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Subramaniam S, Jeet V, Gunter JH, Janjua Khan T, Feng Y, Clements JA, Srinivasan S, Popat A, Batra J. Lactoferrin-encapsulated dichloroacetophenone (DAP) nanoparticles enhance drug delivery and anti-tumor efficacy in prostate cancer. Cancer Lett 2025; 616:217522. [PMID: 39924080 DOI: 10.1016/j.canlet.2025.217522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Revised: 01/28/2025] [Accepted: 01/31/2025] [Indexed: 02/11/2025]
Abstract
Pyruvate Dehydrogenase Kinase 1 (PDK1) regulates glycolysis and oxidative phosphorylation pathways and is linked to prostate cancer metastasis and poor prognosis. The therapeutic application of 2,2-dichloroacetophenone (DAP), a PDK1 inhibitor, remains underexplored in prostate cancer. In this study we demonstrated that DAP exhibited a superior ability to inhibit prostate cancer cell proliferation, migration and colony formation at a lower concentration (20 μM) compared to a previously established inhibitor, dichloroacetate (DCA), which required concentrations of 30 mM or higher. However, poor aqueous solubility and lower stability of DAP limits its therapeutic application. Nano formulation of DAP with natural lactoferrin enhanced its dispersion and stability by increasing polydispersity index and intensity, and reduced zeta potential values upon conjugation that overcame the solubility limitations of DAP. The lactoferrin-DAP nanoparticles exhibited enhanced therapeutic efficacy by precisely targeting prostate cancer cells that express high lactoferrin receptors and high anti-tumor activity in vitro (at 1 μM) and in mouse prostate tumor xenografts (20 mg/kg). Mechanistically, these nanoparticles induce apoptosis in cancer cells by inducing caspase3/7 activity and disrupting the glycolytic and oxidative phosphorylation pathways. Moreover, lactoferrin-conjugated DAP nanoparticles suppressed the viability of docetaxel-resistant cells exhibiting a higher inhibitory efficacy compared to free DAP and DCA. Targeting PDK1 through lactoferrin-conjugated DAP nanoparticles represents a potent targeted therapeutic strategy for disrupting prostate tumor metabolism and offers promising implications for overcoming drug resistance.
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Affiliation(s)
- Sugarniya Subramaniam
- School of Biomedical Sciences, Faculty of Health, Institute of Health and Biomedical Innovation, Queensland University of Technology, Queensland (QLD), Australia; Translational Research Institute, Woolloongabba, QLD, Australia
| | - Varinder Jeet
- School of Biomedical Sciences, Faculty of Health, Institute of Health and Biomedical Innovation, Queensland University of Technology, Queensland (QLD), Australia
| | - Jennifer H Gunter
- School of Biomedical Sciences, Faculty of Health, Institute of Health and Biomedical Innovation, Queensland University of Technology, Queensland (QLD), Australia; Translational Research Institute, Woolloongabba, QLD, Australia; The Centre for Genomics and Personalised Health, Queensland University of Technology, Brisbane, QLD, 4059, Australia
| | | | - Yuran Feng
- School of Pharmacy, The University of Queensland, Brisbane, QLD, Australia
| | - Judith A Clements
- School of Biomedical Sciences, Faculty of Health, Institute of Health and Biomedical Innovation, Queensland University of Technology, Queensland (QLD), Australia; Translational Research Institute, Woolloongabba, QLD, Australia
| | - Srilakshmi Srinivasan
- School of Biomedical Sciences, Faculty of Health, Institute of Health and Biomedical Innovation, Queensland University of Technology, Queensland (QLD), Australia; Translational Research Institute, Woolloongabba, QLD, Australia; The Centre for Genomics and Personalised Health, Queensland University of Technology, Brisbane, QLD, 4059, Australia
| | - Amirali Popat
- School of Pharmacy, The University of Queensland, Brisbane, QLD, Australia; Mater Research Institute, Woolloongabba, QLD, Australia; Department of Functional Materials and Catalysis, Faculty of Chemistry, University of Vienna, Währinger Straße 42, 1090, Vienna, Austria
| | - Jyotsna Batra
- School of Biomedical Sciences, Faculty of Health, Institute of Health and Biomedical Innovation, Queensland University of Technology, Queensland (QLD), Australia; Translational Research Institute, Woolloongabba, QLD, Australia; The Centre for Genomics and Personalised Health, Queensland University of Technology, Brisbane, QLD, 4059, Australia.
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Cordani M, Michetti F, Zarrabi A, Zarepour A, Rumio C, Strippoli R, Marcucci F. The role of glycolysis in tumorigenesis: From biological aspects to therapeutic opportunities. Neoplasia 2024; 58:101076. [PMID: 39476482 PMCID: PMC11555605 DOI: 10.1016/j.neo.2024.101076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 10/13/2024] [Accepted: 10/17/2024] [Indexed: 11/11/2024]
Abstract
Glycolytic metabolism generates energy and intermediates for biomass production. Tumor-associated glycolysis is upregulated compared to normal tissues in response to tumor cell-autonomous or non-autonomous stimuli. The consequences of this upregulation are twofold. First, the metabolic effects of glycolysis become predominant over those mediated by oxidative metabolism. Second, overexpressed components of the glycolytic pathway (i.e. enzymes or metabolites) acquire new functions unrelated to their metabolic effects and which are referred to as "moonlighting" functions. These functions include induction of mutations and other tumor-initiating events, effects on cancer stem cells, induction of increased expression and/or activity of oncoproteins, epigenetic and transcriptional modifications, bypassing of senescence and induction of proliferation, promotion of DNA damage repair and prevention of DNA damage, antiapoptotic effects, inhibition of drug influx or increase of drug efflux. Upregulated metabolic functions and acquisition of new, non-metabolic functions lead to biological effects that support tumorigenesis: promotion of tumor initiation, stimulation of tumor cell proliferation and primary tumor growth, induction of epithelial-mesenchymal transition, autophagy and metastasis, immunosuppressive effects, induction of drug resistance and effects on tumor accessory cells. These effects have negative consequences on the prognosis of tumor patients. On these grounds, it does not come to surprise that tumor-associated glycolysis has become a target of interest in antitumor drug discovery. So far, however, clinical results with glycolysis inhibitors have fallen short of expectations. In this review we propose approaches that may allow to bypass some of the difficulties that have been encountered so far with the therapeutic use of glycolysis inhibitors.
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Affiliation(s)
- Marco Cordani
- Department of Biochemistry and Molecular Biology, Faculty of Biology, Complutense University of Madrid, Madrid 28040, Spain; Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid 28040, Spain
| | - Federica Michetti
- Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 324, Rome 00161, Italy; Department of Epidemiology, Preclinical Research and Advanced Diagnostics, National Institute for Infectious Diseases L., Spallanzani, IRCCS, Via Portuense, 292, Rome 00149, Italy
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul 34396, Türkiye; Graduate School of Biotechnology and Bioengineering, Yuan Ze University, Taoyuan 320315, Taiwan
| | - Atefeh Zarepour
- Department of Research Analytics, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai 600 077, India
| | - Cristiano Rumio
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Via Trentacoste 2, Milan 20134, Italy
| | - Raffaele Strippoli
- Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 324, Rome 00161, Italy; Department of Epidemiology, Preclinical Research and Advanced Diagnostics, National Institute for Infectious Diseases L., Spallanzani, IRCCS, Via Portuense, 292, Rome 00149, Italy.
| | - Fabrizio Marcucci
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Via Trentacoste 2, Milan 20134, Italy.
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Yang MQ, Zhang SL, Sun L, Huang LT, Yu J, Zhang JH, Tian Y, Han CB, Ma JT. Targeting mitochondria: restoring the antitumor efficacy of exhausted T cells. Mol Cancer 2024; 23:260. [PMID: 39563438 PMCID: PMC11575104 DOI: 10.1186/s12943-024-02175-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Accepted: 11/10/2024] [Indexed: 11/21/2024] Open
Abstract
Immune checkpoint blockade therapy has revolutionized cancer treatment, but resistance remains prevalent, often due to dysfunctional tumor-infiltrating lymphocytes. A key contributor to this dysfunction is mitochondrial dysfunction, characterized by defective oxidative phosphorylation, impaired adaptation, and depolarization, which promotes T cell exhaustion and severely compromises antitumor efficacy. This review summarizes recent advances in restoring the function of exhausted T cells through mitochondria-targeted strategies, such as metabolic remodeling, enhanced biogenesis, and regulation of antioxidant and reactive oxygen species, with the aim of reversing the state of T cell exhaustion and improving the response to immunotherapy. A deeper understanding of the role of mitochondria in T cell exhaustion lays the foundation for the development of novel mitochondria-targeted therapies and opens a new chapter in cancer immunotherapy.
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Affiliation(s)
- Mei-Qi Yang
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, 110004, China
- Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Shu-Ling Zhang
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, 110004, China
- Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Li Sun
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, 110004, China
- Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Le-Tian Huang
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, 110004, China
- Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Jing Yu
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, 110004, China
- Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Jie-Hui Zhang
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, 110004, China
- Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Yuan Tian
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, 110004, China
- Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Cheng-Bo Han
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, 110004, China.
- Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical University, Shenyang, 110004, China.
| | - Jie-Tao Ma
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, 110004, China.
- Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical University, Shenyang, 110004, China.
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Lu M, Wu Y, Xia M, Zhang Y. The role of metabolic reprogramming in liver cancer and its clinical perspectives. Front Oncol 2024; 14:1454161. [PMID: 39610917 PMCID: PMC11602425 DOI: 10.3389/fonc.2024.1454161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Accepted: 10/25/2024] [Indexed: 11/30/2024] Open
Abstract
Primary liver cancer (PLC), which includes hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), remains a leading cause of cancer-related death worldwide. Chronic liver diseases, such as hepatitis B and C infections and metabolic dysfunction-associated steatotic liver disease (MASLD), are key risk factors for PLC. Metabolic reprogramming, a defining feature of cancer, enables liver cancer cells to adapt to the demands of rapid proliferation and the challenging tumor microenvironment (TME). This manuscript examines the pivotal role of metabolic reprogramming in PLC, with an emphasis on the alterations in glucose, lipid, and amino acid metabolism that drive tumor progression. The Warburg effect, marked by increased glycolysis, facilitates rapid energy production and biosynthesis of cellular components in HCC. Changes in lipid metabolism, including elevated de novo fatty acid synthesis and lipid oxidation, support membrane formation and energy storage essential for cancer cell survival. Amino acid metabolism, particularly glutamine utilization, supplies critical carbon and nitrogen for nucleotide synthesis and maintains redox homeostasis. These metabolic adaptations not only enhance tumor growth and invasion but also reshape the TME, promoting immune escape. Targeting these metabolic pathways presents promising therapeutic opportunities for PLC. This review underscores the interaction between metabolic reprogramming and tumor immunity, suggesting potential metabolic targets for innovative therapeutic strategies. A comprehensive understanding of PLC's intricate metabolic landscape may lead to more effective treatments and better patient outcomes. Integrating metabolomics, genomics, and proteomics in future research will be vital for identifying precise therapeutic targets and advancing personalized therapies for liver cancer.
