32729639 PMCID: PMC7736558 DOI: 10.1002/jbmr.4142] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 07/14/2020] [Accepted: 07/18/2020] [Indexed: 12/15/2022]
Abstract
Cellular bioenergetics is a promising new therapeutic target in aging, cancer, and diabetes because these pathologies are characterized by a shift from oxidative to glycolytic metabolism. We have previously reported such glycolytic shift in aged bone as a major contributor to bone loss in mice. We and others also showed the importance of oxidative phosphorylation (OxPhos) for osteoblast differentiation. It is therefore reasonable to propose that stimulation of OxPhos will have bone anabolic effect. One strategy widely used in cancer research to stimulate OxPhos is inhibition of glycolysis. In this work, we aimed to evaluate the safety and efficacy of pharmacological inhibition of glycolysis to stimulate OxPhos and promote osteoblast bone-forming function and bone anabolism. We tested a range of glycolytic inhibitors including 2-deoxyglucose, dichloroacetate, 3-bromopyruvate, and oxamate. Of all the studied inhibitors, only a lactate dehydrogenase (LDH) inhibitor, oxamate, did not show any toxicity in either undifferentiated osteoprogenitors or osteoinduced cells in vitro. Oxamate stimulated both OxPhos and osteoblast differentiation in osteoprogenitors. In vivo, oxamate improved bone mineral density, cortical bone architecture, and bone biomechanical strength in both young and aged C57BL/6J male mice. Oxamate also increased bone formation by osteoblasts without affecting bone resorption. In sum, our work provided a proof of concept for the use of anti-glycolytic strategies in bone and identified a small molecule LDH inhibitor, oxamate, as a safe and efficient bone anabolic agent. © 2020 American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Alex M. Hollenberg
- Center for Musculoskeletal Research, University of Rochester School of Medicine & Dentistry, Rochester, NY
| | - Charles O. Smith
- Center for Musculoskeletal Research, University of Rochester School of Medicine & Dentistry, Rochester, NY
| | - Laura C. Shum
- Center for Musculoskeletal Research, University of Rochester School of Medicine & Dentistry, Rochester, NY
| | - Hani Awad
- Center for Musculoskeletal Research, University of Rochester School of Medicine & Dentistry, Rochester, NY
| | - Roman A. Eliseev
- Center for Musculoskeletal Research, University of Rochester School of Medicine & Dentistry, Rochester, NY
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27
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Samec M, Liskova A, Koklesova L, Samuel SM, Zhai K, Buhrmann C, Varghese E, Abotaleb M, Qaradakhi T, Zulli A, Kello M, Mojzis J, Zubor P, Kwon TK, Shakibaei M, Büsselberg D, Sarria GR, Golubnitschaja O, Kubatka P. Flavonoids against the Warburg phenotype-concepts of predictive, preventive and personalised medicine to cut the Gordian knot of cancer cell metabolism. EPMA J 2020; 11:377-398. [PMID: 32843908 PMCID: PMC7429635 DOI: 10.1007/s13167-020-00217-y] [Citation(s) in RCA: 96] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 06/30/2020] [Indexed: 01/10/2023]
Abstract
The Warburg effect is characterised by increased glucose uptake and lactate secretion in cancer cells resulting from metabolic transformation in tumour tissue. The corresponding molecular pathways switch from oxidative phosphorylation to aerobic glycolysis, due to changes in glucose degradation mechanisms known as the 'Warburg reprogramming' of cancer cells. Key glycolytic enzymes, glucose transporters and transcription factors involved in the Warburg transformation are frequently dysregulated during carcinogenesis considered as promising diagnostic and prognostic markers as well as treatment targets. Flavonoids are molecules with pleiotropic activities. The metabolism-regulating anticancer effects of flavonoids are broadly demonstrated in preclinical studies. Flavonoids modulate key pathways involved in the Warburg phenotype including but not limited to PKM2, HK2, GLUT1 and HIF-1. The corresponding molecular mechanisms and clinical relevance of 'anti-Warburg' effects of flavonoids are discussed in this review article. The most prominent examples are provided for the potential application of targeted 'anti-Warburg' measures in cancer management. Individualised profiling and patient stratification are presented as powerful tools for implementing targeted 'anti-Warburg' measures in the context of predictive, preventive and personalised medicine.
