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Hunt S, Thyagarajan A, Sahu RP. Dichloroacetate and Salinomycin as Therapeutic Agents in Cancer. Med Sci (Basel) 2025; 13:47. [PMID: 40407542 PMCID: PMC12101198 DOI: 10.3390/medsci13020047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Revised: 04/09/2025] [Accepted: 04/21/2025] [Indexed: 05/26/2025] Open
Abstract
Cancer is the second leading cause of mortality worldwide. Despite the available treatment options, a majority of cancer patients develop drug resistance, indicating the need for alternative approaches. Repurposed drugs, such as antiglycolytic and anti-microbial agents, have gained substantial attention as potential alternative strategies against different disease pathophysiologies, including lung cancer. To that end, multiple studies have suggested that the antiglycolytic dichloroacetate (DCA) and the antibiotic salinomycin (SAL) possess promising anticarcinogenic activity, attributed to their abilities to target the key metabolic enzymes, ion transport, and oncogenic signaling pathways involved in regulating cancer cell behavior, including cell survival and proliferation. We used the following searches and selection criteria. (1) Biosis and PubMed were used with the search terms dichloroacetate; salinomycin; dichloroacetate as an anticancer agent; salinomycin as an anticancer agent; dichloroacetate side effects; salinomycin side effects; salinomycin combination therapy; dichloroacetate combination therapy; and dichloroacetate or salinomycin in combination with other agents, including chemotherapy and tyrosine kinase inhibitors. (2) The exclusion criteria included not being related to the mechanisms of DCA and SAL or not focusing on their anticancer properties. (3) All the literature was sourced from peer-reviewed journals within a timeframe of 1989 to 2024. Importantly, experimental studies have demonstrated that both DCA and SAL exert promising anticarcinogenic properties, as well as having synergistic effects in combination with other therapeutic agents, against multiple cancer models. The goal of this review is to highlight the mechanistic workings and efficacy of DCA and SAL as monotherapies, and their combination with other therapeutic agents in various cancer models, with a major emphasis on non-small-cell lung cancer (NSCLC) treatment.
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Affiliation(s)
- Sunny Hunt
- Department of Chemistry and Biochemistry, Oberlin College, 173 W Lorain St, Oberlin, OH 44074, USA;
| | - Anita Thyagarajan
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Dayton, OH 45435, USA;
| | - Ravi P. Sahu
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Dayton, OH 45435, USA;
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2
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Gu XY, Yang JL, Lai R, Zhou ZJ, Tang D, Hu L, Zhao LJ. Impact of lactate on immune cell function in the tumor microenvironment: mechanisms and therapeutic perspectives. Front Immunol 2025; 16:1563303. [PMID: 40207222 PMCID: PMC11979165 DOI: 10.3389/fimmu.2025.1563303] [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: 01/19/2025] [Accepted: 03/10/2025] [Indexed: 04/11/2025] Open
Abstract
Lactate has emerged as a key regulator in the tumor microenvironment (TME), influencing both tumor progression and immune dynamics. As a byproduct of aerobic glycolysis, lactate satisfies the metabolic needs of proliferating tumor cells while reshaping the TME to facilitate immune evasion. Elevated lactate levels inhibit effector immune cells such as CD8+ T and natural killer cells, while supporting immunosuppressive cells, such as regulatory T cells and myeloid-derived suppressor cells, thus fostering an immunosuppressive environment. Lactate promotes epigenetic reprogramming, stabilizes hypoxia-inducible factor-1α, and activates nuclear factor kappa B, leading to further immunological dysfunction. In this review, we examined the role of lactate in metabolic reprogramming, immune suppression, and treatment resistance. We also discuss promising therapeutic strategies targeting lactate metabolism, including lactate dehydrogenase inhibitors, monocarboxylate transporter inhibitors, and TME neutralization methods, all of which can restore immune function and enhance immunotherapy outcomes. By highlighting recent advances, this review provides a theoretical foundation for integrating lactate-targeted therapies into clinical practice. We also highlight the potential synergy between these therapies and current immunotherapeutic strategies, providing new avenues for addressing TME-related challenges and improving outcomes for patients with cancer.
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Affiliation(s)
- Xuan-Yu Gu
- Department of General Surgery, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Jia-Li Yang
- Department of General Surgery, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Rui Lai
- Department of Otolaryngology-Head and Neck Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Zheng-Jun Zhou
- Department of General Surgery, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Dan Tang
- Department of General Surgery, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Department of Hepatobiliary and Pancreatic Surgery, Suzhou Medical College of Soochow University, Suzhou, China
| | - Long Hu
- Wisdom Lake Academy of Pharmacy, Xi’an Jiaotong-Liverpool University, Suzhou, China
| | - Li-Jin Zhao
- Department of General Surgery, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
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Ma M, Zhang Y, Pu K, Tang W. Nanomaterial-enabled metabolic reprogramming strategies for boosting antitumor immunity. Chem Soc Rev 2025; 54:653-714. [PMID: 39620588 DOI: 10.1039/d4cs00679h] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2025]
Abstract
Immunotherapy has become a crucial strategy in cancer treatment, but its effectiveness is often constrained. Most cancer immunotherapies focus on stimulating T-cell-mediated immunity by driving the cancer-immunity cycle, which includes tumor antigen release, antigen presentation, T cell activation, infiltration, and tumor cell killing. However, metabolism reprogramming in the tumor microenvironment (TME) supports the viability of cancer cells and inhibits the function of immune cells within this cycle, presenting clinical challenges. The distinct metabolic needs of tumor cells and immune cells require precise and selective metabolic interventions to maximize therapeutic outcomes while minimizing adverse effects. Recent advances in nanotherapeutics offer a promising approach to target tumor metabolism reprogramming and enhance the cancer-immunity cycle through tailored metabolic modulation. In this review, we explore cutting-edge nanomaterial strategies for modulating tumor metabolism to improve therapeutic outcomes. We review the design principles of nanoplatforms for immunometabolic modulation, key metabolic pathways and their regulation, recent advances in targeting these pathways for the cancer-immunity cycle enhancement, and future prospects for next-generation metabolic nanomodulators in cancer immunotherapy. We expect that emerging immunometabolic modulatory nanotechnology will establish a new frontier in cancer immunotherapy in the near future.
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Affiliation(s)
- Muye Ma
- Department of Diagnostic Radiology, Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore, 117597, Singapore.
| | - Yongliang Zhang
- Department of Microbiology and Immunology, Immunology Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Dr 2, Singapore, 117545, Singapore
- Immunology Programme, Life Sciences Institute, National University of Singapore, 28 Medical Dr, Singapore, 117597, Singapore
| | - Kanyi Pu
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, 70 Nanyang Drive, Singapore, 637457, Singapore.
- Lee Kong Chian School of Medicine, Nanyang Technological University, 59 Nanyang Drive, Singapore, 636921, Singapore
| | - Wei Tang
- Department of Diagnostic Radiology, Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore, 117597, Singapore.
- Department of Pharmacy and Pharmaceutic Sciences, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore, 117543, Singapore
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Kuppusamy P, Haque MM, Traub RJ, Melemedjian OK. Targeting metabolic pathways alleviates bortezomib-induced neuropathic pain without compromising anticancer efficacy in a sex-specific manner. FRONTIERS IN PAIN RESEARCH 2024; 5:1424348. [PMID: 38979441 PMCID: PMC11228363 DOI: 10.3389/fpain.2024.1424348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Accepted: 06/10/2024] [Indexed: 07/10/2024] Open
Abstract
Introduction Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating side effect of cancer treatment that significantly impacts patients' quality of life. This study investigated the effects of targeting metabolic pathways on bortezomib-induced neuropathic pain and tumor growth using a Lewis lung carcinoma (LLC) mouse model, while exploring potential sex differences. Methods Male and female C57BL/6J mice were implanted with LLC cells and treated with bortezomib alone or in combination with metformin, dichloroacetate (DCA), or oxamate. Tactile allodynia was assessed using von Frey filaments. Tumor volume and weight were measured to evaluate tumor growth. Results Metformin, DCA, and oxamate effectively attenuated bortezomib-induced neuropathic pain without compromising the anticancer efficacy of bortezomib in both male and female mice. The LLC model exhibited a paraneoplastic neuropathy-like phenotype. Significant sex differences were observed, with male mice exhibiting larger tumors compared to females. Oxamate was more effective in alleviating allodynia in males, while metformin and DCA showed greater efficacy in reducing tumor growth in females. Discussion Targeting metabolic pathways can alleviate CIPN without interfering with bortezomib's anticancer effects. The LLC model may serve as a tool for studying paraneoplastic neuropathy. Sex differences in tumor growth and response to metabolic interventions highlight the importance of considering sex as a biological variable in preclinical and clinical studies investigating cancer biology, CIPN, and potential therapeutic interventions.
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Affiliation(s)
- Panjamurthy Kuppusamy
- Department of Neural and Pain Sciences, University of Maryland School of Dentistry, Baltimore, MD, United States
| | - Md Mamunul Haque
- Department of Neural and Pain Sciences, University of Maryland School of Dentistry, Baltimore, MD, United States
| | - Richard J. Traub
- Department of Neural and Pain Sciences, University of Maryland School of Dentistry, Baltimore, MD, United States
- UM Center to Advance Chronic Pain Research, Baltimore, MD, United States
| | - Ohannes K. Melemedjian
- Department of Neural and Pain Sciences, University of Maryland School of Dentistry, Baltimore, MD, United States
- UM Center to Advance Chronic Pain Research, Baltimore, MD, United States
- UM Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, United States
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Koltai T, Fliegel L. Dichloroacetate for Cancer Treatment: Some Facts and Many Doubts. Pharmaceuticals (Basel) 2024; 17:744. [PMID: 38931411 PMCID: PMC11206832 DOI: 10.3390/ph17060744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 05/23/2024] [Accepted: 06/04/2024] [Indexed: 06/28/2024] Open
Abstract
Rarely has a chemical elicited as much controversy as dichloroacetate (DCA). DCA was initially considered a dangerous toxic industrial waste product, then a potential treatment for lactic acidosis. However, the main controversies started in 2008 when DCA was found to have anti-cancer effects on experimental animals. These publications showed contradictory results in vivo and in vitro such that a thorough consideration of this compound's in cancer is merited. Despite 50 years of experimentation, DCA's future in therapeutics is uncertain. Without adequate clinical trials and health authorities' approval, DCA has been introduced in off-label cancer treatments in alternative medicine clinics in Canada, Germany, and other European countries. The lack of well-planned clinical trials and its use by people without medical training has discouraged consideration by the scientific community. There are few thorough clinical studies of DCA, and many publications are individual case reports. Case reports of DCA's benefits against cancer have been increasing recently. Furthermore, it has been shown that DCA synergizes with conventional treatments and other repurposable drugs. Beyond the classic DCA target, pyruvate dehydrogenase kinase, new target molecules have also been recently discovered. These findings have renewed interest in DCA. This paper explores whether existing evidence justifies further research on DCA for cancer treatment and it explores the role DCA may play in it.
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Affiliation(s)
- Tomas Koltai
- Hospital del Centro Gallego de Buenos Aires, Buenos Aires 2199, Argentina
| | - Larry Fliegel
- Department of Biochemistry, University Alberta, Edmonton, AB T6G 2H7, Canada;
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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: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [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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Schoenmann N, Tannenbaum N, Hodgeman RM, Raju RP. Regulating mitochondrial metabolism by targeting pyruvate dehydrogenase with dichloroacetate, a metabolic messenger. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166769. [PMID: 37263447 PMCID: PMC10776176 DOI: 10.1016/j.bbadis.2023.166769] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 05/20/2023] [Accepted: 05/26/2023] [Indexed: 06/03/2023]
Abstract
Dichloroacetate (DCA) is a naturally occurring xenobiotic that has been used as an investigational drug for over 50 years. Originally found to lower blood glucose levels and alter fat metabolism in diabetic rats, this small molecule was found to serve primarily as a pyruvate dehydrogenase kinase inhibitor. Pyruvate dehydrogenase kinase inhibits pyruvate dehydrogenase complex, the catalyst for oxidative decarboxylation of pyruvate to produce acetyl coenzyme A. Several congenital and acquired disease states share a similar pathobiology with respect to glucose homeostasis under distress that leads to a preferential shift from the more efficient oxidative phosphorylation to glycolysis. By reversing this process, DCA can increase available energy and reduce lactic acidosis. The purpose of this review is to examine the literature surrounding this metabolic messenger as it presents exciting opportunities for future investigation and clinical application in therapy including cancer, metabolic disorders, cerebral ischemia, trauma, and sepsis.
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Affiliation(s)
- Nick Schoenmann
- Department of Emergency Medicine, Medical College of Georgia, Augusta University, Augusta, GA, United States of America
| | - Nicholas Tannenbaum
- Department of Emergency Medicine, Medical College of Georgia, Augusta University, Augusta, GA, United States of America
| | - Ryan M Hodgeman
- Department of Emergency Medicine, Medical College of Georgia, Augusta University, Augusta, GA, United States of America
| | - Raghavan Pillai Raju
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, United States of America.