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Affiliation(s)
- Mengxiao Lu
- Department of Gastrointestinal Minimally Invasive Surgery, The Affiliated People’s Hospital of Ningbo University, Ningbo, China
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Tang Q, Wu S, Zhao B, Li Z, Zhou Q, Yu Y, Yang X, Wang R, Wang X, Wu W, Wang S. Reprogramming of glucose metabolism: The hallmark of malignant transformation and target for advanced diagnostics and treatments. Biomed Pharmacother 2024; 178:117257. [PMID: 39137648 DOI: 10.1016/j.biopha.2024.117257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 07/30/2024] [Accepted: 08/02/2024] [Indexed: 08/15/2024] Open
Abstract
Reprogramming of cancer metabolism has become increasingly concerned over the last decade, particularly the reprogramming of glucose metabolism, also known as the "Warburg effect". The reprogramming of glucose metabolism is considered a novel hallmark of human cancers. A growing number of studies have shown that reprogramming of glucose metabolism can regulate many biological processes of cancers, including carcinogenesis, progression, metastasis, and drug resistance. In this review, we summarize the major biological functions, clinical significance, potential targets and signaling pathways of glucose metabolic reprogramming in human cancers. Moreover, the applications of natural products and small molecule inhibitors targeting glucose metabolic reprogramming are analyzed, some clinical agents targeting glucose metabolic reprogramming and trial statuses are summarized, as well as the pros and cons of targeting glucose metabolic reprogramming for cancer therapy are analyzed. Overall, the reprogramming of glucose metabolism plays an important role in the prediction, prevention, diagnosis and treatment of human cancers. Glucose metabolic reprogramming-related targets have great potential to serve as biomarkers for improving individual outcomes and prognosis in cancer patients. The clinical innovations related to targeting the reprogramming of glucose metabolism will be a hotspot for cancer therapy research in the future. We suggest that more high-quality clinical trials with more abundant drug formulations and toxicology experiments would be beneficial for the development and clinical application of drugs targeting reprogramming of glucose metabolism.This review will provide the researchers with the broader perspective and comprehensive understanding about the important significance of glucose metabolic reprogramming in human cancers.
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Affiliation(s)
- Qing Tang
- State Key Laboratory of Traditional Chinese Medicine Syndrome, Clinical and Basic Research Team of TCM Prevention and Treatment of NSCLC, Guangdong Provincial Hospital of Chinese Medicine; State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Diseases, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China; The Second Clinical Medical College, The Second Affiliated Hospital, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, 510120, P. R. China; Department of Oncology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China.
| | - Siqi Wu
- The First Clinical School of Guangzhou University of Chinese Medicine；Department of Oncology, the First Affiliated Hospital of Guangzhou University of Chinese Medicine,Guangzhou 510000, China; Zhongshan Institute for Drug Discovery, SIMM, CAS, Zhongshan 528400, China
| | - Baiming Zhao
- The Second Clinical Medical College, The Second Affiliated Hospital, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China; Department of Traditional Chinese Medicine, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Zhanyang Li
- School of Biosciences and Biopharmaceutics, Guangdong Province Key Laboratory for Biotechnology Drug Candidates, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Qichun Zhou
- State Key Laboratory of Traditional Chinese Medicine Syndrome, Clinical and Basic Research Team of TCM Prevention and Treatment of NSCLC, Guangdong Provincial Hospital of Chinese Medicine; State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Diseases, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China; The Second Clinical Medical College, The Second Affiliated Hospital, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, 510120, P. R. China; Department of Oncology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China
| | - Yaya Yu
- The Second Clinical Medical College, The Second Affiliated Hospital, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China
| | - Xiaobing Yang
- The Second Clinical Medical College, The Second Affiliated Hospital, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China; Department of Oncology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China
| | - Rui Wang
- State Key Laboratory of Traditional Chinese Medicine Syndrome, Clinical and Basic Research Team of TCM Prevention and Treatment of NSCLC, Guangdong Provincial Hospital of Chinese Medicine; State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Diseases, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China; The Second Clinical Medical College, The Second Affiliated Hospital, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, 510120, P. R. China; Department of Oncology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China
| | - Xi Wang
- State Key Laboratory of Traditional Chinese Medicine Syndrome, Clinical and Basic Research Team of TCM Prevention and Treatment of NSCLC, Guangdong Provincial Hospital of Chinese Medicine; State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Diseases, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China; The Second Clinical Medical College, The Second Affiliated Hospital, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, 510120, P. R. China; Department of Oncology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China
| | - Wanyin Wu
- State Key Laboratory of Traditional Chinese Medicine Syndrome, Clinical and Basic Research Team of TCM Prevention and Treatment of NSCLC, Guangdong Provincial Hospital of Chinese Medicine; State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Diseases, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China; The Second Clinical Medical College, The Second Affiliated Hospital, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, 510120, P. R. China; Department of Oncology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China.
| | - Sumei Wang
- State Key Laboratory of Traditional Chinese Medicine Syndrome, Clinical and Basic Research Team of TCM Prevention and Treatment of NSCLC, Guangdong Provincial Hospital of Chinese Medicine; State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Diseases, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China; The Second Clinical Medical College, The Second Affiliated Hospital, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, 510120, P. R. China; Department of Oncology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China.
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Berrell N, Sadeghirad H, Blick T, Bidgood C, Leggatt GR, O'Byrne K, Kulasinghe A. Metabolomics at the tumor microenvironment interface: Decoding cellular conversations. Med Res Rev 2024; 44:1121-1146. [PMID: 38146814 DOI: 10.1002/med.22010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 11/08/2023] [Accepted: 12/07/2023] [Indexed: 12/27/2023]
Abstract
Cancer heterogeneity remains a significant challenge for effective cancer treatments. Altered energetics is one of the hallmarks of cancer and influences tumor growth and drug resistance. Studies have shown that heterogeneity exists within the metabolic profile of tumors, and personalized-combination therapy with relevant metabolic interventions could improve patient response. Metabolomic studies are identifying novel biomarkers and therapeutic targets that have improved treatment response. The spatial location of elements in the tumor microenvironment are becoming increasingly important for understanding disease progression. The evolution of spatial metabolomics analysis now allows scientists to deeply understand how metabolite distribution contributes to cancer biology. Recently, these techniques have spatially resolved metabolite distribution to a subcellular level. It has been proposed that metabolite mapping could improve patient outcomes by improving precision medicine, enabling earlier diagnosis and intraoperatively identifying tumor margins. This review will discuss how altered metabolic pathways contribute to cancer progression and drug resistance and will explore the current capabilities of spatial metabolomics technologies and how these could be integrated into clinical practice to improve patient outcomes.
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Affiliation(s)
- Naomi Berrell
- Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Habib Sadeghirad
- Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Tony Blick
- Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Charles Bidgood
- APCRC-Q, Queensland University of Technology, Brisbane, Queensland, Australia
| | - Graham R Leggatt
- Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Ken O'Byrne
- Princess Alexandra Hospital, Woolloongabba, Queensland, Australia
| | - Arutha Kulasinghe
- Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
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Lin J, Rao D, Zhang M, Gao Q. Metabolic reprogramming in the tumor microenvironment of liver cancer. J Hematol Oncol 2024; 17:6. [PMID: 38297372 PMCID: PMC10832230 DOI: 10.1186/s13045-024-01527-8] [Citation(s) in RCA: 37] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Accepted: 01/21/2024] [Indexed: 02/02/2024] Open
Abstract
The liver is essential for metabolic homeostasis. The onset of liver cancer is often accompanied by dysregulated liver function, leading to metabolic rearrangements. Overwhelming evidence has illustrated that dysregulated cellular metabolism can, in turn, promote anabolic growth and tumor propagation in a hostile microenvironment. In addition to supporting continuous tumor growth and survival, disrupted metabolic process also creates obstacles for the anticancer immune response and restrains durable clinical remission following immunotherapy. In this review, we elucidate the metabolic communication between liver cancer cells and their surrounding immune cells and discuss how metabolic reprogramming of liver cancer impacts the immune microenvironment and the efficacy of anticancer immunotherapy. We also describe the crucial role of the gut-liver axis in remodeling the metabolic crosstalk of immune surveillance and escape, highlighting novel therapeutic opportunities.
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Affiliation(s)
- Jian Lin
- Center for Tumor Diagnosis and Therapy, Jinshan Hospital, Fudan University, Shanghai, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Dongning Rao
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, 200032, China
| | - Mao Zhang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, 200032, China
| | - Qiang Gao
- Center for Tumor Diagnosis and Therapy, Jinshan Hospital, Fudan University, Shanghai, China.
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, 200032, China.
- Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
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8
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Tu SM, Chen JZ, Singh SR, Maraboyina S, Gokden N, Hsu PC, Langford T. Stem Cell Theory of Cancer: Clinical Implications for Cellular Metabolism and Anti-Cancer Metabolomics. Cancers (Basel) 2024; 16:624. [PMID: 38339375 PMCID: PMC10854810 DOI: 10.3390/cancers16030624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 01/14/2024] [Accepted: 01/29/2024] [Indexed: 02/12/2024] Open
Abstract
Although Otto Warburg may be right about the role of glycolysis versus OXPHOS in cancer metabolism, it remains unclear whether an altered metabolism is causative or correlative and is the main driver or a mere passenger in the pathogenesis of cancer. Currently, most of our successful treatments are designed to eliminate non-cancer stem cells (non-CSCs) such as differentiated cancer cells. When the treatments also happen to control CSCs or the stem-ness niche, it is often unintended, unexpected, or undetected for lack of a pertinent theory about the origin of cancer that clarifies whether cancer is a metabolic, genetic, or stem cell disease. Perhaps cellular context matters. After all, metabolic activity may be different in different cell types and their respective microenvironments-whether it is in a normal progenitor stem cell vs. progeny differentiated cell and whether it is in a malignant CSC vs. non-CSC. In this perspective, we re-examine different types of cellular metabolism, e.g., glycolytic vs. mitochondrial, of glucose, glutamine, arginine, and fatty acids in CSCs and non-CSCs. We revisit the Warburg effect, an obesity epidemic, the aspartame story, and a ketogenic diet. We propose that a pertinent scientific theory about the origin of cancer and of cancer metabolism influences the direction of cancer research as well as the design of drug versus therapy development in cancer care.