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Affiliation(s)
- Marek Samec
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Alena Liskova
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Lenka Koklesova
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Samson Mathews Samuel
- Department of Physiology and Biophysics, Weill Cornell Medicine in Qatar, Education City, Qatar Foundation, 24144, Doha, Qatar
| | - Kevin Zhai
- Department of Physiology and Biophysics, Weill Cornell Medicine in Qatar, Education City, Qatar Foundation, 24144, Doha, Qatar
| | - Constanze Buhrmann
- Musculoskeletal Research Group and Tumour Biology, Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilian-University Munich, 80336 Munich, Germany
| | - Elizabeth Varghese
- Department of Physiology and Biophysics, Weill Cornell Medicine in Qatar, Education City, Qatar Foundation, 24144, Doha, Qatar
| | - Mariam Abotaleb
- Department of Physiology and Biophysics, Weill Cornell Medicine in Qatar, Education City, Qatar Foundation, 24144, Doha, Qatar
| | - Tawar Qaradakhi
- Institute for Health and Sport, Victoria University, Melbourne, VIC 3011 Australia
| | - Anthony Zulli
- Institute for Health and Sport, Victoria University, Melbourne, VIC 3011 Australia
| | - Martin Kello
- Department of Pharmacology, Faculty of Medicine, P. J. Šafarik University, 040 11 Košice, Slovakia
| | - Jan Mojzis
- Department of Pharmacology, Faculty of Medicine, P. J. Šafarik University, 040 11 Košice, Slovakia
| | - Pavol Zubor
- Department of Gynecologic Oncology, Norwegian Radium Hospital, Oslo University Hospital, 0379 Oslo, Norway
- OBGY Health & Care, Ltd., 01001 Zilina, Slovak Republic
| | - Taeg Kyu Kwon
- Department of Immunology and School of Medicine, Keimyung University, Dalseo-Gu, Daegu, 426 01 South Korea
| | - Mehdi Shakibaei
- Musculoskeletal Research Group and Tumour Biology, Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilian-University Munich, 80336 Munich, Germany
| | - Dietrich Büsselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine in Qatar, Education City, Qatar Foundation, 24144, Doha, Qatar
| | - Gustavo R. Sarria
- Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
| | - Olga Golubnitschaja
- Predictive, Preventive Personalised (3P) Medicine, Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia
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28
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Zhu X, Chen HH, Gao CY, Zhang XX, Jiang JX, Zhang Y, Fang J, Zhao F, Chen ZG. Energy metabolism in cancer stem cells. World J Stem Cells 2020; 12:448-461. [PMID: 32742562 PMCID: PMC7360992 DOI: 10.4252/wjsc.v12.i6.448] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 05/09/2020] [Accepted: 05/19/2020] [Indexed: 02/06/2023] Open
Abstract
Normal cells mainly rely on oxidative phosphorylation as an effective energy source in the presence of oxygen. In contrast, most cancer cells use less efficient glycolysis to produce ATP and essential biomolecules. Cancer cells gain the characteristics of metabolic adaptation by reprogramming their metabolic mechanisms to meet the needs of rapid tumor growth. A subset of cancer cells with stem characteristics and the ability to regenerate exist throughout the tumor and are therefore called cancer stem cells (CSCs). New evidence indicates that CSCs have different metabolic phenotypes compared with differentiated cancer cells. CSCs can dynamically transform their metabolic state to favor glycolysis or oxidative metabolism. The mechanism of the metabolic plasticity of CSCs has not been fully elucidated, and existing evidence indicates that the metabolic phenotype of cancer cells is closely related to the tumor microenvironment. Targeting CSC metabolism may provide new and effective methods for the treatment of tumors. In this review, we summarize the metabolic characteristics of cancer cells and CSCs and the mechanisms of the metabolic interplay between the tumor microenvironment and CSCs, and discuss the clinical implications of targeting CSC metabolism.