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Pourbaghi M, Haghani L, Zhao K, Karimi A, Marinelli B, Erinjeri JP, Geschwind JFH, Yarmohammadi H. Anti-Glycolytic Drugs in the Treatment of Hepatocellular Carcinoma: Systemic and Locoregional Options. Curr Oncol 2023; 30:6609-6622. [PMID: 37504345 PMCID: PMC10377758 DOI: 10.3390/curroncol30070485] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 07/01/2023] [Accepted: 07/04/2023] [Indexed: 07/29/2023] Open
Abstract
Hepatocellular cancer (HCC) is the most common primary liver cancer and the third leading cause of cancer-related death. Locoregional therapies, including transarterial embolization (TAE: bland embolization), chemoembolization (TACE), and radioembolization, have demonstrated survival benefits when treating patients with unresectable HCC. TAE and TACE occlude the tumor's arterial supply, causing hypoxia and nutritional deprivation and ultimately resulting in tumor necrosis. Embolization blocks the aerobic metabolic pathway. However, tumors, including HCC, use the "Warburg effect" and survive hypoxia from embolization. An adaptation to hypoxia through the Warburg effect, which was first described in 1956, is when the cancer cells switch to glycolysis even in the presence of oxygen. Hence, this is also known as aerobic glycolysis. In this article, the adaptation mechanisms of HCC, including glycolysis, are discussed, and anti-glycolytic treatments, including systemic and locoregional options that have been previously reported or have the potential to be utilized in the treatment of HCC, are reviewed.
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Affiliation(s)
- Miles Pourbaghi
- Department of Interventional Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; (M.P.); (K.Z.); (A.K.); (B.M.); (J.P.E.)
| | - Leila Haghani
- Department of Interventional Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; (M.P.); (K.Z.); (A.K.); (B.M.); (J.P.E.)
| | - Ken Zhao
- Department of Interventional Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; (M.P.); (K.Z.); (A.K.); (B.M.); (J.P.E.)
| | - Anita Karimi
- Department of Interventional Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; (M.P.); (K.Z.); (A.K.); (B.M.); (J.P.E.)
| | - Brett Marinelli
- Department of Interventional Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; (M.P.); (K.Z.); (A.K.); (B.M.); (J.P.E.)
| | - Joseph P. Erinjeri
- Department of Interventional Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; (M.P.); (K.Z.); (A.K.); (B.M.); (J.P.E.)
| | | | - Hooman Yarmohammadi
- Department of Interventional Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; (M.P.); (K.Z.); (A.K.); (B.M.); (J.P.E.)
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Zhang X, Sarkar S, Ashokan A, Surnar B, Kolishetti N, Dhar S. All-in-One Pyruvate Dehydrogenase Kinase Inhibitor for Tracking, Targeting, and Enhanced Efficacy. Bioconjug Chem 2023; 34:1122-1129. [PMID: 37279374 PMCID: PMC10903362 DOI: 10.1021/acs.bioconjchem.3c00152] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
The metabolic preference of cells toward glycolysis often indicates a diseased state ranging from cancer to other dysfunctions. When a particular cell type utilizes glycolysis as a major energy production pathway, their mitochondria become impaired resulting a cascade of events which eventually contributes to resistance toward therapies to tackle such diseases. In abnormal tissues such as seen in the tumor microenvironment, when cancer cells utilize glycolysis, other cell types such as the immune cells switch their metabolism and prefer such glycolysis. As a result, utilization of therapies to destroy glycolytic preferences by cancer cells results in destruction of immune cells contributing toward an immunosuppressive phenotype. Thus, development of targeted, trackable, comparatively stable glycolysis inhibitors is urgently needed to manage diseases where glycolysis is preferred for disease progression. No glycolysis inhibitor exists which can be tracked and packaged in a delivery vehicle for efficient targeted deployment. Here, we report synthesis, characterization, and formulation of an all-in-one glycolysis inhibitor and document the therapeutic potential along with trackability and glycolysis inhibition of this inhibitor by utilizing an in vivo breast cancer model.
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Affiliation(s)
- Xiao Zhang
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, University of Miami, Miami, Florida 33136, United States
- Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, University of Miami, Miami, Florida 33136, United States
| | - Shrita Sarkar
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, University of Miami, Miami, Florida 33136, United States
- Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, University of Miami, Miami, Florida 33136, United States
| | - Akash Ashokan
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, University of Miami, Miami, Florida 33136, United States
- Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, University of Miami, Miami, Florida 33136, United States
| | - Bapurao Surnar
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, University of Miami, Miami, Florida 33136, United States
- Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, University of Miami, Miami, Florida 33136, United States
| | - Nagesh Kolishetti
- Department of Immunology and Nano-Medicine, Herbert Wertheim, College of Medicine, Florida International University, Miami, Florida 33199, United States
- Institute of Neuroimmune Pharmacology, Herbert Wertheim College of Medicine, Miami, Florida 33199, United States
| | - Shanta Dhar
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, University of Miami, Miami, Florida 33136, United States
- Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, University of Miami, Miami, Florida 33136, United States
- Department of Chemistry, University of Miami, 1301 Memorial Drive, Coral Gables, Florida 33146, United States
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Zhou Y, Zou J, Xu J, Zhou Y, Cen X, Zhao Y. Recent advances of mitochondrial complex I inhibitors for cancer therapy: Current status and future perspectives. Eur J Med Chem 2023; 251:115219. [PMID: 36893622 DOI: 10.1016/j.ejmech.2023.115219] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 02/09/2023] [Accepted: 02/19/2023] [Indexed: 02/26/2023]
Abstract
Mitochondrial complex I (CI) as a critical multifunctional respiratory complex of electron transport chain (ETC) in mitochondrial oxidative phosphorylation has been identified as vital and essence in ATP production, biosynthesis and redox balance. Recent progress in targeting CI has provided both insight and inspiration for oncotherapy, highlighting that the development of CI-targeting inhibitors is a promising therapeutic approach to fight cancer. Natural products possessing of ample scaffold diversity and structural complexity are the majority source of CI inhibitors, although low specificity and safety hinder their extensive application. Along with the gradual deepening in understanding of CI structure and function, significant progress has been achieved in exploiting novel and selective small molecules targeting CI. Among them, IACS-010759 had been approved by FDA for phase I trial in advanced cancers. Moreover, drug repurposing represents an effective and prospective strategy for CI inhibitor discovery. In this review, we mainly elaborate the biological function of CI in tumor progression, summarize the CI inhibitors reported in recent years and discuss the further perspectives for CI inhibitor application, expecting this work may provide insights into innovative discovery of CI-targeting drugs for cancer treatment.
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Affiliation(s)
- Yang Zhou
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China.
| | - Jiao Zou
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China
| | - Jing Xu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China
| | - Yue Zhou
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China
| | - Xiaobo Cen
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China; National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Yinglan Zhao
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China.
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Zare S, Ramezani Z, Ghadiri AA, Fereidoonnezhad M. Synthesis of N‐(2‐(tert‐Butylamino)‐2‐oxoethyl)‐2,2‐dichloro‐N‐aryl(alkyl)acetamides as Anticancer Agents: Molecular Modeling and Biological Evaluations. ChemistrySelect 2023. [DOI: 10.1002/slct.202203931] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Affiliation(s)
- Somayeh Zare
- Cancer Research Center Ahvaz Jundishapur University of Medical Sciences Ahvaz Iran
- Department of Medicinal Chemistry School of Pharmacy Shiraz University of Medical Sciences Shiraz Iran
| | - Zahra Ramezani
- Cancer Research Center Ahvaz Jundishapur University of Medical Sciences Ahvaz Iran
- Department of Medicinal Chemistry Faculty of Pharmacy Ahvaz Jundishapur University of Medical Sciences Ahvaz Iran
| | - Ata A. Ghadiri
- Department of Immunology School of Medicine Ahvaz Jundishapur University of Medical Sciences Ahvaz Iran
| | - Masood Fereidoonnezhad
- Cancer Research Center Ahvaz Jundishapur University of Medical Sciences Ahvaz Iran
- Department of Medicinal Chemistry Faculty of Pharmacy Ahvaz Jundishapur University of Medical Sciences Ahvaz Iran
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Abedi-Gaballu F, Kamal Kazemi E, Salehzadeh SA, Mansoori B, Eslami F, Emami A, Dehghan G, Baradaran B, Mansoori B, Cho WC. Metabolic Pathways in Breast Cancer Reprograming: An Insight to Non-Coding RNAs. Cells 2022; 11:2973. [PMID: 36230935 PMCID: PMC9563138 DOI: 10.3390/cells11192973] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 09/10/2022] [Accepted: 09/19/2022] [Indexed: 11/16/2022] Open
Abstract
Cancer cells reprogram their metabolisms to achieve high energetic requirements and produce precursors that facilitate uncontrolled cell proliferation. Metabolic reprograming involves not only the dysregulation in glucose-metabolizing regulatory enzymes, but also the enzymes engaging in the lipid and amino acid metabolisms. Nevertheless, the underlying regulatory mechanisms of reprograming are not fully understood. Non-coding RNAs (ncRNAs) as functional RNA molecules cannot translate into proteins, but they do play a regulatory role in gene expression. Moreover, ncRNAs have been demonstrated to be implicated in the metabolic modulations in breast cancer (BC) by regulating the metabolic-related enzymes. Here, we will focus on the regulatory involvement of ncRNAs (microRNA, circular RNA and long ncRNA) in BC metabolism, including glucose, lipid and glutamine metabolism. Investigation of this aspect may not only alter the approaches of BC diagnosis and prognosis, but may also open a new avenue in using ncRNA-based therapeutics for BC treatment by targeting different metabolic pathways.
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Affiliation(s)
- Fereydoon Abedi-Gaballu
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 51666-14731, Iran
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz 51666-16471, Iran
| | - Elham Kamal Kazemi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 51666-14731, Iran
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz 51666-16471, Iran
| | - Seyed Ahmad Salehzadeh
- Department of Medicinal Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran 175-14115, Iran
| | - Behnaz Mansoori
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran 175-14115, Iran
| | - Farhad Eslami
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz 51666-16471, Iran
| | - Ali Emami
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz 51666-16471, Iran
| | - Gholamreza Dehghan
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz 51666-16471, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 51666-14731, Iran
| | - Behzad Mansoori
- Cellular and Molecular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104, USA
| | - William C. Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong, China
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13
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Cho H, Cho A, Kang WJ. Prognosis Associated with Glycolytic Activity in Regional Lymph Nodes of Patients with Previously Untreated Metastatic Breast Cancer: A Preliminary Study. Diagnostics (Basel) 2022; 12:diagnostics12081809. [PMID: 36010160 PMCID: PMC9406466 DOI: 10.3390/diagnostics12081809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 07/20/2022] [Accepted: 07/26/2022] [Indexed: 11/16/2022] Open
Abstract
Better mechanisms of predicting prognoses in patients with metastatic breast cancer will improve the identification of patients for whom curative treatments may be the most effective. In this study, the prognostic value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) was assessed in patients with metastatic breast cancer. A retrospective analysis of women who underwent 18F-FDG PET/CT for staging of newly diagnosed metastatic breast cancer was conducted. In each patient, the maximum standardized uptake value (SUV) and total lesion glycolysis (TLG) of primary tumors and regional lymph nodes were measured and analyzed for association with survival using the Cox proportional hazards regression model. From 346 consecutive patients, 32 with metastatic invasive ductal carcinoma of the breast were included in the study. The median duration of follow-up was 22.5 months. Disease progression occurred in 26 patients, and 11 patients died. When multivariate analyses with a stepwise forward regression were applied, only the maximum SUV and TLG of regional lymph nodes showed a significant correlation with progression-free survival and overall survival, respectively. This study demonstrates that increased 18F-FDG uptake in regional lymph nodes is a strong independent predictor of survival in women with metastatic invasive ductal carcinoma of the breast.
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14
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Yadav S, Dwivedi A, Tripathi A. Biology of macrophage fate decision: Implication in inflammatory disorders. Cell Biol Int 2022; 46:1539-1556. [PMID: 35842768 DOI: 10.1002/cbin.11854] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Revised: 05/04/2022] [Accepted: 06/18/2022] [Indexed: 11/11/2022]
Abstract
The activation of immune cells in response to stimuli present in their microenvironment is regulated by their metabolic profile. Unlike the signal transduction events, which overlap to a huge degree in diverse cellular processes, the metabolome of a cell reflects a more precise picture of cell physiology and function. Different factors governing the cellular metabolome include receptor signaling, macro and micronutrients, normoxic and hypoxic conditions, energy needs, and biomass demand. Macrophages have enormous plasticity and can perform diverse functions depending upon their phenotypic state. This review presents recent updates on the cellular metabolome and molecular patterns associated with M1 and M2 macrophages, also termed "classically activated macrophages" and "alternatively activated macrophages," respectively. M1 macrophages are proinflammatory in nature and predominantly Th1-specific immune responses induce their polarization. On the contrary, M2 macrophages are anti-inflammatory in nature and primarily participate in Th2-specific responses. Interestingly, the same macrophage cell can adapt to the M1 or M2 phenotype depending upon the clues from its microenvironment. We elaborate on the various tissue niche-specific factors, which govern macrophage metabolism and heterogeneity. Furthermore, the current review provides an in-depth account of deregulated macrophage metabolism associated with pathological disorders such as cancer, obesity, and atherosclerosis. We further highlight significant differences in various metabolic pathways governing the cellular bioenergetics and their impact on macrophage effector functions and associated disorders.