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Affiliation(s)
- Shi-Ming Tu
- Division of Hematology and Oncology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (J.Z.C.); (S.R.S.)
| | - Jim Z. Chen
- Division of Hematology and Oncology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (J.Z.C.); (S.R.S.)
| | - Sunny R. Singh
- Division of Hematology and Oncology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (J.Z.C.); (S.R.S.)
| | - Sanjay Maraboyina
- Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA;
| | - Neriman Gokden
- Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA;
| | - Ping-Ching Hsu
- Department of Environmental & Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA;
| | - Timothy Langford
- Department of Urology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA;
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Zhang Y, Sun M, Zhao H, Wang Z, Shi Y, Dong J, Wang K, Wang X, Li X, Qi H, Zhao X. Neuroprotective Effects and Therapeutic Potential of Dichloroacetate: Targeting Metabolic Disorders in Nervous System Diseases. Int J Nanomedicine 2023; 18:7559-7581. [PMID: 38106446 PMCID: PMC10725694 DOI: 10.2147/ijn.s439728] [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: 09/15/2023] [Accepted: 11/28/2023] [Indexed: 12/19/2023] Open
Abstract
Dichloroacetate (DCA) is an investigational drug used to treat lactic acidosis and malignant tumours. It works by inhibiting pyruvate dehydrogenase kinase and increasing the rate of glucose oxidation. Some studies have documented the neuroprotective benefits of DCA. By reviewing these studies, this paper shows that DCA has multiple pharmacological activities, including regulating metabolism, ameliorating oxidative stress, attenuating neuroinflammation, inhibiting apoptosis, decreasing autophagy, protecting the blood‒brain barrier, improving the function of endothelial progenitor cells, improving mitochondrial dynamics, and decreasing amyloid β-protein. In addition, DCA inhibits the enzyme that metabolizes it, which leads to peripheral neurotoxicity due to drug accumulation that may be solved by individualized drug delivery and nanovesicle delivery. In summary, in this review, we analyse the mechanisms of neuroprotection by DCA in different diseases and discuss the causes of and solutions to its adverse effects.
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Affiliation(s)
- Yue Zhang
- Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, People’s Republic of China
- Laboratory of Anesthesia and Critical Care Medicine in Colleges and Universities of Shandong Province, School of Anesthesiology, Weifang Medical University, Weifang, Shandong Province, People’s Republic of China
| | - Meiyan Sun
- Laboratory of Anesthesia and Critical Care Medicine in Colleges and Universities of Shandong Province, School of Anesthesiology, Weifang Medical University, Weifang, Shandong Province, People’s Republic of China
| | - Hongxiang Zhao
- Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, People’s Republic of China
- Laboratory of Anesthesia and Critical Care Medicine in Colleges and Universities of Shandong Province, School of Anesthesiology, Weifang Medical University, Weifang, Shandong Province, People’s Republic of China
| | - Zhengyan Wang
- Laboratory of Anesthesia and Critical Care Medicine in Colleges and Universities of Shandong Province, School of Anesthesiology, Weifang Medical University, Weifang, Shandong Province, People’s Republic of China
| | - Yanan Shi
- Laboratory of Anesthesia and Critical Care Medicine in Colleges and Universities of Shandong Province, School of Anesthesiology, Weifang Medical University, Weifang, Shandong Province, People’s Republic of China
| | - Jianxin Dong
- Laboratory of Anesthesia and Critical Care Medicine in Colleges and Universities of Shandong Province, School of Anesthesiology, Weifang Medical University, Weifang, Shandong Province, People’s Republic of China
| | - Kaifang Wang
- Department of Anesthesia, Tangdu Hospital, Fourth Military Medical University, Xian, Shanxi Province, People’s Republic of China
| | - Xi Wang
- Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People’s Republic of China
| | - Xingyue Li
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Weifang Medical University, Weifang, Shandong Province, People’s Republic of China
| | - Haiyan Qi
- Department of Anesthesiology, Jinan Maternity and Child Care Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, People’s Republic of China
| | - Xiaoyong Zhao
- Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, People’s Republic of China
- Laboratory of Anesthesia and Critical Care Medicine in Colleges and Universities of Shandong Province, School of Anesthesiology, Weifang Medical University, Weifang, Shandong Province, People’s Republic of China
- Department of Anesthesiology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, People’s Republic of China
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10
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Dewdney B, Jenkins MR, Best SA, Freytag S, Prasad K, Holst J, Endersby R, Johns TG. From signalling pathways to targeted therapies: unravelling glioblastoma's secrets and harnessing two decades of progress. Signal Transduct Target Ther 2023; 8:400. [PMID: 37857607 PMCID: PMC10587102 DOI: 10.1038/s41392-023-01637-8] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 08/29/2023] [Accepted: 09/07/2023] [Indexed: 10/21/2023] Open
Abstract
Glioblastoma, a rare, and highly lethal form of brain cancer, poses significant challenges in terms of therapeutic resistance, and poor survival rates for both adult and paediatric patients alike. Despite advancements in brain cancer research driven by a technological revolution, translating our understanding of glioblastoma pathogenesis into improved clinical outcomes remains a critical unmet need. This review emphasises the intricate role of receptor tyrosine kinase signalling pathways, epigenetic mechanisms, and metabolic functions in glioblastoma tumourigenesis and therapeutic resistance. We also discuss the extensive efforts over the past two decades that have explored targeted therapies against these pathways. Emerging therapeutic approaches, such as antibody-toxin conjugates or CAR T cell therapies, offer potential by specifically targeting proteins on the glioblastoma cell surface. Combination strategies incorporating protein-targeted therapy and immune-based therapies demonstrate great promise for future clinical research. Moreover, gaining insights into the role of cell-of-origin in glioblastoma treatment response holds the potential to advance precision medicine approaches. Addressing these challenges is crucial to improving outcomes for glioblastoma patients and moving towards more effective precision therapies.
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Affiliation(s)
- Brittany Dewdney
- Cancer Centre, Telethon Kids Institute, Nedlands, WA, 6009, Australia.
- Centre For Child Health Research, University of Western Australia, Perth, WA, 6009, Australia.
| | - Misty R Jenkins
- Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, 3052, Australia
- Department of Medical Biology, University of Melbourne, Melbourne, 3010, Australia
| | - Sarah A Best
- Department of Medical Biology, University of Melbourne, Melbourne, 3010, Australia
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, 3052, Australia
| | - Saskia Freytag
- Department of Medical Biology, University of Melbourne, Melbourne, 3010, Australia
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, 3052, Australia
| | - Krishneel Prasad
- Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, 3052, Australia
- Department of Medical Biology, University of Melbourne, Melbourne, 3010, Australia
| | - Jeff Holst
- School of Biomedical Sciences, University of New South Wales, Sydney, 2052, Australia
| | - Raelene Endersby
- Cancer Centre, Telethon Kids Institute, Nedlands, WA, 6009, Australia
- Centre For Child Health Research, University of Western Australia, Perth, WA, 6009, Australia
| | - Terrance G Johns
- Cancer Centre, Telethon Kids Institute, Nedlands, WA, 6009, Australia
- Centre For Child Health Research, University of Western Australia, Perth, WA, 6009, Australia
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11
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Zhang X, Lee WD, Leitner BP, Zhu W, Fosam A, Li Z, Gaspar RC, Halberstam AA, Robles B, Rabinowitz JD, Perry RJ. Dichloroacetate as a novel pharmaceutical treatment for cancer-related fatigue in melanoma. Am J Physiol Endocrinol Metab 2023; 325:E363-E375. [PMID: 37646579 PMCID: PMC10642987 DOI: 10.1152/ajpendo.00105.2023] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 08/28/2023] [Accepted: 08/28/2023] [Indexed: 09/01/2023]
Abstract
Cancer-related fatigue (CRF) is one of the most common complications in patients with multiple cancer types and severely affects patients' quality of life. However, there have only been single symptom-relieving adjuvant therapies but no effective pharmaceutical treatment for the CRF syndrome. Dichloroacetate (DCA), a small molecule inhibitor of pyruvate dehydrogenase kinase, has been tested as a potential therapy to slow tumor growth, based largely on its effects in vitro to halt cell division. We found that although DCA did not affect rates of tumor growth or the efficacy of standard cancer treatment (immunotherapy and chemotherapy) in two murine cancer models, DCA preserved physical function in mice with late-stage tumors by reducing circulating lactate concentrations. In vivo liquid chromatography-mass spectrometry/mass spectrometry studies suggest that DCA treatment may preserve membrane potential, postpone proteolysis, and relieve oxidative stress in muscles of tumor-bearing mice. In all, this study provides evidence for DCA as a novel pharmaceutical treatment to maintain physical function and motivation in murine models of CRF.NEW & NOTEWORTHY We identify a new metabolic target for cancer-related fatigue, dichloroacetate (DCA). They demonstrate that in mice, DCA preserves physical function and protects against the detrimental effects of cancer treatment by reducing cancer-induced increases in circulating lactate. As DCA is already FDA approved for another indication, these results could be rapidly translated to clinical trials for this condition for which no pharmaceutical therapies exist beyond symptom management.
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Affiliation(s)
- Xinyi Zhang
- Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, United States
- Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, Connecticut, United States
| | - Won D Lee
- Department of Molecular Biology, Princeton University, Princeton, New Jersey, United States
- Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, United States
| | - Brooks P Leitner
- Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, United States
- Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, Connecticut, United States
| | - Wanling Zhu
- Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, United States
- Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, Connecticut, United States
| | - Andin Fosam
- Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, United States
- Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, Connecticut, United States
| | - Zongyu Li
- Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, United States
- Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, Connecticut, United States
| | - Rafael C Gaspar
- Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, United States
- Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, Connecticut, United States
| | - Alexandra A Halberstam
- Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, United States
- Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, Connecticut, United States
| | - Briana Robles
- Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, United States
- Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, Connecticut, United States
- University of Florida, Gainesville, Florida, United States
| | - Joshua D Rabinowitz
- Department of Molecular Biology, Princeton University, Princeton, New Jersey, United States
- Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, United States
- Department of Chemistry, Princeton University, Princeton, New Jersey, United States
- Ludwig Institute for Cancer Research, Princeton, New Jersey, United States
| | - Rachel J Perry
- Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, United States
- Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, Connecticut, United States
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12
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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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13
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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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14
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Stacpoole PW, McCall CE. The pyruvate dehydrogenase complex: Life's essential, vulnerable and druggable energy homeostat. Mitochondrion 2023; 70:59-102. [PMID: 36863425 DOI: 10.1016/j.mito.2023.02.007] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 01/30/2023] [Accepted: 02/13/2023] [Indexed: 03/04/2023]
Abstract
Found in all organisms, pyruvate dehydrogenase complexes (PDC) are the keystones of prokaryotic and eukaryotic energy metabolism. In eukaryotic organisms these multi-component megacomplexes provide a crucial mechanistic link between cytoplasmic glycolysis and the mitochondrial tricarboxylic acid (TCA) cycle. As a consequence, PDCs also influence the metabolism of branched chain amino acids, lipids and, ultimately, oxidative phosphorylation (OXPHOS). PDC activity is an essential determinant of the metabolic and bioenergetic flexibility of metazoan organisms in adapting to changes in development, nutrient availability and various stresses that challenge maintenance of homeostasis. This canonical role of the PDC has been extensively probed over the past decades by multidisciplinary investigations into its causal association with diverse physiological and pathological conditions, the latter making the PDC an increasingly viable therapeutic target. Here we review the biology of the remarkable PDC and its emerging importance in the pathobiology and treatment of diverse congenital and acquired disorders of metabolic integration.