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Affiliation(s)
- Xuan Zhu
- Department of Radiation Oncology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Hui-Hui Chen
- The Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Hangzhou 310000, Zhejiang Province, China
- Department of Breast Surgery, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Chen-Yi Gao
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou 310000, Zhejiang Province, China
- Department of Breast Surgery, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Xin-Xin Zhang
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou 310000, Zhejiang Province, China
- Department of Breast Surgery, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Jing-Xin Jiang
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou 310000, Zhejiang Province, China
- Department of Breast Surgery, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Yi Zhang
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou 310000, Zhejiang Province, China
- Department of Breast Surgery, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Jun Fang
- Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou 310000, Zhejiang Province, China
| | - Feng Zhao
- Department of Radiation Oncology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Zhi-Gang Chen
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou 310000, Zhejiang Province, China
- Department of Breast Surgery, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China.
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29
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Deng X, Pi Y, Li Z, Xiong R, Liu J, Zhao J, Xie Z, Lei X, Tang G. FB-15 inhibits MGC-803 cells growth by regulating energy metabolism. Chem Biol Interact 2020; 327:109186. [PMID: 32590071 DOI: 10.1016/j.cbi.2020.109186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 05/06/2020] [Accepted: 06/17/2020] [Indexed: 11/17/2022]
Abstract
In this study, we scrutinized the anticancer effects of FB-15 on human gastric carcinoma MGC-803 cells in vitro and vivo, and its preliminary effect on tubulin and HIF-1α. We confirmed that FB-15 not only inhibited the proliferation of a large number of cells in a concentration and time-dependent manner but also inhibited proliferation of a single cell to form clones. FB-15 manifested little cytotoxicity for normal stomach cells GES-1. The flow cytometry analysis displayed that FB-15 induced apoptosis MGC-803 cells and mainly arrested cells in the S phase in a concentration-dependent manner. The results of the wound healing assay indicated that FB-15 suppressed cell migration. Furthermore, the western blotting showed that FB-15 down-regulated the expression of β3-tubulin and HIF-1α, consistent with Immunohistochemical assay. The binding modes of FB-15 with tubulin were clarified by molecular docking. FB-15 significantly suppressed the growth of MGC-803 gastric cancer tumors. The inhibitory effect of FB-15 on tumor growth was superior to 5-Fu. Taken together, these results provided evidence for FB-15 to be used as an effective anticancer drug candidate for gastric cancer.
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Affiliation(s)
- Xiangping Deng
- Institute of Pharmacy and Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang City, Hunan Province, PR China; Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hengyang City, Hunan Province, PR China
| | - Yiyuan Pi
- Institute of Pharmacy and Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang City, Hunan Province, PR China; Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hengyang City, Hunan Province, PR China; Xiangnan University, Chenzhou City, Hunan Province, PR China
| | - Zhongli Li
- Institute of Pharmacy and Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang City, Hunan Province, PR China
| | - Runde Xiong
- Institute of Pharmacy and Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang City, Hunan Province, PR China
| | - Juan Liu
- Institute of Pharmacy and Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang City, Hunan Province, PR China
| | - Jingduo Zhao
- Institute of Pharmacy and Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang City, Hunan Province, PR China; Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hengyang City, Hunan Province, PR China
| | - Zhizhong Xie
- Institute of Pharmacy and Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang City, Hunan Province, PR China; Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hengyang City, Hunan Province, PR China
| | - Xiaoyong Lei
- Institute of Pharmacy and Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang City, Hunan Province, PR China; Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hengyang City, Hunan Province, PR China.
| | - Guotao Tang
- Institute of Pharmacy and Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang City, Hunan Province, PR China; Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hengyang City, Hunan Province, PR China.