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Affiliation(s)
- Sarika Yadav
- Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research, Lucknow, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India
| | - Ashish Dwivedi
- Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research, Lucknow, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India
| | - Anurag Tripathi
- Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research, Lucknow, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India
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15
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Wang S, Liu G, Li Y, Pan Y. Metabolic Reprogramming Induces Macrophage Polarization in the Tumor Microenvironment. Front Immunol 2022; 13:840029. [PMID: 35874739 PMCID: PMC9302576 DOI: 10.3389/fimmu.2022.840029] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 06/09/2022] [Indexed: 12/18/2022] Open
Abstract
Macrophages are one of the most important cells in the innate immune system, they are converted into two distinct subtypes with completely different molecular phenotypes and functional features under different stimuli of the microenvironment: M1 macrophages induced by IFN-γ/lipopolysaccharides(LPS) and M2 macrophages induced by IL-4/IL-10/IL-13. Tumor-associated macrophages (TAMs) differentiate from macrophages through various factors in the tumor microenvironment (TME). TAMs have the phenotype and function of M2 macrophages and are capable of secreting multiple cytokines to promote tumor progression. Both tumor cells and macrophages can meet the energy needs for rapid cell growth and proliferation through metabolic reprogramming, so a comprehensive understanding of pro-tumor and antitumor metabolic switches in TAM is essential to understanding immune escape mechanisms. This paper focuses on the functions of relevant signaling pathways and cytokines during macrophage polarization and metabolic reprogramming, and briefly discusses the effects of different microenvironments and macrophage pathogenicity, in addition to describing the research progress of inhibitory drugs for certain metabolic and polarized signaling pathways.
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Affiliation(s)
- Shilin Wang
- Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Guohong Liu
- Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Yirong Li
- Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Yunbao Pan
- Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
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16
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He D, Chen M, Chang L, Gu J, Liu F, Gao X, Ruan Y. De novo pyrimidine synthesis fuels glycolysis and confers chemoresistance in gastric cancer. Cancer Lett 2022; 549:215837. [DOI: 10.1016/j.canlet.2022.215837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 07/16/2022] [Accepted: 07/21/2022] [Indexed: 11/27/2022]
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Khodaei T, Inamdar S, Suresh AP, Acharya AP. Drug delivery for metabolism targeted cancer immunotherapy. Adv Drug Deliv Rev 2022; 184:114242. [PMID: 35367306 DOI: 10.1016/j.addr.2022.114242] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 02/26/2022] [Accepted: 03/26/2022] [Indexed: 02/08/2023]
Abstract
Drug delivery vehicles have made a great impact on cancer immunotherapies in clinics and pre-clinical research. Notably, the science of delivery of cancer vaccines and immunotherapeutics, modulating immune cell functions has inspired development of several successful companies and clinical products. Interestingly, these drug delivery modalities not only modulate the function of immune cells (often quantified at the mRNA and protein levels), but also modulate the metabolism of these cells. Specifically, cancer immunotherapy often leads to activation of different immune cells such as dendritic cells, macrophages and T cells, which is driven by energy metabolism of these cells. Recently, there has been a great excitement about interventions that can directly modulate the energy metabolism of these immune cells and thus affect their function and in turn lead to a robust cancer immune response. Here we review few strategies that have been tested in clinic and pre-clinical research for generating effective metabolism-associated cancer therapies and immunotherapies.
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Zhou Y, Guo Y, Tam KY. Targeting glucose metabolism to develop anticancer treatments and therapeutic patents. Expert Opin Ther Pat 2022; 32:441-453. [PMID: 35001793 DOI: 10.1080/13543776.2022.2027912] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION One of the most distinctive hallmarks of cancer cells is increased glucose consumption for aerobic glycolysis which is named the Warburg effect. In recent decades, extensive research has been carried out to exploit this famous phenomenon, trying to detect promising targetable vulnerabilities in altered metabolism to fight cancer. Targeting aberrant glucose metabolism can perturb cancer malignant proliferation and even induce programmed cell death. AREAS COVERED This review covered the recent patents which focused on targeting key glycolytic enzymes including hexokinase, pyruvate dehydrogenase kinases and lactate dehydrogenase for cancer treatment. EXPERT OPINION Compared with the conventional cancer treatment, specifically targeting the well-known Achilles heel Warburg effect has attracted considerable attention. Although there is still no single glycolytic agent for clinical cancer treatment, the combination of glycolytic inhibitor with conventional anticancer drug or the combined use of multiple glycolytic inhibitors are being investigated extensively in recent years, which could emerge as attractive anticancer strategies.
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Affiliation(s)
- Yan Zhou
- Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau SAR, PR China
| | - Yizhen Guo
- Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau SAR, PR China
| | - Kin Yip Tam
- Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau SAR, PR China
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19
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Bazanov DR, Maximova NA, Seliverstov MY, Zefirov NA, Sosonyuk SE, Lozinskaya NA. Synthesis of Covalent Conjugates of Dichloroacetic Acid with Polyfunctional Compounds. RUSSIAN JOURNAL OF ORGANIC CHEMISTRY 2021. [DOI: 10.1134/s107042802111004x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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20
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Chen CL, Lin CY, Kung HJ. Targeting Mitochondrial OXPHOS and Their Regulatory Signals in Prostate Cancers. Int J Mol Sci 2021; 22:13435. [PMID: 34948229 PMCID: PMC8708687 DOI: 10.3390/ijms222413435] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 12/13/2021] [Accepted: 12/13/2021] [Indexed: 12/26/2022] Open
Abstract
Increasing evidence suggests that tumor development requires not only oncogene/tumor suppressor mutations to drive the growth, survival, and metastasis but also metabolic adaptations to meet the increasing energy demand for rapid cellular expansion and to cope with the often nutritional and oxygen-deprived microenvironment. One well-recognized strategy is to shift the metabolic flow from oxidative phosphorylation (OXPHOS) or respiration in mitochondria to glycolysis or fermentation in cytosol, known as Warburg effects. However, not all cancer cells follow this paradigm. In the development of prostate cancer, OXPHOS actually increases as compared to normal prostate tissue. This is because normal prostate epithelial cells divert citrate in mitochondria for the TCA cycle to the cytosol for secretion into seminal fluid. The sustained level of OXPHOS in primary tumors persists in progression to an advanced stage. As such, targeting OXPHOS and mitochondrial activities in general present therapeutic opportunities. In this review, we summarize the recent findings of the key regulators of the OXPHOS pathway in prostate cancer, ranging from transcriptional regulation, metabolic regulation to genetic regulation. Moreover, we provided a comprehensive update of the current status of OXPHOS inhibitors for prostate cancer therapy. A challenge of developing OXPHOS inhibitors is to selectively target cancer mitochondria and spare normal counterparts, which is also discussed.
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Affiliation(s)
- Chia-Lin Chen
- Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan; (C.-L.C.); (C.-Y.L.)
| | - Ching-Yu Lin
- Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan; (C.-L.C.); (C.-Y.L.)
| | - Hsing-Jien Kung
- Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan; (C.-L.C.); (C.-Y.L.)
- Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 110, Taiwan
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli County 350, Taiwan
- Comprehensive Cancer Center, Department of Biochemistry and Molecular Medicine, University of California at Davis, Sacramento, CA 95817, USA
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21
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Qian XP, Zhang XH, Sun LN, Xing WF, Wang Y, Sun SY, Ma MY, Cheng ZP, Wu ZD, Xing C, Chen BN, Wang YQ. Corosolic acid and its structural analogs: A systematic review of their biological activities and underlying mechanism of action. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2021; 91:153696. [PMID: 34456116 DOI: 10.1016/j.phymed.2021.153696] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 07/29/2021] [Accepted: 07/31/2021] [Indexed: 06/13/2023]
Abstract
BACKGROUND The corosolic acid (CA), also known as plant insulin, is a pentacyclic triterpenoid extracted from plants such as Lagerstroemia speciosa. It has been shown to have anti-diabetic, anti-inflammatory and anti-tumor effects. Its structural analogs ursolic acid (UA), oleanolic acid (OA), maslinic acid (MA), asiatic acid (AA) and betulinic acid (BA) display similar individual pharmacological activities to those of CA. However, there is no systematic review documenting pharmacological activities of CA and its structural analogues. This study aims to fill this gap in literature. PURPOSE This systematic review aims to summarize the medical applications of CA and its analogues. METHODS A systematic review summarizes and compares the extraction techniques, pharmacokinetic parameters, and pharmacological effects of CA and its structural analogs. Hypoglycemic effect is one of the key inclusion criteria for searching Web of Science, PubMed, Embase and Cochrane databases up to October 2020 without language restrictions. 'corosolic acid', 'ursolic acid', 'oleanolic acid', 'maslinic acid', 'asiatic acid', 'betulinic acid', 'extraction', 'pharmacokinetic', 'pharmacological' were used to extract relevant literature. The PRISMA guidelines were followed. RESULTS At the end of the searching process, 140 articles were selected for the systematic review. Information of CA and five of its structural analogs including UA, OA, MA, AA and BA were included in this review. CA and its structural analogs are pentacyclic triterpenes extracted from plants and they have low solubilities in water due to their rigid scaffold and hydrophobic properties. The introduction of water-soluble groups such as sugar or amino groups could increase the solubility of CA and its structural analogs. Their biological activities and underlying mechanism of action are reviewed and compared. CONCLUSION CA and its structural analogs UA, OA, MA, AA and BA are demonstrated to show activities in lowering blood sugar, anti-inflammation and anti-tumor. Their oral absorption and bioavailability can be improved through structural modification and formulation design. CA and its structural analogs are promising natural product-based lead compounds for further development and mechanistic studies.
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Affiliation(s)
- Xu-Ping Qian
- Research Division of Clinical Pharmacology, the First Affiliated Hospital of Nanjing Medical University & Jiangsu Province Hospital, Nanjing, China; Xuzhou Medical University, Xuzhou, China
| | - Xue-Hui Zhang
- Department of Pharmacy, Jiangsu Shengze Hospital, Nanjing Medical University, Suzhou, China
| | - Lu-Ning Sun
- Research Division of Clinical Pharmacology, the First Affiliated Hospital of Nanjing Medical University & Jiangsu Province Hospital, Nanjing, China
| | - Wei-Fan Xing
- Nanjing Chenxiang Pharmaceutical Research Co. Ltd
| | - Yu Wang
- Research Division of Clinical Pharmacology, the First Affiliated Hospital of Nanjing Medical University & Jiangsu Province Hospital, Nanjing, China
| | - Shi-Yu Sun
- Research Division of Clinical Pharmacology, the First Affiliated Hospital of Nanjing Medical University & Jiangsu Province Hospital, Nanjing, China
| | - Meng-Yuan Ma
- Research Division of Clinical Pharmacology, the First Affiliated Hospital of Nanjing Medical University & Jiangsu Province Hospital, Nanjing, China; Xuzhou Medical University, Xuzhou, China
| | - Zi-Ping Cheng
- Research Division of Clinical Pharmacology, the First Affiliated Hospital of Nanjing Medical University & Jiangsu Province Hospital, Nanjing, China
| | - Zu-Dong Wu
- Nanjing Chenxiang Pharmaceutical Research Co. Ltd
| | - Chen Xing
- Nanjing Chenxiang Pharmaceutical Research Co. Ltd
| | - Bei-Ning Chen
- Department of Chemistry, University of Sheffield, Brookhill, Sheffield S3 7HF, United Kingdom.
| | - Yong-Qing Wang
- Research Division of Clinical Pharmacology, the First Affiliated Hospital of Nanjing Medical University & Jiangsu Province Hospital, Nanjing, China; Department of Pharmacy, Jiangsu Shengze Hospital, Nanjing Medical University, Suzhou, China.