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Affiliation(s)
- Peter W Stacpoole
- Department of Medicine (Division of Endocrinology, Metabolism and Diabetes), and Department of Biochemistry and Molecular Biology, University of Florida, College of Medicine, Gainesville, FL, United States.
| | - Charles E McCall
- Department of Internal Medicine and Translational Sciences, and Department of Microbiology and Immunology, Wake Forest University School of Medicine, Winston-Salem, NC, United States
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15
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The "Superoncogene" Myc at the Crossroad between Metabolism and Gene Expression in Glioblastoma Multiforme. Int J Mol Sci 2023; 24:ijms24044217. [PMID: 36835628 PMCID: PMC9966483 DOI: 10.3390/ijms24044217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 02/10/2023] [Accepted: 02/16/2023] [Indexed: 02/22/2023] Open
Abstract
The concept of the Myc (c-myc, n-myc, l-myc) oncogene as a canonical, DNA-bound transcription factor has consistently changed over the past few years. Indeed, Myc controls gene expression programs at multiple levels: directly binding chromatin and recruiting transcriptional coregulators; modulating the activity of RNA polymerases (RNAPs); and drawing chromatin topology. Therefore, it is evident that Myc deregulation in cancer is a dramatic event. Glioblastoma multiforme (GBM) is the most lethal, still incurable, brain cancer in adults, and it is characterized in most cases by Myc deregulation. Metabolic rewiring typically occurs in cancer cells, and GBM undergoes profound metabolic changes to supply increased energy demand. In nontransformed cells, Myc tightly controls metabolic pathways to maintain cellular homeostasis. Consistently, in Myc-overexpressing cancer cells, including GBM cells, these highly controlled metabolic routes are affected by enhanced Myc activity and show substantial alterations. On the other hand, deregulated cancer metabolism impacts Myc expression and function, placing Myc at the intersection between metabolic pathway activation and gene expression. In this review paper, we summarize the available information on GBM metabolism with a specific focus on the control of the Myc oncogene that, in turn, rules the activation of metabolic signals, ensuring GBM growth.
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16
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Marco-Brualla J, de Miguel D, Martínez-Lostao L, Anel A. DR5 Up-Regulation Induced by Dichloroacetate Sensitizes Tumor Cells to Lipid Nanoparticles Decorated with TRAIL. J Clin Med 2023; 12:jcm12020608. [PMID: 36675536 PMCID: PMC9864242 DOI: 10.3390/jcm12020608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 01/04/2023] [Accepted: 01/10/2023] [Indexed: 01/14/2023] Open
Abstract
Cancer resistance to treatments is a challenge that researchers constantly seek to overcome. For instance, TNF-related apoptosis-inducing ligand (TRAIL) is a potential good prospect as an anti-cancer therapy, as it attacks tumor cells but not normal cells. However, treatments based in soluble TRAIL provided incomplete clinical results and diverse formulations have been developed to improve its bioactivity. In previous works, we generated a new TRAIL formulation based in its attachment to the surface of unilamellar nanoliposomes (LUV-TRAIL). This formulation greatly increased apoptosis in a wide selection of tumor cell types, albeit a few of them remained resistant. On the other hand, it has been described that a metabolic shift in cancer cells can also alter its sensitivity to other treatments. In this work, we sought to increase the sensitivity of several tumor cell types resistant to LUV-TRAIL by previous exposure to the metabolic drug dichloroacetate (DCA), which forces oxidative phosphorylation. Results showed that DCA + LUV-TRAIL had a synergistic effect on both lung adenocarcinoma A549, colorectal HT29, and breast cancer MCF7 cells. Despite DCA inducing intracellular changes in a cell-type specific way, the increase in cell death by apoptosis was clearly correlated with an increase in death receptor 5 (DR5) surface expression in all cell lines. Therefore, DCA-induced metabolic shift emerges as a suitable option to overcome TRAIL resistance in cancer cells.
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Affiliation(s)
- Joaquín Marco-Brualla
- Apoptosis, Immunity and Cancer Group, Department of Biochemistry and Molecular and Cell Biology, Aragon Health Research Institute (IIS-Aragón) & University of Zaragoza, 50009 Zargoza, Spain
| | - Diego de Miguel
- Apoptosis, Immunity and Cancer Group, Department of Biochemistry and Molecular and Cell Biology, Aragon Health Research Institute (IIS-Aragón) & University of Zaragoza, 50009 Zargoza, Spain
| | | | - Alberto Anel
- Apoptosis, Immunity and Cancer Group, Department of Biochemistry and Molecular and Cell Biology, Aragon Health Research Institute (IIS-Aragón) & University of Zaragoza, 50009 Zargoza, Spain
- Correspondence:
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17
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Cunha A, Rocha AC, Barbosa F, Baião A, Silva P, Sarmento B, Queirós O. Glycolytic Inhibitors Potentiated the Activity of Paclitaxel and Their Nanoencapsulation Increased Their Delivery in a Lung Cancer Model. Pharmaceutics 2022; 14:pharmaceutics14102021. [PMID: 36297455 PMCID: PMC9611291 DOI: 10.3390/pharmaceutics14102021] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 09/16/2022] [Accepted: 09/19/2022] [Indexed: 11/17/2022] Open
Abstract
Antiglycolytic agents inhibit cell metabolism and modify the tumor’s microenvironment, affecting chemotherapy resistance mechanisms. In this work, we studied the effect of the glycolytic inhibitors 3-bromopyruvate (3BP), dichloroacetate (DCA) and 2-deoxyglucose (2DG) on cancer cell properties and on the multidrug resistance phenotype, using lung cancer cells as a model. All compounds led to the loss of cell viability, with different effects on the cell metabolism, migration and proliferation, depending on the drug and cell line assayed. DCA was the most promising compound, presenting the highest inhibitory effect on cell metabolism and proliferation. DCA treatment led to decreased glucose consumption and ATP and lactate production in both A549 and NCI-H460 cell lines. Furthermore, the DCA pretreatment sensitized the cancer cells to Paclitaxel (PTX), a conventional chemotherapeutic drug, with a 2.7-fold and a 10-fold decrease in PTX IC50 values in A549 and NCI-H460 cell lines, respectively. To increase the intracellular concentration of DCA, thereby potentiating its effect, DCA-loaded poly(lactic-co-glycolic acid) nanoparticles were produced. At higher DCA concentrations, encapsulation was found to increase its toxicity. These results may help find a new treatment strategy through combined therapy, which could open doors to new treatment approaches.
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Affiliation(s)
- Andrea Cunha
- UNIPRO—Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences (IUCS), CESPU, 4585-116 Gandra, Portugal
| | - Ana Catarina Rocha
- UNIPRO—Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences (IUCS), CESPU, 4585-116 Gandra, Portugal
- DCM—Departamento de Ciências Médicas, Universidade de Aveiro, 3810-193 Aveiro, Portugal
| | - Flávia Barbosa
- UNIPRO—Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences (IUCS), CESPU, 4585-116 Gandra, Portugal
- DCM—Departamento de Ciências Médicas, Universidade de Aveiro, 3810-193 Aveiro, Portugal
| | - Ana Baião
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
- INEB—Instituto de Engenharia Biomédica, Universidade do Porto, 4200-135 Porto, Portugal
- ICBAS—Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, 4050-313 Porto, Portugal
| | - Patrícia Silva
- UNIPRO—Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences (IUCS), CESPU, 4585-116 Gandra, Portugal
- TOXRUN—Toxicology Research Unit, University Institute of Health Sciences (IUCS), CESPU, 3810-193 Gandra, Portugal
| | - Bruno Sarmento
- UNIPRO—Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences (IUCS), CESPU, 4585-116 Gandra, Portugal
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
- INEB—Instituto de Engenharia Biomédica, Universidade do Porto, 4200-135 Porto, Portugal
| | - Odília Queirós
- UNIPRO—Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences (IUCS), CESPU, 4585-116 Gandra, Portugal
- Correspondence:
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18
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Shi X, Yang J, Deng S, Xu H, Wu D, Zeng Q, Wang S, Hu T, Wu F, Zhou H. TGF-β signaling in the tumor metabolic microenvironment and targeted therapies. J Hematol Oncol 2022; 15:135. [PMID: 36115986 PMCID: PMC9482317 DOI: 10.1186/s13045-022-01349-6] [Citation(s) in RCA: 112] [Impact Index Per Article: 37.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 08/24/2022] [Indexed: 12/30/2022] Open
Abstract
AbstractTransforming growth factor-β (TGF-β) signaling has a paradoxical role in cancer progression, and it acts as a tumor suppressor in the early stages but a tumor promoter in the late stages of cancer. Once cancer cells are generated, TGF-β signaling is responsible for the orchestration of the immunosuppressive tumor microenvironment (TME) and supports cancer growth, invasion, metastasis, recurrence, and therapy resistance. These progressive behaviors are driven by an “engine” of the metabolic reprogramming in cancer. Recent studies have revealed that TGF-β signaling regulates cancer metabolic reprogramming and is a metabolic driver in the tumor metabolic microenvironment (TMME). Intriguingly, TGF-β ligands act as an “endocrine” cytokine and influence host metabolism. Therefore, having insight into the role of TGF-β signaling in the TMME is instrumental for acknowledging its wide range of effects and designing new cancer treatment strategies. Herein, we try to illustrate the concise definition of TMME based on the published literature. Then, we review the metabolic reprogramming in the TMME and elaborate on the contribution of TGF-β to metabolic rewiring at the cellular (intracellular), tissular (intercellular), and organismal (cancer-host) levels. Furthermore, we propose three potential applications of targeting TGF-β-dependent mechanism reprogramming, paving the way for TGF-β-related antitumor therapy from the perspective of metabolism.