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Abdel-Wahab AF, Mahmoud W, Al-Harizy RM. Targeting glucose metabolism to suppress cancer progression: prospective of anti-glycolytic cancer therapy. Pharmacol Res 2019; 150:104511. [DOI: 10.1016/j.phrs.2019.104511] [Citation(s) in RCA: 136] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2019] [Revised: 10/19/2019] [Accepted: 10/23/2019] [Indexed: 12/24/2022]
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Wu Z, Wu J, Zhao Q, Fu S, Jin J. Emerging roles of aerobic glycolysis in breast cancer. Clin Transl Oncol 2019; 22:631-646. [PMID: 31359335 DOI: 10.1007/s12094-019-02187-8] [Citation(s) in RCA: 132] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Accepted: 07/05/2019] [Indexed: 12/25/2022]
Abstract
Altered aerobic glycolysis is a well-recognized characteristic of cancer cell energy metabolism, known as the Warburg effect. Even in the presence of abundant oxygen, a majority of tumor cells produce substantial amounts of energy through a high glycolytic metabolism, and breast cancer (BC) is no exception. Breast cancer continues to be the second leading cause of cancer-associated mortality in women worldwide. However, the precise role of aerobic glycolysis in the development of BC remains elusive. Therefore, the present review attempts to address the implication of key enzymes of the aerobic glycolytic pathway including hexokinase (HK), phosphofructokinase (PFK) and pyruvate kinase (PK), glucose transporters (GLUTs), together with related signaling pathways including protein kinase B(PI3K/AKT), mammalian target of rapamycin (mTOR) and adenosine monophosphate-activated protein kinase (AMPK) and transcription factors (c-myc, p53 and HIF-1) in the research of BC. Thus, the review of aerobic glycolysis in BC may evoke novel ideas for the BC treatment.
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Affiliation(s)
- Z Wu
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People's Republic of China
| | - J Wu
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People's Republic of China
| | - Q Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, People's Republic of China.,South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, People's Republic of China
| | - S Fu
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People's Republic of China.
| | - J Jin
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People's Republic of China.
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32
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Xiong R, He D, Deng X, Liu J, Lei X, Xie Z, Cao X, Chen Y, Peng J, Tang G. Design, synthesis and biological evaluation of tryptamine salicylic acid derivatives as potential antitumor agents. MEDCHEMCOMM 2019; 10:573-583. [PMID: 31057737 PMCID: PMC6482410 DOI: 10.1039/c8md00484f] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Accepted: 01/05/2019] [Indexed: 12/21/2022]
Abstract
A series of tryptamine salicylic acid derivatives were synthesized and their antiproliferative activity against MGC-803, MCF-7, HepG2, A549 and HeLa cell lines was evaluated. The structure-activity relationship (SAR) study revealed that different substitutions of the C5 and C3'-C5' positions have certain effects on the anti-proliferation activity. The growth assay revealed that N-[2-(5-bromo-1H-indol-3-yl)-ethyl]-2-hydroxy-3-methyl-benzamide (E20) showed the most potent and broad-spectrum anticancer inhibition of all the cell lines evaluated, and was only more potent than 5-Fu for the gastric cancer cell line. Preliminary studies indicated that compound E20 could inhibit colony formation and migration of MGC-803 cells. The flow cytometry (FCM) results showed that compound E20 arrested the cell cycle in the G2/M phase and induced apoptosis of MGC-803 cells in a concentration-dependent manner. In addition, the western blot results showed that E20 can down-regulate the expression of hexokinase 2. Our studies suggest that the framework of N-[2-(5-bromo-1H-indol-3-yl)-ethyl]-2-hydroxy-3-methyl-benzamide may be consider as a new type of chemical for designing effective anti-cancer drugs targeting gastric cancer cells.