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22
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Suppression of Pyruvate Dehydrogenase Kinase by Dichloroacetate in Cancer and Skeletal Muscle Cells Is Isoform Specific and Partially Independent of HIF-1α. Int J Mol Sci 2021; 22:ijms22168610. [PMID: 34445316 PMCID: PMC8395311 DOI: 10.3390/ijms22168610] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 07/28/2021] [Accepted: 08/03/2021] [Indexed: 02/01/2023] Open
Abstract
Inhibition of pyruvate dehydrogenase kinase (PDK) emerged as a potential strategy for treatment of cancer and metabolic disorders. Dichloroacetate (DCA), a prototypical PDK inhibitor, reduces the abundance of some PDK isoenzymes. However, the underlying mechanisms are not fully characterized and may differ across cell types. We determined that DCA reduced the abundance of PDK1 in breast (MDA-MB-231) and prostate (PC-3) cancer cells, while it suppressed both PDK1 and PDK2 in skeletal muscle cells (L6 myotubes). The DCA-induced PDK1 suppression was partially dependent on hypoxia-inducible factor-1α (HIF-1α), a transcriptional regulator of PDK1, in cancer cells but not in L6 myotubes. However, the DCA-induced alterations in the mRNA and the protein levels of PDK1 and/or PDK2 did not always occur in parallel, implicating a role for post-transcriptional mechanisms. DCA did not inhibit the mTOR signaling, while inhibitors of the proteasome or gene silencing of mitochondrial proteases CLPP and AFG3L2 did not prevent the DCA-induced reduction of the PDK1 protein levels. Collectively, our results suggest that DCA reduces the abundance of PDK in an isoform-dependent manner via transcriptional and post-transcriptional mechanisms. Differential response of PDK isoenzymes to DCA might be important for its pharmacological effects in different types of cells.
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23
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Zanotelli MR, Zhang J, Reinhart-King CA. Mechanoresponsive metabolism in cancer cell migration and metastasis. Cell Metab 2021; 33:1307-1321. [PMID: 33915111 PMCID: PMC9015673 DOI: 10.1016/j.cmet.2021.04.002] [Citation(s) in RCA: 199] [Impact Index Per Article: 49.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 03/16/2021] [Accepted: 04/05/2021] [Indexed: 12/12/2022]
Abstract
Altered tissue mechanics and metabolism are defining characteristics of cancer that impact not only proliferation but also migration. While migrating through a mechanically and spatially heterogeneous microenvironment, changes in metabolism allow cells to dynamically tune energy generation and bioenergetics in response to fluctuating energy needs. Physical cues from the extracellular matrix influence mechanosignaling pathways, cell mechanics, and cytoskeletal architecture to alter presentation and function of metabolic enzymes. In cancer, altered mechanosensing and metabolic reprogramming supports metabolic plasticity and high energy production while cells migrate and metastasize. Here, we discuss the role of mechanoresponsive metabolism in regulating cell migration and supporting metastasis as well as the potential of therapeutically targeting cancer metabolism to block motility and potentially metastasis.
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Affiliation(s)
- Matthew R Zanotelli
- Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA
| | - Jian Zhang
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA
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24
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Evers B, Gerding A, Boer T, Heiner-Fokkema MR, Jalving M, Wahl SA, Reijngoud DJ, Bakker BM. Simultaneous Quantification of the Concentration and Carbon Isotopologue Distribution of Polar Metabolites in a Single Analysis by Gas Chromatography and Mass Spectrometry. Anal Chem 2021; 93:8248-8256. [PMID: 34060804 PMCID: PMC8253487 DOI: 10.1021/acs.analchem.1c01040] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
13C-isotope tracing is a frequently employed approach to study metabolic pathway activity. When combined with the subsequent quantification of absolute metabolite concentrations, this enables detailed characterization of the metabolome in biological specimens and facilitates computational time-resolved flux quantification. Classically, a 13C-isotopically labeled sample is required to quantify 13C-isotope enrichments and a second unlabeled sample for the quantification of metabolite concentrations. The rationale for a second unlabeled sample is that the current methods for metabolite quantification rely mostly on isotope dilution mass spectrometry (IDMS) and thus isotopically labeled internal standards are added to the unlabeled sample. This excludes the absolute quantification of metabolite concentrations in 13C-isotopically labeled samples. To address this issue, we have developed and validated a new strategy using an unlabeled internal standard to simultaneously quantify metabolite concentrations and 13C-isotope enrichments in a single 13C-labeled sample based on gas chromatography-mass spectrometry (GC/MS). The method was optimized for amino acids and citric acid cycle intermediates and was shown to have high analytical precision and accuracy. Metabolite concentrations could be quantified in small tissue samples (≥20 mg). Also, we applied the method on 13C-isotopically labeled mammalian cells treated with and without a metabolic inhibitor. We proved that we can quantify absolute metabolite concentrations and 13C-isotope enrichments in a single 13C-isotopically labeled sample.
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Affiliation(s)
- Bernard Evers
- Laboratory of Pediatrics, Section Systems Medicine of Metabolism and Signalling, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands
| | - Albert Gerding
- Laboratory of Pediatrics, Section Systems Medicine of Metabolism and Signalling, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.,Laboratory of Metabolic Diseases, Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands
| | - Theo Boer
- Laboratory of Metabolic Diseases, Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands
| | - M Rebecca Heiner-Fokkema
- Laboratory of Metabolic Diseases, Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands
| | - Mathilde Jalving
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
| | - S Aljoscha Wahl
- Department of Biotechnology, Applied Science Faculty, Delft University of Technology, van der Maasweg 9, 2629 HZ Delft, The Netherlands
| | - Dirk-Jan Reijngoud
- Laboratory of Pediatrics, Section Systems Medicine of Metabolism and Signalling, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands
| | - Barbara M Bakker
- Laboratory of Pediatrics, Section Systems Medicine of Metabolism and Signalling, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands
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25
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Anwar S, Shamsi A, Mohammad T, Islam A, Hassan MI. Targeting pyruvate dehydrogenase kinase signaling in the development of effective cancer therapy. Biochim Biophys Acta Rev Cancer 2021; 1876:188568. [PMID: 34023419 DOI: 10.1016/j.bbcan.2021.188568] [Citation(s) in RCA: 86] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 05/06/2021] [Accepted: 05/11/2021] [Indexed: 02/06/2023]
Abstract
Pyruvate is irreversibly decarboxylated to acetyl coenzyme A by mitochondrial pyruvate dehydrogenase complex (PDC). Decarboxylation of pyruvate is considered a crucial step in cell metabolism and energetics. The cancer cells prefer aerobic glycolysis rather than mitochondrial oxidation of pyruvate. This attribute of cancer cells allows them to sustain under indefinite proliferation and growth. Pyruvate dehydrogenase kinases (PDKs) play critical roles in many diseases because they regulate PDC activity. Recent findings suggest an altered metabolism of cancer cells is associated with impaired mitochondrial function due to PDC inhibition. PDKs inhibit the PDC activity via phosphorylation of the E1a subunit and subsequently cause a glycolytic shift. Thus, inhibition of PDK is an attractive strategy in anticancer therapy. This review highlights that PDC/PDK axis could be implicated in cancer's therapeutic management by developing potential small-molecule PDK inhibitors. In recent years, a dramatic increase in the targeting of the PDC/PDK axis for cancer treatment gained an attention from the scientific community. We further discuss breakthrough findings in the PDC-PDK axis. In addition, structural features, functional significance, mechanism of activation, involvement in various human pathologies, and expression of different forms of PDKs (PDK1-4) in different types of cancers are discussed in detail. We further emphasized the gene expression profiling of PDKs in cancer patients to prognosis and therapeutic manifestations. Additionally, inhibition of the PDK/PDC axis by small molecule inhibitors and natural compounds at different clinical evaluation stages has also been discussed comprehensively.
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Affiliation(s)
- Saleha Anwar
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
| | - Anas Shamsi
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
| | - Taj Mohammad
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
| | - Asimul Islam
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
| | - Md Imtaiyaz Hassan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India.
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Sharma P, Singh S. Combinatorial Effect of DCA and Let-7a on Triple-Negative MDA-MB-231 Cells: A Metabolic Approach of Treatment. Integr Cancer Ther 2021; 19:1534735420911437. [PMID: 32248711 PMCID: PMC7136934 DOI: 10.1177/1534735420911437] [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] [Indexed: 12/17/2022] Open
Abstract
Dichloroacetate (DCA) is a metabolic modulator that inhibits pyruvate dehydrogenase activity and promotes the influx of pyruvate into the tricarboxylic acid cycle for complete oxidation of glucose. DCA stimulates oxidative phosphorylation (OXPHOS) more than glycolysis by altering the morphology of the mitochondria and supports mitochondrial apoptosis. As a consequence, DCA induces apoptosis in cancer cells and inhibits the proliferation of cancer cells. Recently, the role of miRNAs has been reported in regulating gene expression at the transcriptional level and also in reprogramming energy metabolism. In this article, we indicate that DCA treatment leads to the upregulation of let-7a expression, but DCA-induced cancer cell death is independent of let-7a. We observed that the combined effect of DCA and let-7a induces apoptosis, reduces reactive oxygen species generation and autophagy, and stimulates mitochondrial biogenesis. This was later accompanied by stimulation of OXPHOS in combined treatment and was thus involved in metabolic reprogramming of MDA-MB-231 cells.
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Affiliation(s)
| | - Sandeep Singh
- Central University of Punjab, Bathinda, Punjab, India
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27
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Fu Y, Ricciardiello F, Yang G, Qiu J, Huang H, Xiao J, Cao Z, Zhao F, Liu Y, Luo W, Chen G, You L, Chiaradonna F, Zheng L, Zhang T. The Role of Mitochondria in the Chemoresistance of Pancreatic Cancer Cells. Cells 2021; 10:497. [PMID: 33669111 PMCID: PMC7996512 DOI: 10.3390/cells10030497] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 01/16/2021] [Accepted: 02/14/2021] [Indexed: 02/06/2023] Open
Abstract
The first-line chemotherapies for patients with unresectable pancreatic cancer (PC) are 5-fluorouracil (5-FU) and gemcitabine therapy. However, due to chemoresistance the prognosis of patients with PC has not been significantly improved. Mitochondria are essential organelles in eukaryotes that evolved from aerobic bacteria. In recent years, many studies have shown that mitochondria play important roles in tumorigenesis and may act as chemotherapeutic targets in PC. In addition, according to recent studies, mitochondria may play important roles in the chemoresistance of PC by affecting apoptosis, metabolism, mtDNA metabolism, and mitochondrial dynamics. Interfering with some of these factors in mitochondria may improve the sensitivity of PC cells to chemotherapeutic agents, such as gemcitabine, making mitochondria promising targets for overcoming chemoresistance in PC.
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Affiliation(s)
- Yibo Fu
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (Y.F.); (G.Y.); (J.Q.); (H.H.); (J.X.); (Z.C.); (F.Z.); (Y.L.); (W.L.); (G.C.); (L.Y.)
| | - Francesca Ricciardiello
- Department of Biotechnology and Bioscience, University of Milano Bicocca, 20126 Milano, Italy;
| | - Gang Yang
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (Y.F.); (G.Y.); (J.Q.); (H.H.); (J.X.); (Z.C.); (F.Z.); (Y.L.); (W.L.); (G.C.); (L.Y.)
| | - Jiangdong Qiu
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (Y.F.); (G.Y.); (J.Q.); (H.H.); (J.X.); (Z.C.); (F.Z.); (Y.L.); (W.L.); (G.C.); (L.Y.)
| | - Hua Huang
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (Y.F.); (G.Y.); (J.Q.); (H.H.); (J.X.); (Z.C.); (F.Z.); (Y.L.); (W.L.); (G.C.); (L.Y.)
| | - Jianchun Xiao
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (Y.F.); (G.Y.); (J.Q.); (H.H.); (J.X.); (Z.C.); (F.Z.); (Y.L.); (W.L.); (G.C.); (L.Y.)
| | - Zhe Cao
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (Y.F.); (G.Y.); (J.Q.); (H.H.); (J.X.); (Z.C.); (F.Z.); (Y.L.); (W.L.); (G.C.); (L.Y.)
| | - Fangyu Zhao
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (Y.F.); (G.Y.); (J.Q.); (H.H.); (J.X.); (Z.C.); (F.Z.); (Y.L.); (W.L.); (G.C.); (L.Y.)
| | - Yueze Liu
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (Y.F.); (G.Y.); (J.Q.); (H.H.); (J.X.); (Z.C.); (F.Z.); (Y.L.); (W.L.); (G.C.); (L.Y.)
| | - Wenhao Luo
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (Y.F.); (G.Y.); (J.Q.); (H.H.); (J.X.); (Z.C.); (F.Z.); (Y.L.); (W.L.); (G.C.); (L.Y.)
| | - Guangyu Chen
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (Y.F.); (G.Y.); (J.Q.); (H.H.); (J.X.); (Z.C.); (F.Z.); (Y.L.); (W.L.); (G.C.); (L.Y.)
| | - Lei You
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (Y.F.); (G.Y.); (J.Q.); (H.H.); (J.X.); (Z.C.); (F.Z.); (Y.L.); (W.L.); (G.C.); (L.Y.)
| | - Ferdinando Chiaradonna
- Department of Biotechnology and Bioscience, University of Milano Bicocca, 20126 Milano, Italy;
| | - Lianfang Zheng
- Department of Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China;
| | - Taiping Zhang
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (Y.F.); (G.Y.); (J.Q.); (H.H.); (J.X.); (Z.C.); (F.Z.); (Y.L.); (W.L.); (G.C.); (L.Y.)
- Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
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Duraj T, García-Romero N, Carrión-Navarro J, Madurga R, Ortiz de Mendivil A, Prat-Acin R, Garcia-Cañamaque L, Ayuso-Sacido A. Beyond the Warburg Effect: Oxidative and Glycolytic Phenotypes Coexist within the Metabolic Heterogeneity of Glioblastoma. Cells 2021; 10:202. [PMID: 33498369 PMCID: PMC7922554 DOI: 10.3390/cells10020202] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 01/16/2021] [Accepted: 01/18/2021] [Indexed: 12/12/2022] Open
Abstract
Glioblastoma (GBM) is the most aggressive primary brain tumor, with a median survival at diagnosis of 16-20 months. Metabolism represents a new attractive therapeutic target; however, due to high intratumoral heterogeneity, the application of metabolic drugs in GBM is challenging. We characterized the basal bioenergetic metabolism and antiproliferative potential of metformin (MF), dichloroacetate (DCA), sodium oxamate (SOD) and diazo-5-oxo-L-norleucine (DON) in three distinct glioma stem cells (GSCs) (GBM18, GBM27, GBM38), as well as U87MG. GBM27, a highly oxidative cell line, was the most resistant to all treatments, except DON. GBM18 and GBM38, Warburg-like GSCs, were sensitive to MF and DCA, respectively. Resistance to DON was not correlated with basal metabolic phenotypes. In combinatory experiments, radiomimetic bleomycin exhibited therapeutically relevant synergistic effects with MF, DCA and DON in GBM27 and DON in all other cell lines. MF and DCA shifted the metabolism of treated cells towards glycolysis or oxidation, respectively. DON consistently decreased total ATP production. Our study highlights the need for a better characterization of GBM from a metabolic perspective. Metabolic therapy should focus on both glycolytic and oxidative subpopulations of GSCs.
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Affiliation(s)
- Tomás Duraj
- Faculty of Medicine, Institute for Applied Molecular Medicine (IMMA), CEU San Pablo University, 28668 Madrid, Spain;
| | - Noemí García-Romero
- Faculty of Experimental Sciences, Universidad Francisco de Vitoria, 28223 Madrid, Spain; (N.G.-R.); (J.C.-N.); (R.M.)
- Brain Tumor Laboratory, Fundación Vithas, Grupo Hospitales Vithas, 28043 Madrid, Spain
| | - Josefa Carrión-Navarro
- Faculty of Experimental Sciences, Universidad Francisco de Vitoria, 28223 Madrid, Spain; (N.G.-R.); (J.C.-N.); (R.M.)
- Brain Tumor Laboratory, Fundación Vithas, Grupo Hospitales Vithas, 28043 Madrid, Spain
| | - Rodrigo Madurga
- Faculty of Experimental Sciences, Universidad Francisco de Vitoria, 28223 Madrid, Spain; (N.G.-R.); (J.C.-N.); (R.M.)
- Brain Tumor Laboratory, Fundación Vithas, Grupo Hospitales Vithas, 28043 Madrid, Spain
| | | | - Ricardo Prat-Acin
- Neurosurgery Department, Hospital Universitario La Fe, 46026 Valencia, Spain;
| | | | - Angel Ayuso-Sacido
- Faculty of Experimental Sciences, Universidad Francisco de Vitoria, 28223 Madrid, Spain; (N.G.-R.); (J.C.-N.); (R.M.)
- Brain Tumor Laboratory, Fundación Vithas, Grupo Hospitales Vithas, 28043 Madrid, Spain
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29
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Liu Y, Xu R, Gu H, Zhang E, Qu J, Cao W, Huang X, Yan H, He J, Cai Z. Metabolic reprogramming in macrophage responses. Biomark Res 2021; 9:1. [PMID: 33407885 PMCID: PMC7786975 DOI: 10.1186/s40364-020-00251-y] [Citation(s) in RCA: 322] [Impact Index Per Article: 80.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Accepted: 11/20/2020] [Indexed: 12/16/2022] Open
Abstract
Macrophages are critical mediators of tissue homeostasis, with the function of tissue development and repair, but also in defense against pathogens. Tumor-associated macrophages (TAMs) are considered as the main component in the tumor microenvironment and play an important role in tumor initiation, growth, invasion, and metastasis. Recently, metabolic studies have revealeded specific metabolic pathways in macrophages are tightly associated with their phenotype and function. Generally, pro-inflammatory macrophages (M1) rely mainly on glycolysis and exhibit impairment of the tricarboxylic acid (TCA) cycle and mitochondrial oxidative phosphorylation (OXPHOS), whereas anti-inflammatory macrophages (M2) are more dependent on mitochondrial OXPHOS. However, accumulating evidence suggests that macrophage metabolism is not as simple as previously thought. This review discusses recent advances in immunometabolism and describes how metabolism determines macrophage phenotype and function. In addition, we describe the metabolic characteristics of TAMs as well as their therapeutic implications. Finally, we discuss recent obstacles facing this area as well as promising directions for future study.
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Affiliation(s)
- Yang Liu
- Bone Marrow Transplantation Center, The First Afliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China.,Zhejiang Laboratory for Systems & Precison Medicine, Zhejiang University Medical Center, Hangzhou, Zhejiang, China
| | - Ruyi Xu
- Bone Marrow Transplantation Center, The First Afliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China.,Zhejiang Laboratory for Systems & Precison Medicine, Zhejiang University Medical Center, Hangzhou, Zhejiang, China
| | - Huiyao Gu
- Bone Marrow Transplantation Center, The First Afliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China.,Zhejiang Laboratory for Systems & Precison Medicine, Zhejiang University Medical Center, Hangzhou, Zhejiang, China
| | - Enfan Zhang
- Bone Marrow Transplantation Center, The First Afliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China.,Zhejiang Laboratory for Systems & Precison Medicine, Zhejiang University Medical Center, Hangzhou, Zhejiang, China
| | - Jianwei Qu
- Bone Marrow Transplantation Center, The First Afliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China.,Zhejiang Laboratory for Systems & Precison Medicine, Zhejiang University Medical Center, Hangzhou, Zhejiang, China
| | - Wen Cao
- Bone Marrow Transplantation Center, The First Afliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China.,Zhejiang Laboratory for Systems & Precison Medicine, Zhejiang University Medical Center, Hangzhou, Zhejiang, China
| | - Xi Huang
- Bone Marrow Transplantation Center, The First Afliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China.,Zhejiang Laboratory for Systems & Precison Medicine, Zhejiang University Medical Center, Hangzhou, Zhejiang, China
| | - Haimeng Yan
- Bone Marrow Transplantation Center, The First Afliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China.,Zhejiang Laboratory for Systems & Precison Medicine, Zhejiang University Medical Center, Hangzhou, Zhejiang, China
| | - Jingsong He
- Bone Marrow Transplantation Center, The First Afliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China.,Zhejiang Laboratory for Systems & Precison Medicine, Zhejiang University Medical Center, Hangzhou, Zhejiang, China
| | - Zhen Cai
- Bone Marrow Transplantation Center, The First Afliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. .,Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China. .,Zhejiang Laboratory for Systems & Precison Medicine, Zhejiang University Medical Center, Hangzhou, Zhejiang, China.
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30
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Targeting Cancer Metabolism and Current Anti-Cancer Drugs. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1286:15-48. [PMID: 33725343 DOI: 10.1007/978-3-030-55035-6_2] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Several studies have exploited the metabolic hallmarks that distinguish between normal and cancer cells, aiming at identifying specific targets of anti-cancer drugs. It has become apparent that metabolic flexibility allows cancer cells to survive during high anabolic demand or the depletion of nutrients and oxygen. Cancers can reprogram their metabolism to the microenvironments by increasing aerobic glycolysis to maximize ATP production, increasing glutaminolysis and anabolic pathways to support bioenergetic and biosynthetic demand during rapid proliferation. The increased key regulatory enzymes that support the relevant pathways allow us to design small molecules which can specifically block activities of these enzymes, preventing growth and metastasis of tumors. In this review, we discuss metabolic adaptation in cancers and highlight the crucial metabolic enzymes involved, specifically those involved in aerobic glycolysis, glutaminolysis, de novo fatty acid synthesis, and bioenergetic pathways. Furthermore, we also review the success and the pitfalls of the current anti-cancer drugs which have been applied in pre-clinical and clinical studies.
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31
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The Suitability of Glioblastoma Cell Lines as Models for Primary Glioblastoma Cell Metabolism. Cancers (Basel) 2020; 12:cancers12123722. [PMID: 33322454 PMCID: PMC7764800 DOI: 10.3390/cancers12123722] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 11/30/2020] [Accepted: 12/07/2020] [Indexed: 12/21/2022] Open
Abstract
Simple Summary Glioblastoma (GBM) is a deadly brain tumour with no effective treatments. Recently, new treatments which target the cancer’s unique metabolic properties are beginning to emerge. However, this preclinical research is commonly undertaken in human cell lines which poorly recapitulate the properties of the cancer in situ. This study has examined the metabolic properties of five commonly used GBM cell lines in comparison to healthy brain and GBM tissue. While no cell line faithfully recapitulates GBM, certain lines are useful for aspects of metabolic analysis in GBM cells. We identified three cell lines which accurately reflect the mitochondrial metabolism of GBM tumours, and one cell line suited for studies into glycolysis. In addition to providing detailed metabolic profiles of these commonly used cell lines, this research can guide preclinical experiments to assess the efficacy of desperately needed, novel therapeutics for GBM. Abstract In contrast to most non-malignant tissue, cells comprising the brain tumour glioblastoma (GBM) preferentially utilise glycolysis for metabolism via “the Warburg effect”. Research into therapeutics targeting the disease’s highly glycolytic state offer a promising avenue to improve patient survival. These studies often employ GBM cell lines for in vitro studies which translate poorly to the in vivo patient context. The metabolic traits of five of the most used GBM cell lines were assessed and compared to primary GBM and matched, healthy brain tissue. In patient-derived GBM cell lines, the basal mitochondrial rate (p = 0.043) and ATP-linked respiration (p < 0.001) were lower than primary adjacent normal cells from the same patient, while reserve capacity (p = 0.037) and Krebs cycle capacity (p = 0.002) were higher. Three cell lines, U251MG, U373MG and D54, replicate the mitochondrial metabolism of primary GBM cells. Surprisingly, glycolytic capacity is not different between healthy and GBM tissue. The T98G cell line recapitulated glycolysis-related metabolic parameters of the primary GBM cells and is recommended for research relating to glycolysis. These findings can guide preclinical research into the development of novel therapeutics targeting metabolic pathways in GBM.
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Harguindey S, Alfarouk K, Polo Orozco J, Fais S, Devesa J. Towards an Integral Therapeutic Protocol for Breast Cancer Based upon the New H +-Centered Anticancer Paradigm of the Late Post-Warburg Era. Int J Mol Sci 2020; 21:E7475. [PMID: 33050492 PMCID: PMC7589677 DOI: 10.3390/ijms21207475] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 10/05/2020] [Accepted: 10/06/2020] [Indexed: 12/13/2022] Open
Abstract
A brand new approach to the understanding of breast cancer (BC) is urgently needed. In this contribution, the etiology, pathogenesis, and treatment of this disease is approached from the new pH-centric anticancer paradigm. Only this unitarian perspective, based upon the hydrogen ion (H+) dynamics of cancer, allows for the understanding and integration of the many dualisms, confusions, and paradoxes of the disease. The new H+-related, wide-ranging model can embrace, from a unique perspective, the many aspects of the disease and, at the same time, therapeutically interfere with most, if not all, of the hallmarks of cancer known to date. The pH-related armamentarium available for the treatment of BC reviewed here may be beneficial for all types and stages of the disease. In this vein, we have attempted a megasynthesis of traditional and new knowledge in the different areas of breast cancer research and treatment based upon the wide-ranging approach afforded by the hydrogen ion dynamics of cancer. The concerted utilization of the pH-related drugs that are available nowadays for the treatment of breast cancer is advanced.