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19
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The Pyruvate Dehydrogenase Complex Mitigates LPS-Induced Endothelial Barrier Dysfunction by Metabolic Regulation. Shock 2022; 57:308-317. [PMID: 35759309 DOI: 10.1097/shk.0000000000001931] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
ABSTRACT Sepsis is a fatal health issue induced by an aberrant host response to infection, and it correlates with organ damage and a high mortality rate. Endothelial barrier dysfunction and subsequent capillary leakage play major roles in sepsis-induced multiorgan dysfunction. Anaerobic glycolysis is the primary metabolic mode in sepsis and the pyruvate dehydrogenase complex (PDHC) serves as a critical hub in energy regulation. Therefore, it is important to understand the role of PDHC in metabolic regulation during the development of sepsis-induced endothelial barrier dysfunction.In present study, human umbilical vein endothelial cells (HUVECs) and C57 BL/6 mice were treated with lipopolysaccharide (LPS) as models of endotoxemia. LPS increased basal glycolysis, compensatory glycolysis, and lactate secretion, indicating increased glycolysis level in endothelial cells (ECs). Activation of PDHC with dichloroacetate (DCA) reversed LPS-induced glycolysis, allowing PDHC to remain in the active dephosphorylated state, thereby preventing lactic acid production and HUVECs monolayers barrier dysfunction, as assessed by transendothelial electrical resistance and Fluorescein Isothiocyanate-labeled dextran. The in vivo study also showed that the lactate level and vascular permeability were increased in LPS-treated mice, but pretreatment with DCA attenuated these increases. The LPS-treated HUVEC model showed that DCA reversed LPS-induced phosphorylation of pyruvate dehydrogenase E1α Ser293 and Ser300 to restore PDHC activity. Immunoprecipitation results showed that LPS treatment increased the acetylation level of PDH E1α in HUVECs.Our study suggested that activation of PDHC may represent a therapeutic target for treatment of LPS-induced endothelial barrier dysfunction.
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Pająk B. Looking for the Holy Grail—Drug Candidates for Glioblastoma Multiforme Chemotherapy. Biomedicines 2022; 10:biomedicines10051001. [PMID: 35625738 PMCID: PMC9138518 DOI: 10.3390/biomedicines10051001] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 04/23/2022] [Accepted: 04/25/2022] [Indexed: 02/05/2023] Open
Abstract
Glioblastoma multiforme (GBM) is the deadliest and the most heterogeneous brain cancer. The median survival time of GBM patients is approximately 8 to 15 months after initial diagnosis. GBM development is determined by numerous signaling pathways and is considered one of the most challenging and complicated-to-treat cancer types. Standard GBM therapy consist of surgery followed by radiotherapy or chemotherapy, and combined treatment. Current standard of care (SOC) does not offer a significant chance for GBM patients to combat cancer, and the selection of available drugs is limited. For almost 20 years, there has been only one drug, Temozolomide (TMZ), approved as a first-line GBM treatment. Due to the limited efficacy of TMZ and the high rate of resistant patients, the implementation of new chemotherapeutics is highly desired. However, due to the unique properties of GBM, many challenges still need to be overcome before reaching a ‘breakthrough’. This review article describes the most recent compounds introduced into clinical trials as drug candidates for GBM chemotherapy.
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Affiliation(s)
- Beata Pająk
- Independent Laboratory of Genetics and Molecular Biology, Kaczkowski Military Institute of Hygiene and Epidemiology, Kozielska 4, 01-163 Warsaw, Poland
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21
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Vang S, Cochran P, Sebastian Domingo J, Krick S, Barnes JW. The Glycobiology of Pulmonary Arterial Hypertension. Metabolites 2022; 12:metabo12040316. [PMID: 35448503 PMCID: PMC9026683 DOI: 10.3390/metabo12040316] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 03/23/2022] [Accepted: 03/28/2022] [Indexed: 01/27/2023] Open
Abstract
Pulmonary arterial hypertension (PAH) is a progressive pulmonary vascular disease of complex etiology. Cases of PAH that do not receive therapy after diagnosis have a low survival rate. Multiple reports have shown that idiopathic PAH, or IPAH, is associated with metabolic dysregulation including altered bioavailability of nitric oxide (NO) and dysregulated glucose metabolism. Multiple processes such as increased proliferation of pulmonary vascular cells, angiogenesis, apoptotic resistance, and vasoconstriction may be regulated by the metabolic changes demonstrated in PAH. Recent reports have underscored similarities between metabolic abnormalities in cancer and IPAH. In particular, increased glucose uptake and altered glucose utilization have been documented and have been linked to the aforementioned processes. We were the first to report a link between altered glucose metabolism and changes in glycosylation. Subsequent reports have highlighted similar findings, including a potential role for altered metabolism and aberrant glycosylation in IPAH pathogenesis. This review will detail research findings that demonstrate metabolic dysregulation in PAH with an emphasis on glycobiology. Furthermore, this report will illustrate the similarities in the pathobiology of PAH and cancer and highlight the novel findings that researchers have explored in the field.
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Tiersma JF, Evers B, Bakker BM, Jalving M, de Jong S. Pyruvate Dehydrogenase Kinase Inhibition by Dichloroacetate in Melanoma Cells Unveils Metabolic Vulnerabilities. Int J Mol Sci 2022; 23:ijms23073745. [PMID: 35409102 PMCID: PMC8999016 DOI: 10.3390/ijms23073745] [Citation(s) in RCA: 5] [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: 01/31/2022] [Revised: 03/21/2022] [Accepted: 03/25/2022] [Indexed: 12/03/2022] Open
Abstract
Melanoma is characterized by high glucose uptake, partially mediated through elevated pyruvate dehydrogenase kinase (PDK), making PDK a potential treatment target in melanoma. We aimed to reduce glucose uptake in melanoma cell lines through PDK inhibitors dichloroacetate (DCA) and AZD7545 and through PDK knockdown, to inhibit cell growth and potentially unveil metabolic co-vulnerabilities resulting from PDK inhibition. MeWo cells were most sensitive to DCA, while SK-MEL-2 was the least sensitive, with IC50 values ranging from 13.3 to 27.0 mM. DCA strongly reduced PDH phosphorylation and increased the oxygen consumption rate:extracellular acidification rate (OCR:ECAR) ratio up to 6-fold. Knockdown of single PDK isoforms had similar effects on PDH phosphorylation and OCR:ECAR ratio as DCA but did not influence sensitivity to DCA. Growth inhibition by DCA was synergistic with the glutaminase inhibitor CB-839 (2- to 5-fold sensitization) and with diclofenac, known to inhibit monocarboxylate transporters (MCTs) (3- to 8-fold sensitization). CB-839 did not affect the OCR:ECAR response to DCA, whereas diclofenac strongly inhibited ECAR and further increased the OCR:ECAR ratio. We conclude that in melanoma cell lines, DCA reduces proliferation through reprogramming of cellular metabolism and synergizes with other metabolically targeted drugs.
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Affiliation(s)
- Jiske F. Tiersma
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands;
| | - 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; (B.E.); (B.M.B.)
| | - 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; (B.E.); (B.M.B.)
| | - Mathilde Jalving
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands;
- Correspondence: (M.J.); (S.d.J.); Tel.: +31-50-3615692 (M.J.); +31-50-3612964 (S.d.J.)
| | - Steven de Jong
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands;
- Correspondence: (M.J.); (S.d.J.); Tel.: +31-50-3615692 (M.J.); +31-50-3612964 (S.d.J.)
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23
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Phase II study of dichloroacetate, an inhibitor of pyruvate dehydrogenase, in combination with chemoradiotherapy for unresected, locally advanced head and neck squamous cell carcinoma. Invest New Drugs 2022; 40:622-633. [DOI: 10.1007/s10637-022-01235-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 03/11/2022] [Indexed: 12/14/2022]
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Kanan Y, Hackett SF, Taneja K, Khan M, Campochiaro PA. Oxidative stress-induced alterations in retinal glucose metabolism in Retinitis Pigmentosa. Free Radic Biol Med 2022; 181:143-153. [PMID: 35134532 PMCID: PMC8891093 DOI: 10.1016/j.freeradbiomed.2022.01.032] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Revised: 01/21/2022] [Accepted: 01/31/2022] [Indexed: 10/19/2022]
Abstract
Retinitis pigmentosa occurs due to mutations that cause rod photoreceptor degeneration. Once most rods are lost, gradual degeneration of cone photoreceptors occurs. Oxidative damage and abnormal glucose metabolism have been implicated as contributors to cone photoreceptor death. Herein, we show increased phosphorylation of key enzymes of glucose metabolism in the retinas of rd10 mice, a model of RP, and retinas of wild type mice with paraquat-induced oxidative stress, thereby inhibiting these key enzymes. Dietary supplementation with glucose and pyruvate failed to overcome the inhibition, but increased reducing equivalents in the retina and improved cone function and survival. Dichloroacetate reversed the increased phosphorylation of pyruvate dehydrogenase in rd10 retina and increased histone acetylation and levels of TP53-induced glycolysis and apoptosis regulator (TIGAR), which redirected glucose metabolism toward the pentose phosphate pathway. These data indicate that oxidative stress induced damage can be reversed by shifting glycolytic intermediates toward the pentose phosphate pathway which increases reducing equivalents and provides photoreceptor protection.
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Affiliation(s)
- Yogita Kanan
- The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Sean F Hackett
- The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Kamil Taneja
- The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Mahmood Khan
- The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Peter A Campochiaro
- The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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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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Zeng Z, Huang Q, Mao L, Wu J, An S, Chen Z, Zhang W. The Pyruvate Dehydrogenase Complex in Sepsis: Metabolic Regulation and Targeted Therapy. Front Nutr 2022; 8:783164. [PMID: 34970577 PMCID: PMC8712327 DOI: 10.3389/fnut.2021.783164] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Accepted: 11/24/2021] [Indexed: 12/24/2022] Open
Abstract
Anaerobic glycolysis is the process by which glucose is broken down into pyruvate and lactate and is the primary metabolic pathway in sepsis. The pyruvate dehydrogenase complex (PDHC) is a multienzyme complex that serves as a critical hub in energy metabolism. Under aerobic conditions, pyruvate translocates to mitochondria, where it is oxidized into acetyl-CoA through the activation of PDHC, thereby accelerating aerobic oxidation. Both phosphorylation and acetylation affect PDHC activity and, consequently, the regulation of energy metabolism. The mechanisms underlying the protective effects of PDHC in sepsis involve the regulation on the balance of lactate, the release of inflammatory mediators, the remodeling of tricarboxylic acid (TCA) cycle, as well as on the improvement of lipid and energy metabolism. Therapeutic drugs that target PDHC activation for sepsis treatment include dichloroacetate, thiamine, amrinone, TNF-binding protein, and ciprofloxacin. In this review, we summarize the recent findings regarding the metabolic regulation of PDHC in sepsis and the therapies targeting PDHC for the treatment of this condition.