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Affiliation(s)
- Runde Xiong
- Institute of Pharmacy and Pharmacology , Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study , University of South China , Hengyang , China .
| | - Dongxiu He
- Institute of Pharmacy and Pharmacology , Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study , University of South China , Hengyang , China .
| | - Xiangping Deng
- Institute of Pharmacy and Pharmacology , Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study , University of South China , Hengyang , China .
| | - Juan Liu
- Institute of Pharmacy and Pharmacology , Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study , University of South China , Hengyang , China .
| | - Xiaoyong Lei
- Institute of Pharmacy and Pharmacology , Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study , University of South China , Hengyang , China .
| | - Zhizhong Xie
- Institute of Pharmacy and Pharmacology , Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study , University of South China , Hengyang , China .
| | - Xuan Cao
- Institute of Pharmacy and Pharmacology , Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study , University of South China , Hengyang , China .
| | | | - Junmei Peng
- Institute of Pharmacy and Pharmacology , Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study , University of South China , Hengyang , China .
| | - Guotao Tang
- Institute of Pharmacy and Pharmacology , Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study , University of South China , Hengyang , China .
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Deng X, Li Z, Xiong R, Liu J, Liu R, Peng J, Chen Y, Lei X, Cao X, Zheng X, Xie Z, Tang G. FS-7 inhibits MGC-803 cells growth in vitro and in vivo via down-regulating glycolysis. Biomed Pharmacother 2019; 109:1659-1669. [DOI: 10.1016/j.biopha.2018.11.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Revised: 11/01/2018] [Accepted: 11/01/2018] [Indexed: 12/20/2022] Open
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Deng X, Liu R, Li J, Li Z, Liu J, Xiong R, Lei X, Zheng X, Xie Z, Tang G. Design, synthesis, and preliminary biological evaluation of 3′,4′,5′-trimethoxy flavonoid salicylate derivatives as potential anti-tumor agents. NEW J CHEM 2019. [DOI: 10.1039/c8nj04533j] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
According to the combination principle, target compounds were designed; compound10vmight be a promising multiple target anti-tumor agent candidate.
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Guerra AR, Duarte MF, Duarte IF. Targeting Tumor Metabolism with Plant-Derived Natural Products: Emerging Trends in Cancer Therapy. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2018; 66:10663-10685. [PMID: 30227704 DOI: 10.1021/acs.jafc.8b04104] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
Recognition of neoplastic metabolic reprogramming as one of cancer's hallmarks has paved the way for developing novel metabolism-targeted therapeutic approaches. The use of plant-derived natural bioactive compounds for this endeavor is especially promising, due to their diverse structures and multiple targets. Hence, over the past decade, a growing number of studies have assessed the impact of phytochemicals on tumor cell metabolism, aiming at improving current knowledge on their mechanisms of action and, at the same time, evaluating their potential as anti-cancer metabolic modulators. In this Review, we focus on three classes of plant-derived compounds with promising anti-cancer activity-phenolic compounds, isoprenoids, and alkaloids-to describe their effects on major energetic and biosynthetic pathways of human tumor cells. Such a comprehensive and integrated account of the ability of these compounds to hit different metabolic targets is expected to contribute to the rational design and critical assessment of novel anti-cancer therapies based on natural-product-mediated metabolic reprogramming.