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Affiliation(s)
- Salvador Harguindey
- Department of Oncology, Institute of Clinical Biology and Metabolism, 01004 Vitoria, Spain;
| | - Khalid Alfarouk
- Department of Pharmacology, Al-Ghad International Colleges for Applied Medical Sciences, Al-Madinah Al-Munawarah 42316, Saudi Arabia and Alfarouk Biomedical Research LLC, Tampa, FL 33617, USA;
| | - Julián Polo Orozco
- Department of Oncology, Institute of Clinical Biology and Metabolism, 01004 Vitoria, Spain;
| | - Stefano Fais
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità (National Institute of Health), 00161 Rome, Italy;
| | - Jesús Devesa
- Scientific Direction, Foltra Medical Centre, 15886 Teo, Spain;
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Varghese E, Samuel SM, Líšková A, Samec M, Kubatka P, Büsselberg D. Targeting Glucose Metabolism to Overcome Resistance to Anticancer Chemotherapy in Breast Cancer. Cancers (Basel) 2020; 12:E2252. [PMID: 32806533 PMCID: PMC7464784 DOI: 10.3390/cancers12082252] [Citation(s) in RCA: 137] [Impact Index Per Article: 27.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Revised: 08/05/2020] [Accepted: 08/06/2020] [Indexed: 01/10/2023] Open
Abstract
Breast cancer (BC) is the most prevalent cancer in women. BC is heterogeneous, with distinct phenotypical and morphological characteristics. These are based on their gene expression profiles, which divide BC into different subtypes, among which the triple-negative breast cancer (TNBC) subtype is the most aggressive one. The growing interest in tumor metabolism emphasizes the role of altered glucose metabolism in driving cancer progression, response to cancer treatment, and its distinct role in therapy resistance. Alterations in glucose metabolism are characterized by increased uptake of glucose, hyperactivated glycolysis, decreased oxidative phosphorylation (OXPHOS) component, and the accumulation of lactate. These deviations are attributed to the upregulation of key glycolytic enzymes and transporters of the glucose metabolic pathway. Key glycolytic enzymes such as hexokinase, lactate dehydrogenase, and enolase are upregulated, thereby conferring resistance towards drugs such as cisplatin, paclitaxel, tamoxifen, and doxorubicin. Besides, drug efflux and detoxification are two energy-dependent mechanisms contributing to resistance. The emergence of resistance to chemotherapy can occur at an early or later stage of the treatment, thus limiting the success and outcome of the therapy. Therefore, understanding the aberrant glucose metabolism in tumors and its link in conferring therapy resistance is essential. Using combinatory treatment with metabolic inhibitors, for example, 2-deoxy-D-glucose (2-DG) and metformin, showed promising results in countering therapy resistance. Newer drug designs such as drugs conjugated to sugars or peptides that utilize the enhanced expression of tumor cell glucose transporters offer selective and efficient drug delivery to cancer cells with less toxicity to healthy cells. Last but not least, naturally occurring compounds of plants defined as phytochemicals manifest a promising approach for the eradication of cancer cells via suppression of essential enzymes or other compartments associated with glycolysis. Their benefits for human health open new opportunities in therapeutic intervention, either alone or in combination with chemotherapeutic drugs. Importantly, phytochemicals as efficacious instruments of anticancer therapy can suppress events leading to chemoresistance of cancer cells. Here, we review the current knowledge of altered glucose metabolism in contributing to resistance to classical anticancer drugs in BC treatment and various ways to target the aberrant metabolism that will serve as a promising strategy for chemosensitizing tumors and overcoming resistance in BC.
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Affiliation(s)
- Elizabeth Varghese
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar; (E.V.); (S.M.S.)
| | - Samson Mathews Samuel
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar; (E.V.); (S.M.S.)
| | - Alena Líšková
- Department of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia; (A.L.); (M.S.)
| | - Marek Samec
- Department of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia; (A.L.); (M.S.)
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia;
| | - Dietrich Büsselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar; (E.V.); (S.M.S.)
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Wang J, Li J, Xiao Y, Fu B, Qin Z. TPP-based mitocans: a potent strategy for anticancer drug design. RSC Med Chem 2020; 11:858-875. [PMID: 33479681 PMCID: PMC7489259 DOI: 10.1039/c9md00572b] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Accepted: 05/11/2020] [Indexed: 12/24/2022] Open
Abstract
Cancer is one of the most important problems that endanger human health. The number of cancer patients is increasing rapidly worldwide. Compared with normal cells, cancer cells exhibit abnormal metabolism (abnormal glycolysis and oxidative phosphorylation, high levels of reactive oxygen species, anti-apoptosis, high mitochondrial membrane potential, and so on), and specific targeting of these metabolic abnormalities would be a promising drug design direction. These physiological characteristics are closely related to tumorigenesis and development, which are mainly regulated by mitochondria. Therefore, mitochondria have become important anticancer drug targets, attracting much attention in recent years. In this review, we systematically summarize various mitochondrial anticancer drugs developed, especially mitocans based on triphenylphosphonium (TPP), and discuss the advantages of TPP in endowing mitochondrial targeting function.
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Affiliation(s)
- Jiayao Wang
- College of science , China Agriculture University , Haidian District 100089 , China . ; Tel: +86 130 0199 1198
| | - Jiaqi Li
- College of science , China Agriculture University , Haidian District 100089 , China . ; Tel: +86 130 0199 1198
| | - Yumei Xiao
- College of science , China Agriculture University , Haidian District 100089 , China . ; Tel: +86 130 0199 1198
| | - Bin Fu
- College of science , China Agriculture University , Haidian District 100089 , China . ; Tel: +86 130 0199 1198
| | - Zhaohai Qin
- College of science , China Agriculture University , Haidian District 100089 , China . ; Tel: +86 130 0199 1198
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Reiter RJ, Sharma R, Ma Q, Rorsales-Corral S, de Almeida Chuffa LG. Melatonin inhibits Warburg-dependent cancer by redirecting glucose oxidation to the mitochondria: a mechanistic hypothesis. Cell Mol Life Sci 2020; 77:2527-2542. [PMID: 31970423 PMCID: PMC11104865 DOI: 10.1007/s00018-019-03438-1] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Revised: 12/16/2019] [Accepted: 12/23/2019] [Indexed: 12/16/2022]
Abstract
Melatonin has the ability to intervene in the initiation, progression and metastasis of some experimental cancers. A large variety of potential mechanisms have been advanced to describe the metabolic and molecular events associated with melatonin's interactions with cancer cells. There is one metabolic perturbation that is common to a large number of solid tumors and accounts for the ability of cancer cells to actively proliferate, avoid apoptosis, and readily metastasize, i.e., they use cytosolic aerobic glycolysis (the Warburg effect) to rapidly generate the necessary ATP required for the high metabolic demands of the cancer cells. There are several drugs, referred to as glycolytic agents, that cause cancer cells to abandon aerobic glycolysis and shift to the more conventional mitochondrial oxidative phosphorylation for ATP synthesis as in normal cells. In doing so, glycolytic agents also inhibit cancer growth. Herein, we hypothesize that melatonin also functions as an inhibitor of cytosolic glycolysis in cancer cells using mechanisms, i.e., downregulation of the enzyme (pyruvate dehydrogenase kinase) that interferes with the conversion of pyruvate to acetyl CoA in the mitochondria, as do other glycolytic drugs. In doing so, melatonin halts the proliferative activity of cancer cells, reduces their metastatic potential and causes them to more readily undergo apoptosis. This hypothesis is discussed in relation to the previously published reports. Whereas melatonin is synthesized in the mitochondria of normal cells, we hypothesize that this synthetic capability is not present in cancer cell mitochondria because of the depressed acetyl CoA; acetyl CoA is necessary for the rate limiting enzyme in melatonin synthesis, arylalkylamine-N-acetyltransferase. Finally, the ability of melatonin to switch glucose oxidation from the cytosol to the mitochondria also explains how tumors that become resistant to conventional chemotherapies are re-sensitized to the same treatment when melatonin is applied.
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Affiliation(s)
- Russel J Reiter
- Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX, USA.
| | - Ramaswamy Sharma
- Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX, USA
| | - Qiang Ma
- Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX, USA
| | - Sergio Rorsales-Corral
- Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Mexico
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Abstract
The Warburg effect is prevalent in human cancer. Accordingly, most cancer cells display highly elevated glycolysis without proportionally increasing pyruvate oxidation. The metastatic process imposes strong selective pressure on cancer cells, and metastasizing cancer cells experience heightened oxidative stress. By constraining mitochondrial oxidative metabolism, the Warburg effect helps cancer cells to minimize oxidative stress, thereby facilitating metastatic dissemination. The PGC1α transcriptional coactivator is a central coordinator of oxidative metabolism. While promoting oxidative metabolism and reversing the Warburg effect, PGC1α critically activates antioxidant genes and protects cells against oxidative damage. Therefore, depending on the context, PGC1α may promote or suppress tumor metastasis. Cancer cells generally retain metabolic flexibility and can resist antiglycolysis treatment by undergoing metabolic reprogramming. Synthetic lethal combination therapies are thus essential to attack the liabilities of the Warburg metabolism for therapeutic benefit.
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Affiliation(s)
- Jianrong Lu
- Department of Biochemistry and Molecular Biology, UF Health Cancer Center, College of Medicine, University of Florida, Gainesville, FL, 32610-3633, USA.
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Deng X, Wang Q, Cheng M, Chen Y, Yan X, Guo R, Sun L, Li Y, Liu Y. Pyruvate dehydrogenase kinase 1 interferes with glucose metabolism reprogramming and mitochondrial quality control to aggravate stress damage in cancer. J Cancer 2020; 11:962-973. [PMID: 31949499 PMCID: PMC6959030 DOI: 10.7150/jca.34330] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Accepted: 10/26/2019] [Indexed: 12/28/2022] Open
Abstract
Pyruvate dehydrogenase kinase 1 (PDK1) is a key factor in the connection between glycolysis and the tricarboxylic acid cycle. Restoring the mitochondrial OXPHOS function by inhibiting glycolysis through targeting PDK1 has become a hot spot for tumor therapy. However, the specific mechanism by which metabolic changes affect mitochondrial function remains unclear. Recent studies have found that mitochondrial quality control such as mitochondrial protein homeostasis plays an important role in maintaining mitochondrial function. Here, we focused on PDK1 and explored the specific mechanism by which metabolic changes affect mitochondrial OXPHOS function. We showed that glucose metabolism in HepG2 and HepG3B cells switched from anaerobic glycolysis to the mitochondrial tricarboxylic acid cycle under different concentrations of dichloroacetate (DCA) or short hairpin PDK1. After DCA treatment or knockdown of PDK1, the mitochondrial morphology was gradually condensed and exhibited shorter and more fragmented filaments. Additionally, expression of the mitochondrial autophagy proteins parkin and PTEN-induced kinase was down-regulated, and the biosynthetic protein peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α) and its regulated complex I, III, IV, and V protein were down-regulated. This indicated that PDK1 inhibition affected the level of mitochondrial quality control. Analysis of mitochondrial function revealed significantly increased mitochondrial reactive oxygen species and decreased membrane potential. Therefore, glucose metabolism reprogramming by PDK1 inhibition could induce mitochondrial quality control disorders to aggravate mitochondrial stress damage.
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Affiliation(s)
- Xinyue Deng
- Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China
| | - Quan Wang
- Department of Radiation Oncology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China
| | - Meiyu Cheng
- Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China
| | - Yingying Chen
- Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China
| | - Xiaoyu Yan
- Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China
| | - Rui Guo
- Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China
| | - Liankun Sun
- Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China
| | - Yang Li
- Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China
| | - Yanan Liu
- Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China
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38
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Lozinskaya NA, Maximova NA, Bazanov DR, Sosonyuk SE, Wobith B, Zefirov NA, Kharitonashvili EV, Zefirova ON, Kuznetsov SA, Proskurnina MV. Synthesis and biotesting of new carrier prodrugs of 2-methoxyestradiol. MENDELEEV COMMUNICATIONS 2020. [DOI: 10.1016/j.mencom.2020.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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39
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Tian DD, Bennett SK, Coupland LA, Forwood K, Lwin Y, Pooryousef N, Tea I, Truong TT, Neeman T, Crispin P, D’Rozario J, Blackburn AC. GSTZ1 genotypes correlate with dichloroacetate pharmacokinetics and chronic side effects in multiple myeloma patients in a pilot phase 2 clinical trial. Pharmacol Res Perspect 2019; 7:e00526. [PMID: 31624634 PMCID: PMC6783648 DOI: 10.1002/prp2.526] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Revised: 08/08/2019] [Accepted: 08/29/2019] [Indexed: 12/16/2022] Open
Abstract
Dichloroacetate (DCA) is an investigational drug targeting the glycolytic hallmark of cancer by inhibiting pyruvate dehydrogenase kinases (PDK). It is metabolized by GSTZ1, which has common polymorphisms altering enzyme or promoter activity. GSTZ1 is also irreversibly inactivated by DCA. In the first clinical trial of DCA in a hematological malignancy, DiCAM (DiChloroAcetate in Myeloma), we have examined the relationship between DCA concentrations, GSTZ1 genotype, side effects, and patient response. DiCAM recruited seven myeloma patients in partial remission. DCA was administered orally for 3 months with a loading dose. Pharmacokinetics were performed on day 1 and 8. Trough and peak concentrations of DCA were measured monthly. GSTZ1 genotypes were correlated with drug concentrations, tolerability, and disease outcomes. One patient responded and two patients showed a partial response after one month of DCA treatment, which included the loading dose. The initial half-life of DCA was shorter in two patients, correlating with heterozygosity for GSTZ1*A genotype, a high enzyme activity variant. Over 3 months, one patient maintained DCA trough concentrations approximately threefold higher than other patients, which correlated with a low activity promoter genotype (-1002A, rs7160195) for GSTZ1. This patient displayed the strongest response, but also the strongest neuropathy. Overall, serum concentrations of DCA were sufficient to inhibit the constitutive target PDK2, but unlikely to inhibit targets induced in cancer. Promoter GSTZ1 polymorphisms may be important determinants of DCA concentrations and neuropathy during chronic treatment. Novel dosing regimens may be necessary to achieve effective DCA concentrations in most cancer patients while avoiding neuropathy.