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Affiliation(s)
- Zhenhua Zeng
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Qiaobing Huang
- Department of Pathophysiology, Guangdong Provincial Key Lab of Shock and Microcirculation, Southern Medical University, Guangzhou, China
| | - Liangfeng Mao
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jie Wu
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Sheng An
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhongqing Chen
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Weijin Zhang
- Department of Internal Medicine General Ward, Shantou Central Hospital, Shantou, China
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Mitchel J, Bajaj P, Patil K, Gunnarson A, Pourchet E, Kim YN, Skolnick J, Pai SB. Computational Identification of Stearic Acid as a Potential PDK1 Inhibitor and In Vitro Validation of Stearic Acid as Colon Cancer Therapeutic in Combination with 5-Fluorouracil. Cancer Inform 2021; 20:11769351211065979. [PMID: 34924752 PMCID: PMC8679029 DOI: 10.1177/11769351211065979] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 11/22/2021] [Indexed: 12/02/2022] Open
Abstract
Background: Colorectal cancer is the third largest cause of cancer-related mortality
worldwide. Although current treatments with chemotherapeutics have allowed
for management of colorectal cancer, additional novel treatments are
essential. Intervening with the metabolic reprogramming observed in cancers
called “Warburg Effect,” is one of the novel strategies considered to combat
cancers. In the metabolic reprogramming pathway, pyruvate dehydrogenase
kinase (PDK1) plays a pivotal role. Identification and characterization of a
PDK1 inhibitor is of paramount importance. Further, for efficacious
treatment of colorectal cancers, combinatorial regimens are essential. To
this end, we opted to identify a PDK1 inhibitor using computational
structure-based drug design FINDSITEcomb and perform
combinatorial studies with 5-FU for efficacious treatment of colorectal
cancers. Methods: Using computational structure-based drug design FINDSITEcomb,
stearic acid (SA) was identified as a possible PDK1 inhibitor. Elucidation
of the mechanism of action of SA was performed using flow cytometry,
clonogenic assays. Results: When the growth inhibitory potential of SA was tested on colorectal
adenocarcinoma (DLD-1) cells, a 50% inhibitory concentration
(IC50) of 60 µM was recorded. Moreover, SA inhibited the
proliferation potential of DLD-1 cells as shown by the clonogenic assay and
there was a sustained response even after withdrawal of the compound.
Elucidation of the mechanism of action revealed, that the inhibitory effect
of SA was through the programmed cell death pathway. There was increase in
the number of apoptotic and multicaspase positive cells. SA also impacted
the levels of the cell survival protein Bcl-2. With the aim of achieving
improved treatment for colorectal cancer, we opted to combine 5-fluorouracil
(5-FU), the currently used drug in the clinic, with SA. Combining SA with
5-FU, revealed a synergistic effect in which the IC50 of 5-FU
decreased from 25 to 6 µM upon combination with 60 µM SA. Further, SA did
not inhibit non-tumorigenic NIH-3T3 proliferation. Conclusions: We envision that this significant decrease in the IC50 of 5-FU
could translate into less side effects of 5-FU and increase the efficacy of
the treatment due to the multifaceted action of SA. The data generated from
the current studies on the inhibition of colorectal adenocarcinoma by SA
discovered by the use of the computational program as well as synergistic
action with 5-FU should open up novel therapeutic options for the management
of colorectal adenocarcinomas.
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Affiliation(s)
- Jonathan Mitchel
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
| | - Pratima Bajaj
- School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, USA
| | - Ketki Patil
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
| | - Austin Gunnarson
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
| | - Emilie Pourchet
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
| | - Yoo Na Kim
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
| | - Jeffrey Skolnick
- School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, USA
| | - S Balakrishna Pai
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA.,School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, USA
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Kaur J, Bhattacharyya S. Cancer Stem Cells: Metabolic Characterization for Targeted Cancer Therapy. Front Oncol 2021; 11:756888. [PMID: 34804950 PMCID: PMC8602811 DOI: 10.3389/fonc.2021.756888] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 10/18/2021] [Indexed: 02/02/2023] Open
Abstract
The subpopulation of cancer stem cells (CSCs) within tumor bulk are known for tumor recurrence and metastasis. CSCs show intrinsic resistance to conventional therapies and phenotypic plasticity within the tumor, which make these a difficult target for conventional therapies. CSCs have different metabolic phenotypes based on their needs as compared to the bulk cancer cells. CSCs show metabolic plasticity and constantly alter their metabolic state between glycolysis and oxidative metabolism (OXPHOS) to adapt to scarcity of nutrients and therapeutic stress. The metabolic characteristics of CSCs are distinct compared to non-CSCs and thus provide an opportunity to devise more effective strategies to target CSCs. Mechanism for metabolic switch in CSCs is still unravelled, however existing evidence suggests that tumor microenvironment affects the metabolic phenotype of cancer cells. Understanding CSCs metabolism may help in discovering new and effective clinical targets to prevent cancer relapse and metastasis. This review summarises the current knowledge of CSCs metabolism and highlights the potential targeted treatment strategies.
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Affiliation(s)
- Jasmeet Kaur
- Department of Biophysics, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Shalmoli Bhattacharyya
- Department of Biophysics, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
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van Doorn CLR, Schouten GK, van Veen S, Walburg KV, Esselink JJ, Heemskerk MT, Vrieling F, Ottenhoff THM. Pyruvate Dehydrogenase Kinase Inhibitor Dichloroacetate Improves Host Control of Salmonella enterica Serovar Typhimurium Infection in Human Macrophages. Front Immunol 2021; 12:739938. [PMID: 34552598 PMCID: PMC8450447 DOI: 10.3389/fimmu.2021.739938] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 08/23/2021] [Indexed: 01/11/2023] Open
Abstract
Global increases in the prevalence of antimicrobial resistance highlight the urgent need for novel strategies to combat infectious diseases. Recent studies suggest that host metabolic pathways play a key role in host control of intracellular bacterial pathogens. In this study we explored the potential of targeting host metabolic pathways for innovative host-directed therapy (HDT) against intracellular bacterial infections. Through gene expression profiling in human macrophages, pyruvate metabolism was identified as potential key pathway involved in Salmonella enterica serovar Typhimurium (Stm) infections. Next, the effect of targeting pyruvate dehydrogenase kinases (PDKs) - which are regulators of the metabolic checkpoint pyruvate dehydrogenase complex (PDC) - on macrophage function and bacterial control was studied. Chemical inhibition of PDKs by dichloroacetate (DCA) induced PDC activation and was accompanied with metabolic rewiring in classically activated macrophages (M1) but not in alternatively activated macrophages (M2), suggesting cell-type specific effects of dichloroacetate on host metabolism. Furthermore, DCA treatment had minor impact on cytokine and chemokine secretion on top of infection, but induced significant ROS production by M1 and M2. DCA markedly and rapidly reduced intracellular survival of Stm, but interestingly not Mycobacterium tuberculosis, in human macrophages in a host-directed manner. In conclusion, DCA represents a promising novel HDT compound targeting pyruvate metabolism for the treatment of Stm infections.
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Capozza M, Anemone A, Dhakan C, Della Peruta M, Bracesco M, Zullino S, Villano D, Terreno E, Longo DL, Aime S. GlucoCEST MRI for the Evaluation Response to Chemotherapeutic and Metabolic Treatments in a Murine Triple-Negative Breast Cancer: A Comparison with[ 18F]F-FDG-PET. Mol Imaging Biol 2021; 24:126-134. [PMID: 34383241 DOI: 10.1007/s11307-021-01637-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 06/30/2021] [Accepted: 07/28/2021] [Indexed: 12/24/2022]
Abstract
PURPOSE Triple-negative breast cancer (TNBC) patients have usually poor outcome after chemotherapy and early prediction of therapeutic response would be helpful. [18F]F-FDG-PET/CT acquisitions are often carried out to monitor variation in metabolic activity associated with response to the therapy, despite moderate accuracy and radiation exposure limit its application. The glucoCEST technique relies on the use of unlabelled D-glucose to assess glucose uptake with conventional MRI scanners and is currently under active investigations at clinical level. This work aims at validating the potential of MRI-glucoCEST in monitoring the therapeutic responses in a TNBC tumor murine model. PROCEDURES Breast tumor (4T1)-bearing mice were treated with doxorubicin or dichloroacetate for 1 week. PET/CT with [18F]F-FDG and MRI-glucoCEST were performed at baseline and after 3 cycles of treatment. Metabolic changes measured with [18F]F-FDG-PET and glucoCEST were compared and evaluated with changes in tumor volumes. RESULTS Doxorubicin-treated mice showed a significant decrease in tumor growth when compared to the control group. GlucoCEST imaging provided metabolic response after three cycles of treatment. Conversely, no variations were detected in [18F]F-FDG uptake. Dichloroacetate-treated mice did not show any decrease either in tumor volume or in tumor metabolic activity as assessed by both glucoCEST and [18F]F-FDG-PET. CONCLUSIONS Metabolic changes during doxorubicin treatment can be predicted by glucoCEST imaging that appears more sensitive than [18F]F-FDG-PET in reporting on therapeutic response. These findings support the view that glucoCEST may be a sensitive technique for monitoring metabolic response, but future studies are needed to explore the accuracy of this approach in other tumor types and treatments.
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Affiliation(s)
- Martina Capozza
- Center for Preclinical Imaging, Department of Molecular Biotechnology and Health Sciences, University of Turin, Via Nizza, 52, Turin, 10126, Italy
| | - Annasofia Anemone
- Molecular Imaging Center, Department of Molecular Biotechnology and Health Sciences, University of Turin, Via Nizza, 52, Turin, 10126, Italy
| | - Chetan Dhakan
- Institute of Biostructures and Bioimaging (IBB), National Research Council of Italy (CNR), Via Nizza 52, Turin, 10126, Italy
| | - Melania Della Peruta
- Center for Preclinical Imaging, Department of Molecular Biotechnology and Health Sciences, University of Turin, Via Nizza, 52, Turin, 10126, Italy
| | - Martina Bracesco
- Center for Preclinical Imaging, Department of Molecular Biotechnology and Health Sciences, University of Turin, Via Nizza, 52, Turin, 10126, Italy
| | - Sara Zullino
- Molecular Imaging Center, Department of Molecular Biotechnology and Health Sciences, University of Turin, Via Nizza, 52, Turin, 10126, Italy
| | - Daisy Villano
- Molecular Imaging Center, Department of Molecular Biotechnology and Health Sciences, University of Turin, Via Nizza, 52, Turin, 10126, Italy
| | - Enzo Terreno
- Center for Preclinical Imaging, Department of Molecular Biotechnology and Health Sciences, University of Turin, Via Nizza, 52, Turin, 10126, Italy.,Molecular Imaging Center, Department of Molecular Biotechnology and Health Sciences, University of Turin, Via Nizza, 52, Turin, 10126, Italy.,Institute of Biostructures and Bioimaging (IBB), National Research Council of Italy (CNR), Via Nizza 52, Turin, 10126, Italy
| | - Dario Livio Longo
- Institute of Biostructures and Bioimaging (IBB), National Research Council of Italy (CNR), Via Nizza 52, Turin, 10126, Italy
| | - Silvio Aime
- Molecular Imaging Center, Department of Molecular Biotechnology and Health Sciences, University of Turin, Via Nizza, 52, Turin, 10126, Italy.,Institute of Biostructures and Bioimaging (IBB), National Research Council of Italy (CNR), Via Nizza 52, Turin, 10126, Italy
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Mosier JA, Schwager SC, Boyajian DA, Reinhart-King CA. Cancer cell metabolic plasticity in migration and metastasis. Clin Exp Metastasis 2021; 38:343-359. [PMID: 34076787 DOI: 10.1007/s10585-021-10102-1] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Accepted: 05/08/2021] [Indexed: 12/13/2022]
Abstract
Metabolic reprogramming is a hallmark of cancer metastasis in which cancer cells manipulate their metabolic profile to meet the dynamic energetic requirements of the tumor microenvironment. Though cancer cell proliferation and migration through the extracellular matrix are key steps of cancer progression, they are not necessarily fueled by the same metabolites and energy production pathways. The two main metabolic pathways cancer cells use to derive energy from glucose, glycolysis and oxidative phosphorylation, are preferentially and plastically utilized by cancer cells depending on both their intrinsic metabolic properties and their surrounding environment. Mechanical factors in the microenvironment, such as collagen density, pore size, and alignment, and biochemical factors, such as oxygen and glucose availability, have been shown to influence both cell migration and glucose metabolism. As cancer cells have been identified as preferentially utilizing glycolysis or oxidative phosphorylation based on heterogeneous intrinsic or extrinsic factors, the relationship between cancer cell metabolism and metastatic potential is of recent interest. Here, we review current in vitro and in vivo findings in the context of cancer cell metabolism during migration and metastasis and extrapolate potential clinical applications of this work that could aid in diagnosing and tracking cancer progression in vivo by monitoring metabolism. We also review current progress in the development of a variety of metabolically targeted anti-metastatic drugs, both in clinical trials and approved for distribution, and highlight potential routes for incorporating our recent understanding of metabolic plasticity into therapeutic directions. By further understanding cancer cell energy production pathways and metabolic plasticity, more effective and successful clinical imaging and therapeutics can be developed to diagnose, target, and inhibit metastasis.