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Affiliation(s)
- Angela R Guerra
- Centro de Biotecnologia Agrícola e Agro-Alimentar do Alentejo (CEBAL), Instituto Politécnico de Beja , Apartado 6158 , 7801-908 Beja , Portugal
- CICECO - Instituto de Materiais de Aveiro, Departamento de Quı́mica , Universidade de Aveiro , Campus de Santiago , 3810-193 Aveiro , Portugal
| | - Maria F Duarte
- Centro de Biotecnologia Agrícola e Agro-Alimentar do Alentejo (CEBAL), Instituto Politécnico de Beja , Apartado 6158 , 7801-908 Beja , Portugal
- ICAAM - Instituto de Ciências Agrárias e Ambientais Mediterrânicas , Universidade de Évora , Pólo da Mitra, 7006-554 Évora , Portugal
| | - Iola F Duarte
- CICECO - Instituto de Materiais de Aveiro, Departamento de Quı́mica , Universidade de Aveiro , Campus de Santiago , 3810-193 Aveiro , Portugal
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Pontes O, Costa M, Santos F, Sampaio-Marques B, Dias T, Ludovico P, Baltazar F, Proença F. Exploitation of new chalcones and 4H-chromenes as agents for cancer treatment. Eur J Med Chem 2018; 157:101-114. [DOI: 10.1016/j.ejmech.2018.07.058] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Revised: 07/20/2018] [Accepted: 07/25/2018] [Indexed: 12/31/2022]
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Hui L, Zhang J, Guo X. MiR-125b-5p suppressed the glycolysis of laryngeal squamous cell carcinoma by down-regulating hexokinase-2. Biomed Pharmacother 2018; 103:1194-1201. [PMID: 29864898 DOI: 10.1016/j.biopha.2018.04.098] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Revised: 04/13/2018] [Accepted: 04/13/2018] [Indexed: 12/26/2022] Open
Abstract
Laryngeal squamous cell carcinoma (LSCC) is the most common form of laryngeal carcinoma with poor prognosis. Exploring novel factors involved in the progression of LSCC is quite necessary for understanding the mechanisms and designing therapeutic strategies for LSCC. In this study, we showed that miR-125b-5p was significantly down-regulated in LSCC tissues and cell lines. The decreased expression of miR-125b-5p was associated with the tumor differentiation, metastasis and high clinical stage of the LSCC patients. Overexpression of miR-125b-5p suppressed the proliferation and induced apoptosis of LSCC cells. Bioinformatics analysis predicted hexokinase-2 (HK2), an essential enzyme involved in the glycolysis of cancer cells, as one of the downstream targets of miR-125b-5p. Further molecular studies showed that highly expressed miR-125b-5p bound the 3'-UTR of HK2 and decreased both the mRNA and protein levels of HK2. Consistent with the function of HK2 in glycolytic metabolism, overexpression of miR-125b-5p significantly suppressed the glucose consumption and lactate production of LSCC cells. Notably, restoration the expression of HK2 attenuated the inhibitory effect of miR-125b-5p on the glycolysis of LSCC cells. The inverse correlation between the expression of miR-125b-5p and HK2 in LSCC tissues further supported the involvement of miR-125b-5p-HK2 axis in the progression of LSCC. Collectively, these finding suggested the miR-125b-5p-HK2 pathway as a novel mechanism in regulating the glycolysis and progression of LSCC.
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Affiliation(s)
- Lian Hui
- Department of Otolaryngology, The First Hospital of China Medical University, No. 155 Nanjing Bei Street, Shenyang, 110001, China.
| | - Jingru Zhang
- Department of Otolaryngology, The First Hospital of China Medical University, No. 155 Nanjing Bei Street, Shenyang, 110001, China
| | - Xing Guo
- Department of Otolaryngology, The First Hospital of China Medical University, No. 155 Nanjing Bei Street, Shenyang, 110001, China
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Khiewkamrop P, Phunsomboon P, Richert L, Pekthong D, Srisawang P. Epistructured catechins, EGCG and EC facilitate apoptosis induction through targeting de novo lipogenesis pathway in HepG2 cells. Cancer Cell Int 2018; 18:46. [PMID: 29588626 PMCID: PMC5863485 DOI: 10.1186/s12935-018-0539-6] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Accepted: 03/13/2018] [Indexed: 02/06/2023] Open
Abstract