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Affiliation(s)
- Dan Dan Tian
- ACRF Department of Cancer Biology and TherapeuticsThe John Curtin School of Medical ResearchThe Australian National UniversityCanberraACTAustralia
| | | | - Lucy A. Coupland
- ACRF Department of Cancer Biology and TherapeuticsThe John Curtin School of Medical ResearchThe Australian National UniversityCanberraACTAustralia
| | - Kathryn Forwood
- Department of HaematologyThe Canberra HospitalGarranACTAustralia
| | - Yadanar Lwin
- Department of HaematologyThe Canberra HospitalGarranACTAustralia
| | - Niloofar Pooryousef
- ACRF Department of Cancer Biology and TherapeuticsThe John Curtin School of Medical ResearchThe Australian National UniversityCanberraACTAustralia
| | - Illa Tea
- ACRF Department of Cancer Biology and TherapeuticsThe John Curtin School of Medical ResearchThe Australian National UniversityCanberraACTAustralia
| | - Thy T. Truong
- Joint Mass Spectrometry FacilityThe Australian National UniversityActonACTAustralia
| | - Teresa Neeman
- Statistical Consulting UnitThe Australian National UniversityActonACTAustralia
| | - Philip Crispin
- Department of HaematologyThe Canberra HospitalGarranACTAustralia
| | - James D’Rozario
- Department of HaematologyThe Canberra HospitalGarranACTAustralia
| | - Anneke C. Blackburn
- ACRF Department of Cancer Biology and TherapeuticsThe John Curtin School of Medical ResearchThe Australian National UniversityCanberraACTAustralia
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40
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Roles for Autophagy in Esophageal Carcinogenesis: Implications for Improving Patient Outcomes. Cancers (Basel) 2019; 11:cancers11111697. [PMID: 31683722 PMCID: PMC6895837 DOI: 10.3390/cancers11111697] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 10/25/2019] [Accepted: 10/26/2019] [Indexed: 02/07/2023] Open
Abstract
Esophageal cancer is among the most aggressive forms of human malignancy with five-year survival rates of <20%. Autophagy is an evolutionarily conserved catabolic process that degrades and recycles damaged organelles and misfolded proteins to maintain cellular homeostasis. While alterations in autophagy have been associated with carcinogenesis across tissues, cell type- and context-dependent roles for autophagy have been reported. Herein, we review the current knowledge related to autophagy in esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC), the two most common subtypes of esophageal malignancy. We explore roles for autophagy in the development and progression of ESCC and EAC. We then continue to discuss molecular markers of autophagy as they relate to esophageal patient outcomes. Finally, we summarize current literature examining roles for autophagy in ESCC and EAC response to therapy and discuss considerations for the potential use of autophagy inhibitors as experimental therapeutics that may improve patient outcomes in esophageal cancer.
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41
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Lu H, Lu Y, Xie Y, Qiu S, Li X, Fan Z. Rational combination with PDK1 inhibition overcomes cetuximab resistance in head and neck squamous cell carcinoma. JCI Insight 2019; 4:131106. [PMID: 31578313 DOI: 10.1172/jci.insight.131106] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Accepted: 08/31/2019] [Indexed: 12/28/2022] Open
Abstract
Cetuximab, an EGFR-blocking antibody, is currently approved for treatment of metastatic head and neck squamous cell carcinoma (HNSCC), but its response rate is limited. In addition to blocking EGFR-stimulated cell signaling, cetuximab can induce endocytosis of ASCT2, a glutamine transporter associated with EGFR in a complex, leading to glutathione biosynthesis inhibition and cellular sensitization to ROS. Pyruvate dehydrogenase kinase-1 (PDK1), a key mitochondrial enzyme overexpressed in cancer cells, redirects glucose metabolism from oxidative phosphorylation toward aerobic glycolysis. In this study, we tested the hypothesis that targeting PDK1 is a rational approach to synergize with cetuximab through ROS overproduction. We found that combination of PDK1 knockdown or inhibition by dichloroacetic acid (DCA) with ASCT2 knockdown or with cetuximab treatment induced ROS overproduction and apoptosis in HNSCC cells, and this effect was independent of effective inhibition of EGFR downstream pathways but could be lessened by N-acetyl cysteine, an anti-oxidative agent. In several cetuximab-resistant HNSCC xenograft models, DCA plus cetuximab induced marked tumor regression, whereas either agent alone failed to induce tumor regression. Our findings call for potentially novel clinical trials of combining cetuximab and DCA in patients with cetuximab-sensitive EGFR-overexpressing tumors and patients with cetuximab-resistant EGFR-overexpressing tumors.
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Affiliation(s)
- Haiquan Lu
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.,MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas, USA
| | - Yang Lu
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Yangyiran Xie
- Program in Neuroscience, Krieger School of Arts and Sciences, Johns Hopkins University, Baltimore, Maryland, USA
| | - Songbo Qiu
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Xinqun Li
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Zhen Fan
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.,MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas, USA
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42
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Hsieh IS, Gopula B, Chou CC, Wu HY, Chang GD, Wu WJ, Chang CS, Chu PC, Chen CS. Development of Novel Irreversible Pyruvate Kinase M2 Inhibitors. J Med Chem 2019; 62:8497-8510. [PMID: 31465224 DOI: 10.1021/acs.jmedchem.9b00763] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
As cancer cells undergo metabolic reprogramming in the course of tumorigenesis, targeting energy metabolism represents a promising strategy in cancer therapy. Among various metabolic enzymes examined, pyruvate kinase M2 type (PKM2) has received much attention in light of its multifaceted function in promoting tumor growth and progression. In this study, we reported the development of a novel irreversible inhibitor of PKM2, compound 1, that exhibits a differential tumor-suppressive effect among an array of cancer cell lines. We further used a clickable activity-based protein profiling (ABPP) probe and SILAC coupled with LC-MS/MS to identify the Cys-317 and Cys-326 residues of PKM2 as the covalent binding sites. Equally important, compound 1 at 10 mg/kg was effective in suppressing xenograft tumor growth in nude mice without causing acute toxicity by targeting both metabolic and oncogenic functions. Together, these data suggest its translational potential to foster new strategies for cancer therapy.
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Affiliation(s)
- I-Shan Hsieh
- Institute of Biological Chemistry , Academia Sinica , Taipei 11529 , Taiwan
| | - Balraj Gopula
- Institute of Biological Chemistry , Academia Sinica , Taipei 11529 , Taiwan
- Drug Development Center , China Medical University , Taichung 40402 , Taiwan
| | - Chi-Chi Chou
- Institute of Biological Chemistry , Academia Sinica , Taipei 11529 , Taiwan
| | - Hsiang-Yi Wu
- Institute of Biological Chemistry , Academia Sinica , Taipei 11529 , Taiwan
| | - Geen-Dong Chang
- Institute of Biochemical Sciences , National Taiwan University , Taipei 10617 , Taiwan
| | - Wen-Jin Wu
- Institute of Biological Chemistry , Academia Sinica , Taipei 11529 , Taiwan
| | - Chih-Shiang Chang
- Drug Development Center , China Medical University , Taichung 40402 , Taiwan
- School of Pharmacy, College of Pharmacy, China Medical University , Taichung 40402 , Taiwan
| | - Po-Chen Chu
- Drug Development Center , China Medical University , Taichung 40402 , Taiwan
- Department of Cosmeceutics and Graduate Institute of Cosmeceutics , China Medical University , Taichung 40402 , Taiwan
| | - Ching S Chen
- Institute of New Drug Development , China Medical University , Taichung 40402 , Taiwan
- Department of Medical Research , China Medical University Hospital, China Medical University , Taichung 40447 , Taiwan
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43
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Wei G, Sun J, Luan W, Hou Z, Wang S, Cui S, Cheng M, Liu Y. Natural Product Albiziabioside A Conjugated with Pyruvate Dehydrogenase Kinase Inhibitor Dichloroacetate To Induce Apoptosis-Ferroptosis-M2-TAMs Polarization for Combined Cancer Therapy. J Med Chem 2019; 62:8760-8772. [DOI: 10.1021/acs.jmedchem.9b00644] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Gaofei Wei
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
- Institute of Medical Research, Northwestern Polytechnical University, Xi’an 710072, China
| | - Jiahong Sun
- Department of Biopharmaceutical Science, School of Pharmacy and Health Sciences, Keck Graduate Institute, Claremont, California 91711, United States
| | - Weijing Luan
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
- Yantai Branch, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Yantai 264000, China
| | - Zhuang Hou
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Shuai Wang
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Shanshan Cui
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Maosheng Cheng
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Yang Liu
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
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44
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Omran Z, Alarja M, Abdalla AN, Ibrahim MM, Hossain MA, Chen L, Liu Y, Wang Q. Design, Synthesis, and in Vitro Biological Evaluation of 14-Hydroxytylophorine-dichloroacetate Co-drugs as Antiproliferative Agents. Chem Pharm Bull (Tokyo) 2019; 67:1208-1210. [PMID: 31495803 DOI: 10.1248/cpb.c19-00520] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Co-drug, or mutual-prodrug, is a drug design approach consisting of covalently linking two active drugs so as to improve the pharmacokinetics and/or pharmacodynamics properties of one or both drugs. Co-drug strategy has proven good success in overcoming undesirable properties such as absorption, poor bioavailability, nonspecificity, and gastrointestine tract (GIT) side effects. In this work, we successfully developed a co-drug of 14-hydroxytylophorine, a phenanthroindolizidine derivative with remarkable antiproliferative activity, and dichloroacetate, a known inhibitor of pyruvate dehydrogenase kinase. Dichloroacetate steers tumour cell metabolism from glycolysis back to glucose oxidation, which in turn reverses the Warburg effect and renders tumour cells with a proliferative disadvantage. The obtained co-drugs retained the cytotoxicity of 14-hydroxytylophorine. However, they showed similar unselectivity towards normal cells.
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Affiliation(s)
- Ziad Omran
- College of Pharmacy, Umm Al-Qura University
| | | | | | | | | | - Linwei Chen
- State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University
| | - Yuxiu Liu
- State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University
| | - Qingmin Wang
- State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University
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45
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Iorio J, Petroni G, Duranti C, Lastraioli E. Potassium and Sodium Channels and the Warburg Effect: Biophysical Regulation of Cancer Metabolism. Bioelectricity 2019; 1:188-200. [PMID: 34471821 PMCID: PMC8370285 DOI: 10.1089/bioe.2019.0017] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Ion channels are progressively emerging as a novel class of membrane proteins expressed in several types of human cancers and regulating the different aspects of cancer cell behavior. The metabolism of cancer cells, usually composed by a variable proportion of respiration, glycolysis, and glutaminolysis, leads to the excessive production of acidic metabolic products. The presence of these acidic metabolites inside the cells results in intracellular acidosis, and hinders survival and proliferation. For this reason, tumor cells activate mechanisms of pH control that produce a constitutive increase in intracellular pH (pHi) that is more acidic than the extracellular pH (pHe). This condition forms a perfect microenvironment for metastatic progression and may be permissive for some of the acquired characteristics of tumors. Recent analyses have revealed complex interconnections between oncogenic activation, ion channels, hypoxia signaling and metabolic pathways that are dysregulated in cancer. Here, we summarize the molecular mechanisms of the Warburg effect and hypoxia and their association. Moreover, we discuss the recent findings concerning the involvement of ion channels in various aspects of the Warburg effect and hypoxia, focusing on the role of Na+ and K+ channels in hypoxic and metabolic reprogramming in cancer.
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Affiliation(s)
- Jessica Iorio
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Giulia Petroni
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Claudia Duranti
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Elena Lastraioli
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
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46
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Stakišaitis D, Juknevičienė M, Damanskienė E, Valančiūtė A, Balnytė I, Alonso MM. The Importance of Gender-Related Anticancer Research on Mitochondrial Regulator Sodium Dichloroacetate in Preclinical Studies In Vivo. Cancers (Basel) 2019; 11:cancers11081210. [PMID: 31434295 PMCID: PMC6721567 DOI: 10.3390/cancers11081210] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 08/16/2019] [Accepted: 08/16/2019] [Indexed: 12/28/2022] Open
Abstract
Sodium dichloroacetate (DCA) is an investigational medicinal product which has a potential anticancer preparation as a metabolic regulator in cancer cells’ mitochondria. Inhibition of pyruvate dehydrogenase kinases by DCA keeps the pyruvate dehydrogenase complex in the active form, resulting in decreased lactic acid in the tumor microenvironment. This literature review displays the preclinical research data on DCA’s effects on the cell pyruvate dehydrogenase deficiency, pyruvate mitochondrial oxidative phosphorylation, reactive oxygen species generation, and the Na+–K+–2Cl− cotransporter expression regulation in relation to gender. It presents DCA pharmacokinetics and the hepatocarcinogenic effect, and the safety data covers the DCA monotherapy efficacy for various human cancer xenografts in vivo in male and female animals. Preclinical cancer researchers report the synergistic effects of DCA combined with different drugs on cancer by reversing resistance to chemotherapy and promoting cell apoptosis. Researchers note that female and male animals differ in the mechanisms of cancerogenesis but often ignore studying DCA’s effects in relation to gender. Preclinical gender-related differences in DCA pharmacology, pharmacological mechanisms, and the elucidation of treatment efficacy in gonad hormone dependency could be relevant for individualized therapy approaches so that gender-related differences in treatment response and safety can be proposed.