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Affiliation(s)
- Jenna A Mosier
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA
| | - Samantha C Schwager
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA
| | - David A Boyajian
- Department of Radiology, Weill Cornell Medical College, New York, NY, USA
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Targeting Glucose Metabolism of Cancer Cells with Dichloroacetate to Radiosensitize High-Grade Gliomas. Int J Mol Sci 2021; 22:7265. [PMID: 34298883 PMCID: PMC8305417 DOI: 10.3390/ijms22147265;] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
As the cornerstone of high-grade glioma (HGG) treatment, radiotherapy temporarily controls tumor cells via inducing oxidative stress and subsequent DNA breaks. However, almost all HGGs recur within months. Therefore, it is important to understand the underlying mechanisms of radioresistance, so that novel strategies can be developed to improve the effectiveness of radiotherapy. While currently poorly understood, radioresistance appears to be predominantly driven by altered metabolism and hypoxia. Glucose is a central macronutrient, and its metabolism is rewired in HGG cells, increasing glycolytic flux to produce energy and essential metabolic intermediates, known as the Warburg effect. This altered metabolism in HGG cells not only supports cell proliferation and invasiveness, but it also contributes significantly to radioresistance. Several metabolic drugs have been used as a novel approach to improve the radiosensitivity of HGGs, including dichloroacetate (DCA), a small molecule used to treat children with congenital mitochondrial disorders. DCA reverses the Warburg effect by inhibiting pyruvate dehydrogenase kinases, which subsequently activates mitochondrial oxidative phosphorylation at the expense of glycolysis. This effect is thought to block the growth advantage of HGGs and improve the radiosensitivity of HGG cells. This review highlights the main features of altered glucose metabolism in HGG cells as a contributor to radioresistance and describes the mechanism of action of DCA. Furthermore, we will summarize recent advances in DCA's pre-clinical and clinical studies as a radiosensitizer and address how these scientific findings can be translated into clinical practice to improve the management of HGG patients.
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Cook KM, Shen H, McKelvey KJ, Gee HE, Hau E. Targeting Glucose Metabolism of Cancer Cells with Dichloroacetate to Radiosensitize High-Grade Gliomas. Int J Mol Sci 2021; 22:ijms22147265. [PMID: 34298883 PMCID: PMC8305417 DOI: 10.3390/ijms22147265] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 06/30/2021] [Accepted: 07/01/2021] [Indexed: 02/06/2023] Open
Abstract
As the cornerstone of high-grade glioma (HGG) treatment, radiotherapy temporarily controls tumor cells via inducing oxidative stress and subsequent DNA breaks. However, almost all HGGs recur within months. Therefore, it is important to understand the underlying mechanisms of radioresistance, so that novel strategies can be developed to improve the effectiveness of radiotherapy. While currently poorly understood, radioresistance appears to be predominantly driven by altered metabolism and hypoxia. Glucose is a central macronutrient, and its metabolism is rewired in HGG cells, increasing glycolytic flux to produce energy and essential metabolic intermediates, known as the Warburg effect. This altered metabolism in HGG cells not only supports cell proliferation and invasiveness, but it also contributes significantly to radioresistance. Several metabolic drugs have been used as a novel approach to improve the radiosensitivity of HGGs, including dichloroacetate (DCA), a small molecule used to treat children with congenital mitochondrial disorders. DCA reverses the Warburg effect by inhibiting pyruvate dehydrogenase kinases, which subsequently activates mitochondrial oxidative phosphorylation at the expense of glycolysis. This effect is thought to block the growth advantage of HGGs and improve the radiosensitivity of HGG cells. This review highlights the main features of altered glucose metabolism in HGG cells as a contributor to radioresistance and describes the mechanism of action of DCA. Furthermore, we will summarize recent advances in DCA’s pre-clinical and clinical studies as a radiosensitizer and address how these scientific findings can be translated into clinical practice to improve the management of HGG patients.
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Affiliation(s)
- Kristina M. Cook
- Charles Perkins Centre, Faculty of Medicine and Health, University of Sydney, Sydney 2006, Australia; (H.S.); (K.J.M.); (H.E.G.); (E.H.)
- Correspondence: ; Tel.: +61-286274858
| | - Han Shen
- Charles Perkins Centre, Faculty of Medicine and Health, University of Sydney, Sydney 2006, Australia; (H.S.); (K.J.M.); (H.E.G.); (E.H.)
- Translational Radiation Biology and Oncology Laboratory, Centre for Cancer Research, Westmead Institute for Medical Research, Westmead 2145, Australia
| | - Kelly J. McKelvey
- Charles Perkins Centre, Faculty of Medicine and Health, University of Sydney, Sydney 2006, Australia; (H.S.); (K.J.M.); (H.E.G.); (E.H.)
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, University of Sydney, St. Leonards 2065, Australia
| | - Harriet E. Gee
- Charles Perkins Centre, Faculty of Medicine and Health, University of Sydney, Sydney 2006, Australia; (H.S.); (K.J.M.); (H.E.G.); (E.H.)
- Translational Radiation Biology and Oncology Laboratory, Centre for Cancer Research, Westmead Institute for Medical Research, Westmead 2145, Australia
- Sydney West Radiation Oncology Network, University of Sydney, Sydney 2006, Australia
- Children’s Medical Research Institute, Westmead 2145, Australia
| | - Eric Hau
- Charles Perkins Centre, Faculty of Medicine and Health, University of Sydney, Sydney 2006, Australia; (H.S.); (K.J.M.); (H.E.G.); (E.H.)
- Translational Radiation Biology and Oncology Laboratory, Centre for Cancer Research, Westmead Institute for Medical Research, Westmead 2145, Australia
- Sydney West Radiation Oncology Network, University of Sydney, Sydney 2006, Australia
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Kim CJ, Terado T, Tambe Y, Mukaisho KI, Kageyama S, Kawauchi A, Inoue H. Cryptotanshinone, a novel PDK 4 inhibitor, suppresses bladder cancer cell invasiveness via the mTOR/β‑catenin/N‑cadherin axis. Int J Oncol 2021; 59:40. [PMID: 33982789 PMCID: PMC8131085 DOI: 10.3892/ijo.2021.5220] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Accepted: 04/19/2021] [Indexed: 12/13/2022] Open
Abstract
The phosphorylation of pyruvate dehydrogenase (PDH) by pyruvate dehydrogenase kinase (PDK) 4 inhibits its ability to induce a glycolytic shift. PDK4 expression is upregulated in various types of human cancer. Because PDK4 regulation is critical for metabolic changes in cancer cells, it is an attractive target for cancer therapy given its ability to shift glucose metabolism. It was previously shown that a novel PDK4 inhibitor, cryptotanshinone (CPT), suppressed the three‑dimensional (3D)‑spheroid formation of pancreatic and colorectal cancer cells. In the present study, the effects of CPT on the invasiveness of bladder cancer cells were investigated. CPT significantly suppressed the invasiveness and 3D‑spheroid formation of T24 and J82 bladder cancer cells. CPT also suppressed the phosphorylation of PDH and β‑catenin, as well as the expression of N‑cadherin, which are all critical for inducing epithelial‑mesenchymal transition (EMT). The knockdown of β‑catenin or PDK4 using specific small interfering RNAs suppressed N‑cadherin expression and invasiveness in T24 cells. An mTOR inhibitor also suppressed the phosphorylation of β‑catenin and N‑cadherin expression. Furthermore, CPT injection significantly suppressed pancreatic tumor growth and peritoneal dissemination of highly metastatic SUIT‑2 pancreatic cancer cells in a mouse orthotopic pancreatic cancer model, without evident toxicity. Moreover, immunohistochemistry analyses demonstrated decreased β‑catenin expression in CPT‑treated pancreatic tumors compared with control tumors. Taken together, these results indicate that CPT reduced the invasiveness and metastasis of bladder cancer cells by suppressing EMT via the mTOR/β‑catenin/N‑cadherin pathway.