Background Abnormally high expression of the mammalian de novo lipogenesis (DNL) pathway in various cancer cells promotes cell over-proliferation and resistance to apoptosis. Inhibition of key enzymes in the DNL pathway, namely, ATP citrate lyase, acetyl-CoA carboxylase, and fatty acid synthase (FASN) can increase apoptosis without cytotoxicity to non-cancerous cells, leading to the search for and presentation of novel selective and powerful targets for cancer therapy. Previous studies reported that epistructured catechins, epigallocatechin gallate (EGCG) and epicatechin (EC) exhibit different mechanisms regarding a strong inducer of apoptosis in various cancer cell lines. Thus, the current study investigated the growth inhibitory effect of EGCG and EC, on the enzyme expression and activity of the DNL pathway, which leads to the prominent activity of carnitine palmitoyl transferase-1 (CPT-1) mediating apoptosis in HepG2 cells. Methods The cytotoxicity on HepG2 cells of EGCG and EC was determined by MTT assay. Cell death caused by apoptosis, the dissipation of mitochondrial membrane potential (MMP), and cell cycle arrest were then detected by flow cytometry. We further investigated the decrease of fatty acid levels associated with DNL retardation, followed by evaluation of DNL protein expression. Then, the negative inhibitory effect of depleted fatty acid synthesis on malonyl-CoA synthesis followed by regulating of CPT-1 activity was investigated. Thereafter, we inspected the enhanced reactive oxygen species (ROS) generation, which is recognized as one of the causes of apoptosis in HepG2 cells. Results We found that EGCG and EC decreased cancer cell viability by increasing apoptosis as well as causing cell cycle arrest in HepG2 cells. Apoptosis was associated with MMP dissipation. Herein, EGCG and EC inhibited the expression of FASN enzymes contributing to decreasing fatty acid levels. Notably, this decrease consequently showed a suppressing effect on the CPT-1 activity. We suggest that epistructured catechin-induced apoptosis targets CPT-1 activity suppression mediated through diminishing the DNL pathway in HepG2 cells. In addition, increased ROS production was found after treatment with EGCG and EC, indicating oxidative stress mechanism-induced apoptosis. The strong apoptotic effect of EGCG and EC was specifically absent in primary human hepatocytes. Conclusion Our supportive evidence confirms potential alternative cancer treatments by EGCG and EC that selectively target the DNL pathway.
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Affiliation(s)
- Phuriwat Khiewkamrop
- 1Department of Physiology, Faculty of Medical Science, Naresuan University, Phitsanulok, 65000 Thailand
| | - Pattamaphron Phunsomboon
- 2Clinical Research Unit Floor 5 His Majesty's 7th Cycle Birthday Anniversary 2, Faculty of Medicine, Naresuan University, Phitsanulok, 65000 Thailand
| | - Lysiane Richert
- KaLy-Cell, 20A rue du Général Leclerc, 67115 Plobsheim, France.,Laboratoire de Toxicologie Cellulaire, Université de Bourgogne Franche-Comté, EA 4267, Besançon, France
| | - Dumrongsak Pekthong
- 5Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, 65000 Thailand
| | - Piyarat Srisawang
- 1Department of Physiology, Faculty of Medical Science, Naresuan University, Phitsanulok, 65000 Thailand
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Akins NS, Nielson TC, Le HV. Inhibition of Glycolysis and Glutaminolysis: An Emerging Drug Discovery Approach to Combat Cancer. Curr Top Med Chem 2018; 18:494-504. [PMID: 29788892 PMCID: PMC6110043 DOI: 10.2174/1568026618666180523111351] [Citation(s) in RCA: 177] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2018] [Revised: 05/05/2018] [Accepted: 05/11/2018] [Indexed: 12/15/2022]
Abstract
Cancer cells have a very different metabolism from that of normal cells from which they are derived. Their metabolism is elevated, which allows them to sustain higher proliferative rate and resist some cell death signals. This phenomenon, known as the "Warburg effect", has become the focus of intensive efforts in the discovery of new therapeutic targets and new cancer drugs. Both glycolysis and glutaminolysis pathways are enhanced in cancer cells. While glycolysis is enhanced to satisfy the increasing energy demand of cancer cells, glutaminolysis is enhanced to provide biosynthetic precursors for cancer cells. It was recently discovered that there is a tyrosine phosphorylation of a specific isoform of pyruvate kinase, the M2 isoform, that is preferentially expressed in all cancer cells, which results in the generation of pyruvate through a unique enzymatic mechanism that is uncoupled from ATP production. Pyruvate produced through this unique enzymatic mechanism is converted primarily into lactic acid, rather than acetyl-CoA for the synthesis of citrate, which would normally then enter the citric acid cycle. Inhibition of key enzymes in glycolysis and glutaminolysis pathways with small molecules has provided a novel but emerging area of cancer research and has been proven effective in slowing the proliferation of cancer cells, with several inhibitors being in clinical trials. This review paper will cover recent advances in the development of chemotherapeutic agents against several metabolic targets for cancer therapy, including glucose transporters, hexokinase, pyruvate kinase M2, glutaminase, and isocitrate dehydrogenase.