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Affiliation(s)
- Donatas Stakišaitis
- Laboratory of Molecular Oncology, National Cancer Institute, 08660 Vilnius, Lithuania.
- Department of Histology and Embryology, Medical Academy, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania.
| | - Milda Juknevičienė
- Department of Histology and Embryology, Medical Academy, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania
| | - Eligija Damanskienė
- Department of Histology and Embryology, Medical Academy, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania
| | - Angelija Valančiūtė
- Department of Histology and Embryology, Medical Academy, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania
| | - Ingrida Balnytė
- Department of Histology and Embryology, Medical Academy, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania
| | - Marta Maria Alonso
- Department of Pediatrics, Clínica Universidad de Navarra, University of Navarra, 55 Pamplona, Spain.
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Ludman T, Melemedjian OK. Bortezomib-induced aerobic glycolysis contributes to chemotherapy-induced painful peripheral neuropathy. Mol Pain 2019; 15:1744806919837429. [PMID: 30810076 PMCID: PMC6452581 DOI: 10.1177/1744806919837429] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Chemotherapy-induced painful peripheral neuropathy (CIPN) is the most common toxicity associated with widely used chemotherapeutics. CIPN is the major cause of dose reduction or discontinuation of otherwise life-saving treatment. Unfortunately, CIPN can persist in cancer survivors, which adversely affects their quality of life. Moreover, available treatments are vastly inadequate, warranting a better understanding of the biochemical and metabolic mechanisms that occur in response to chemotherapeutics which would be critical for the development of novel therapies for CIPN. Using extracellular flux analysis, this study demonstrated that the proteasome inhibitor, bortezomib, enhanced glycolysis while suppressing oxidative phosphorylation in the sensory neurons of mice. This metabolic phenotype is known as aerobic glycolysis. Bortezomib upregulated lactate dehydrogenase A and pyruvate dehydrogenase kinase 1, which consequently enhanced the production of lactate and repressed pyruvate oxidation, respectively. Moreover, lactate dehydrogenase A- and pyruvate dehydrogenase kinase 1-driven aerobic glycolysis was associated with increased extracellular acidification, augmented calcium responses, and pain in bortezomib-induced CIPN. Remarkably, pharmacological blockade and in vivo knockdown of lactate dehydrogenase A or pyruvate dehydrogenase kinase 1 reversed the metabolic phenotype, attenuated calcium responses, and alleviated pain induced by bortezomib. Collectively, these results elucidate the mechanisms by which bortezomib induces aerobic glycolysis. Moreover, these findings establish aerobic glycolysis as a metabolic phenotype that underpins bortezomib-induced CIPN.
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Affiliation(s)
- Taylor Ludman
- 1 Department of Neural and Pain Sciences, School of Dentistry, University of Maryland Baltimore, Baltimore, MD, USA
| | - Ohannes K Melemedjian
- 1 Department of Neural and Pain Sciences, School of Dentistry, University of Maryland Baltimore, Baltimore, MD, USA.,2 Center to Advance Chronic Pain Research, University of Maryland Baltimore, Baltimore, MD, USA
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48
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Kennedy BE, Murphy JP, Clements DR, Konda P, Holay N, Kim Y, Pathak GP, Giacomantonio MA, Hiani YE, Gujar S. Inhibition of Pyruvate Dehydrogenase Kinase Enhances the Antitumor Efficacy of Oncolytic Reovirus. Cancer Res 2019; 79:3824-3836. [PMID: 31088833 DOI: 10.1158/0008-5472.can-18-2414] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Revised: 02/27/2019] [Accepted: 05/10/2019] [Indexed: 11/16/2022]
Abstract
Oncolytic viruses (OV) such as reovirus preferentially infect and kill cancer cells. Thus, the mechanisms that dictate the susceptibility of cancer cells to OV-induced cytotoxicity hold the key to their success in clinics. Here, we investigated whether cancer cell metabolism defines its susceptibility to OV and if OV-induced metabolic perturbations can be therapeutically targeted. Using mass spectrometry-based metabolomics and extracellular flux analysis on a panel of cancer cell lines with varying degrees of susceptibility to reovirus, we found that OV-induced changes in central energy metabolism, pyruvate metabolism, and oxidative stress correlate with their susceptibility to reovirus. In particular, reovirus infection accentuated Warburg-like metabolic perturbations in cell lines relatively resistant to oncolysis. These metabolic changes were facilitated by oxidative stress-induced inhibitory phosphorylation of pyruvate dehydrogenase (PDH) that impaired the routing of pyruvate into the tricarboxylic acid cycle and established a metabolic state unsupportive of OV replication. From the therapeutic perspective, reactivation of PDH in cancer cells that were weakly sensitive for reovirus, either through PDH kinase (PDK) inhibitors dichloroacetate and AZD7545 or short hairpin RNA-specific depletion of PDK1, enhanced the efficacy of reovirus-induced oncolysis in vitro and in vivo. These findings identify targeted metabolic reprogramming as a possible combination strategy to enhance the antitumor effects of OV in clinics. SIGNIFICANCE: This study proposes targeted metabolic reprogramming as a valid combinatorial strategy to enhance the translational efficacy of oncolytic virus-based cancer therapies.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/15/3824/F1.large.jpg.
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Affiliation(s)
- Barry E Kennedy
- Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada
| | | | - Derek R Clements
- Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Prathyusha Konda
- Department Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Namit Holay
- Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Youra Kim
- Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Gopal P Pathak
- Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada
| | | | - Yassine El Hiani
- Department Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Shashi Gujar
- Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada. .,Department Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.,Department Biology, Dalhousie University, Halifax, Nova Scotia, Canada.,Centre for Innovative and Collaborative Health Systems Research, IWK Health Centre, Halifax, Nova Scotia, Canada
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Korga A, Ostrowska M, Jozefczyk A, Iwan M, Wojcik R, Zgorka G, Herbet M, Vilarrubla GG, Dudka J. Apigenin and hesperidin augment the toxic effect of doxorubicin against HepG2 cells. BMC Pharmacol Toxicol 2019; 20:22. [PMID: 31053173 PMCID: PMC6499973 DOI: 10.1186/s40360-019-0301-2] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2018] [Accepted: 04/11/2019] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most common malignancies, with an increasing incidence. Despite the fact that systematic chemotherapy with a doxorubicin provides only marginal improvements in survival of the HCC patients, the doxorubicin is being used in transarterial therapies or combined with the target drug - sorafenib. The aim of the study was to evaluate the effect of natural flavonoids on the cytotoxicity of the doxorubicin against human hepatocellular carcinoma cell line HepG2. METHODS The effect of apigenin and its glycosides - cosmosiin, rhoifolin; baicalein and its glycosides - baicalin as well as hesperetin and its glycosides - hesperidin on glycolytic genes expression of HepG2 cell line, morphology and cells' viability at the presence of doxorubicin have been tested. In an attempt to elucidate the mechanism of observed results, the fluorogenic probe for reactive oxygen species (ROS), the DNA oxidative damage, the lipid peroxidation and the double strand breaks were evaluated. To assess impact on the glycolysis pathway, the mRNA expression for a hexokinase 2 (HK2) and a lactate dehydrogenase A (LDHA) enzymes were measured. The results were analysed statistically with the one-way analysis of variance (ANOVA) and post hoc multiple comparisons. RESULTS The apigenin and the hesperidin revealed the strongest effect on the toxicity of doxorubicin. Both flavonoids simultaneously changed the expression of the glycolytic pathway genes - HK2 and LDHA, which play a key role in the Warburg effect. Although separate treatment with doxorubicin, apigenin and hesperidin led to a significant oxidative DNA damage and double strand breaks, simultaneous administration of doxorubicin and apigenin or hesperidin abolished these damage with the simultaneous increase in the doxorubicin toxicity. CONCLUSION The obtained results indicate the existence of a very effective cytotoxic mechanism in the HepG2 cells of the combined effect of doxorubicin and apigenin (or hesperidin), not related to the oxidative stress. To explain this synergy mechanism, further research is needed, The observed intensification of the cytotoxic effect of doxorubicin by this flavonoids may be a promising direction of the research on the therapy of hepatocellular carcinoma, especially in a chemoembolization.
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Affiliation(s)
- Agnieszka Korga
- Independent Medical Biology Unit, Medical University of Lublin, 8b Jaczewski Street, 20-090 Lublin, Poland
| | - Marta Ostrowska
- Department of Toxicology, Medical University of Lublin, 8b Jaczewski Street, 20-090 Lublin, Poland
| | - Aleksandra Jozefczyk
- Department of Pharmacognosy with Medicinal Plant Laboratory, Medical University of Lublin, 1 Chodzko Street, 20-093 Lublin, Poland
| | - Magdalena Iwan
- Independent Medical Biology Unit, Medical University of Lublin, 8b Jaczewski Street, 20-090 Lublin, Poland
| | - Rafal Wojcik
- Department of Human Anatomy, Medical University of Lublin, 4 Jaczewski Street, 20-090 Lublin, Poland
| | - Grazyna Zgorka
- Department of Pharmacognosy with Medicinal Plant Laboratory, Medical University of Lublin, 1 Chodzko Street, 20-093 Lublin, Poland
| | - Mariola Herbet
- Department of Toxicology, Medical University of Lublin, 8b Jaczewski Street, 20-090 Lublin, Poland
| | - Gemma Gomez Vilarrubla
- Independent Medical Biology Unit, Medical University of Lublin, 8b Jaczewski Street, 20-090 Lublin, Poland
| | - Jaroslaw Dudka
- Department of Toxicology, Medical University of Lublin, 8b Jaczewski Street, 20-090 Lublin, Poland
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Zhou Z, Kinslow CJ, Hibshoosh H, Guo H, Cheng SK, He C, Gentry MS, Sun RC. Clinical Features, Survival and Prognostic Factors of Glycogen-Rich Clear Cell Carcinoma (GRCC) of the Breast in the U.S. Population. J Clin Med 2019; 8:E246. [PMID: 30769905 PMCID: PMC6406344 DOI: 10.3390/jcm8020246] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Revised: 02/08/2019] [Accepted: 02/11/2019] [Indexed: 01/07/2023] Open
Abstract
The World Health Organization (WHO) defines glycogen-rich clear cell carcinoma (GRCC) of the breast as a carcinoma with glycogen accumulation in more than 90% of its tumor cells. Due to the rarity of this disease, its reported survival and clinical associations have been inconsistent due to reliance on case reports and limited case series. As a result, the prognostic implication of this cancer subtype remains unclear. Using the U.S. Surveillance, Epidemiology, and End Results (SEER) program database, we compared the incidence, demographics and prognostic factors of 155 cases of GRCC of the breast to 1,251,584 cases of other (non-GRCC) breast carcinomas. We demonstrate that GRCC is more likely to be identified as high grade, advanced stage, and more likely to have triple negative receptor status. GRCC cases display a poorer prognosis than non-GRCC carcinomas of the breast irrespective of age, AJCC staging, tumor grade, joint hormone receptor/human epidermal growth factor receptor 2 (HER2) status, and treatment. Similar to non-GRCC carcinomas, older age and higher American Joint Committee on Cancer (AJCC)/TNM staging were associated with poorer prognosis for GRCC, while treatment with surgery and radiation were associated with improved survival. Radiation, specifically in the setting of breast-conserving surgery, further improved survival compared to surgery alone. Our study highlights the poorer prognosis associated with glycogen accumulation in breast cancers and hence stresses the importance of identifying this more aggressive tumor type.
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Affiliation(s)
- Zhengqiu Zhou
- Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
| | - Connor J Kinslow
- Department of Radiation Oncology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY 10032, USA.
| | - Hanina Hibshoosh
- Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY 10032, USA.
| | - Hua Guo
- Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY 10032, USA.
| | - Simon K Cheng
- Department of Radiation Oncology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY 10032, USA.
| | - Chunyan He
- Department of Internal Medicine, Division of Medical Oncology, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
- Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.
| | - Matthew S Gentry
- Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
- Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.
| | - Ramon C Sun
- Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
- Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.
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