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Affiliation(s)
- Nicholas S. Akins
- Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, Mississippi 38677, USA
| | - Tanner C. Nielson
- Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, Mississippi 38677, USA
| | - Hoang V. Le
- Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, Mississippi 38677, USA
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Shi X, Qin T, Liu W, Zhang X, Li L, Huo J, Zhou K, Yang D, Zhang Y, Wang C. Selective anticancer activity of the novel steroidal dihydropyridine spirooxindoles against human esophageal EC109 cells. Biomed Pharmacother 2017; 96:1186-1192. [PMID: 29196102 DOI: 10.1016/j.biopha.2017.11.100] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Revised: 11/17/2017] [Accepted: 11/17/2017] [Indexed: 01/15/2023] Open
Abstract
A series of small-molecule compounds built on steroidal dihydropyridine spirooxindoles has been reported previously. In this study, the compound 5l showed strong anti-cancer activity, especially in the esophageal cancer. Three esophageal squamous cell lines and paclitaxel-resistant cell line were investigated. The results demonstrated that compound 5l was most efficient in the EC109 cells, induced cell apoptosis through elevation of cellular ROS levels, caused G2/M phase arrest and mitochondrial dysfunction. Further study confirmed that the mechanism of 5l in esophageal cancer treatment was related to the Bcl-2 family and caspase receptor-mediated apoptotic pathway.
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Affiliation(s)
- Xiaoli Shi
- School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, PR China; Key Laboratory of Technology of Drug Preparation, Zhengzhou University, Ministry of Education of China, Zhengzhou, Henan 450001, PR China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou, Henan 450001, PR China
| | - Tiantian Qin
- School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, PR China; Key Laboratory of Technology of Drug Preparation, Zhengzhou University, Ministry of Education of China, Zhengzhou, Henan 450001, PR China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou, Henan 450001, PR China
| | - Weihua Liu
- School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, PR China; Key Laboratory of Technology of Drug Preparation, Zhengzhou University, Ministry of Education of China, Zhengzhou, Henan 450001, PR China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou, Henan 450001, PR China
| | - Xueyan Zhang
- School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, PR China; Key Laboratory of Technology of Drug Preparation, Zhengzhou University, Ministry of Education of China, Zhengzhou, Henan 450001, PR China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou, Henan 450001, PR China
| | - Leilei Li
- School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, PR China; Key Laboratory of Technology of Drug Preparation, Zhengzhou University, Ministry of Education of China, Zhengzhou, Henan 450001, PR China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou, Henan 450001, PR China
| | - Junfeng Huo
- School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, PR China; Key Laboratory of Technology of Drug Preparation, Zhengzhou University, Ministry of Education of China, Zhengzhou, Henan 450001, PR China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou, Henan 450001, PR China
| | - Kairui Zhou
- School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, PR China; Key Laboratory of Technology of Drug Preparation, Zhengzhou University, Ministry of Education of China, Zhengzhou, Henan 450001, PR China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou, Henan 450001, PR China
| | - Dongxiao Yang
- School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, PR China; Key Laboratory of Technology of Drug Preparation, Zhengzhou University, Ministry of Education of China, Zhengzhou, Henan 450001, PR China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou, Henan 450001, PR China
| | - Yanling Zhang
- School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, PR China; Key Laboratory of Technology of Drug Preparation, Zhengzhou University, Ministry of Education of China, Zhengzhou, Henan 450001, PR China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou, Henan 450001, PR China
| | - Cong Wang
- School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, PR China; Key Laboratory of Technology of Drug Preparation, Zhengzhou University, Ministry of Education of China, Zhengzhou, Henan 450001, PR China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou, Henan 450001, PR China.
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