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Affiliation(s)
- Chul Jang Kim
- Department of Urology, Kohka Public Hospital, Minakuchi-cho, Kohka, Shiga 528-0074, Japan
- Department of Urology, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, Shiga 520-2192, Japan
| | - Tokio Terado
- Department of Stem Cell Biology and Regenerative Medicine, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, Shiga 520-2192, Japan
| | - Yukihiro Tambe
- Division of Microbiology and Infectious Diseases, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, Shiga 520-2192, Japan
| | - Ken-Ichi Mukaisho
- Division of Human Pathology, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, Shiga 520-2192, Japan
| | - Susumu Kageyama
- Department of Urology, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, Shiga 520-2192, Japan
| | - Akihiro Kawauchi
- Department of Urology, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, Shiga 520-2192, Japan
| | - Hirokazu Inoue
- Division of Microbiology and Infectious Diseases, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, Shiga 520-2192, Japan
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Wu D, Dasgupta A, Read AD, Bentley RET, Motamed M, Chen KH, Al-Qazazi R, Mewburn JD, Dunham-Snary KJ, Alizadeh E, Tian L, Archer SL. Oxygen sensing, mitochondrial biology and experimental therapeutics for pulmonary hypertension and cancer. Free Radic Biol Med 2021; 170:150-178. [PMID: 33450375 PMCID: PMC8217091 DOI: 10.1016/j.freeradbiomed.2020.12.452] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 12/24/2020] [Accepted: 12/30/2020] [Indexed: 02/06/2023]
Abstract
The homeostatic oxygen sensing system (HOSS) optimizes systemic oxygen delivery. Specialized tissues utilize a conserved mitochondrial sensor, often involving NDUFS2 in complex I of the mitochondrial electron transport chain, as a site of pO2-responsive production of reactive oxygen species (ROS). These ROS are converted to a diffusible signaling molecule, hydrogen peroxide (H2O2), by superoxide dismutase (SOD2). H2O2 exits the mitochondria and regulates ion channels and enzymes, altering plasma membrane potential, intracellular Ca2+ and Ca2+-sensitization and controlling acute, adaptive, responses to hypoxia that involve changes in ventilation, vascular tone and neurotransmitter release. Subversion of this O2-sensing pathway creates a pseudohypoxic state that promotes disease progression in pulmonary arterial hypertension (PAH) and cancer. Pseudohypoxia is a state in which biochemical changes, normally associated with hypoxia, occur despite normal pO2. Epigenetic silencing of SOD2 by DNA methylation alters H2O2 production, activating hypoxia-inducible factor 1α, thereby disrupting mitochondrial metabolism and dynamics, accelerating cell proliferation and inhibiting apoptosis. Other epigenetic mechanisms, including dysregulation of microRNAs (miR), increase pyruvate dehydrogenase kinase and pyruvate kinase muscle isoform 2 expression in both diseases, favoring uncoupled aerobic glycolysis. This Warburg metabolic shift also accelerates cell proliferation and impairs apoptosis. Disordered mitochondrial dynamics, usually increased mitotic fission and impaired fusion, promotes disease progression in PAH and cancer. Epigenetic upregulation of dynamin-related protein 1 (Drp1) and its binding partners, MiD49 and MiD51, contributes to the pathogenesis of PAH and cancer. Finally, dysregulation of intramitochondrial Ca2+, resulting from impaired mitochondrial calcium uniporter complex (MCUC) function, links abnormal mitochondrial metabolism and dynamics. MiR-mediated decreases in MCUC function reduce intramitochondrial Ca2+, promoting Warburg metabolism, whilst increasing cytosolic Ca2+, promoting fission. Epigenetically disordered mitochondrial O2-sensing, metabolism, dynamics, and Ca2+ homeostasis offer new therapeutic targets for PAH and cancer. Promoting glucose oxidation, restoring the fission/fusion balance, and restoring mitochondrial calcium regulation are promising experimental therapeutic strategies.
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Affiliation(s)
- Danchen Wu
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Asish Dasgupta
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Austin D Read
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Rachel E T Bentley
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Mehras Motamed
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Kuang-Hueih Chen
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Ruaa Al-Qazazi
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Jeffrey D Mewburn
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Kimberly J Dunham-Snary
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada; Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, K7L 3N6, Canada
| | - Elahe Alizadeh
- Queen's Cardiopulmonary Unit (QCPU), Department of Medicine, Queen's University, 116 Barrie Street, Kingston, ON, K7L 3J9, Canada
| | - Lian Tian
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, G4 0RE, UK
| | - Stephen L Archer
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada.
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Hung SW, Zhang R, Tan Z, Chung JPW, Zhang T, Wang CC. Pharmaceuticals targeting signaling pathways of endometriosis as potential new medical treatment: A review. Med Res Rev 2021; 41:2489-2564. [PMID: 33948974 PMCID: PMC8252000 DOI: 10.1002/med.21802] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Revised: 12/23/2020] [Accepted: 03/19/2021] [Indexed: 12/13/2022]
Abstract
Endometriosis (EM) is defined as endometrial tissues found outside the uterus. Growth and development of endometriotic cells in ectopic sites can be promoted via multiple pathways, including MAPK/MEK/ERK, PI3K/Akt/mTOR, NF-κB, Rho/ROCK, reactive oxidative stress, tumor necrosis factor, transforming growth factor-β, Wnt/β-catenin, vascular endothelial growth factor, estrogen, and cytokines. The underlying pathophysiological mechanisms include proliferation, apoptosis, autophagy, migration, invasion, fibrosis, angiogenesis, oxidative stress, inflammation, and immune escape. Current medical treatments for EM are mainly hormonal and symptomatic, and thus the development of new, effective, and safe pharmaceuticals targeting specific molecular and signaling pathways is needed. Here, we systematically reviewed the literature focused on pharmaceuticals that specifically target the molecular and signaling pathways involved in the pathophysiology of EM. Potential drug targets, their upstream and downstream molecules with key aberrant signaling, and the regulatory mechanisms promoting the growth and development of endometriotic cells and tissues were discussed. Hormonal pharmaceuticals, including melatonin, exerts proapoptotic via regulating matrix metallopeptidase activity while nonhormonal pharmaceutical sorafenib exerts antiproliferative effect via MAPK/ERK pathway and antiangiogenesis activity via VEGF/VEGFR pathway. N-acetyl cysteine, curcumin, and ginsenoside exert antioxidant and anti-inflammatory effects via radical scavenging activity. Natural products have high efficacy with minimal side effects; for example, resveratrol and epigallocatechin gallate have multiple targets and provide synergistic efficacy to resolve the complexity of the pathophysiology of EM, showing promising efficacy in treating EM. Although new medical treatments are currently being developed, more detailed pharmacological studies and large sample size clinical trials are needed to confirm the efficacy and safety of these treatments in the near future.
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Affiliation(s)
- Sze Wan Hung
- Department of Obstetrics and GynaecologyThe Chinese University of Hong KongHong Kong
| | - Ruizhe Zhang
- Department of Obstetrics and GynaecologyThe Chinese University of Hong KongHong Kong
- Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and GeneticsThe First Affiliated Hospital of Zhengzhou UniversityZhengzhou
| | - Zhouyurong Tan
- Department of Obstetrics and GynaecologyThe Chinese University of Hong KongHong Kong
| | | | - Tao Zhang
- Department of Obstetrics and GynaecologyThe Chinese University of Hong KongHong Kong
| | - Chi Chiu Wang
- Department of Obstetrics and GynaecologyThe Chinese University of Hong KongHong Kong
- Reproduction and Development, Li Ka Shing Institute of Health SciencesThe Chinese University of Hong KongHong Kong
- School of Biomedical SciencesThe Chinese University of Hong KongHong Kong
- Chinese University of Hong Kong‐Sichuan University Joint Laboratory in Reproductive MedicineThe Chinese University of Hong KongHong Kong
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Sun L, Zhang H, Gao P. Metabolic reprogramming and epigenetic modifications on the path to cancer. Protein Cell 2021; 13:877-919. [PMID: 34050894 PMCID: PMC9243210 DOI: 10.1007/s13238-021-00846-7] [Citation(s) in RCA: 353] [Impact Index Per Article: 88.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 04/02/2021] [Indexed: 02/07/2023] Open
Abstract
Metabolic rewiring and epigenetic remodeling, which are closely linked and reciprocally regulate each other, are among the well-known cancer hallmarks. Recent evidence suggests that many metabolites serve as substrates or cofactors of chromatin-modifying enzymes as a consequence of the translocation or spatial regionalization of enzymes or metabolites. Various metabolic alterations and epigenetic modifications also reportedly drive immune escape or impede immunosurveillance within certain contexts, playing important roles in tumor progression. In this review, we focus on how metabolic reprogramming of tumor cells and immune cells reshapes epigenetic alterations, in particular the acetylation and methylation of histone proteins and DNA. We also discuss other eminent metabolic modifications such as, succinylation, hydroxybutyrylation, and lactylation, and update the current advances in metabolism- and epigenetic modification-based therapeutic prospects in cancer.
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Affiliation(s)
- Linchong Sun
- Guangzhou First People's Hospital, School of Medicine, Institutes for Life Sciences, South China University of Technology, Guangzhou, 510006, China.
| | - Huafeng Zhang
- The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, 230027, China. .,CAS Centre for Excellence in Cell and Molecular Biology, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China.
| | - Ping Gao
- Guangzhou First People's Hospital, School of Medicine, Institutes for Life Sciences, South China University of Technology, Guangzhou, 510006, China. .,School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou, 510006, China. .,Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, 510005, China.
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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: 84] [Impact Index Per Article: 21.0] [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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Parczyk J, Ruhnau J, Pelz C, Schilling M, Wu H, Piaskowski NN, Eickholt B, Kühn H, Danker K, Klein A. Dichloroacetate and PX-478 exhibit strong synergistic effects in a various number of cancer cell lines. BMC Cancer 2021; 21:481. [PMID: 33931028 PMCID: PMC8086110 DOI: 10.1186/s12885-021-08186-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 04/14/2021] [Indexed: 02/08/2023] Open
Abstract
Background One key approach for anticancer therapy is drug combination. Drug combinations can help reduce doses and thereby decrease side effects. Furthermore, the likelihood of drug resistance is reduced. Distinct alterations in tumor metabolism have been described in past decades, but metabolism has yet to be targeted in clinical cancer therapy. Recently, we found evidence for synergism between dichloroacetate (DCA), a pyruvate dehydrogenase kinase inhibitor, and the HIF-1α inhibitor PX-478. In this study, we aimed to analyse this synergism in cell lines of different cancer types and to identify the underlying biochemical mechanisms. Methods The dose-dependent antiproliferative effects of the single drugs and their combination were assessed using SRB assays. FACS, Western blot and HPLC analyses were performed to investigate changes in reactive oxygen species levels, apoptosis and the cell cycle. Additionally, real-time metabolic analyses (Seahorse) were performed with DCA-treated MCF-7 cells. Results The combination of DCA and PX-478 produced synergistic effects in all eight cancer cell lines tested, including colorectal, lung, breast, cervical, liver and brain cancer. Reactive oxygen species generation and apoptosis played important roles in this synergism. Furthermore, cell proliferation was inhibited by the combination treatment. Conclusions Here, we found that these tumor metabolism-targeting compounds exhibited a potent synergism across all tested cancer cell lines. Thus, we highly recommend the combination of these two compounds for progression to in vivo translational and clinical trials. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-08186-9.
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Affiliation(s)
- Jonas Parczyk
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117, Berlin, Germany.
| | - Jérôme Ruhnau
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117, Berlin, Germany.
| | - Carsten Pelz
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117, Berlin, Germany
| | - Max Schilling
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117, Berlin, Germany
| | - Hao Wu
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117, Berlin, Germany
| | - Nicole Nadine Piaskowski
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117, Berlin, Germany
| | - Britta Eickholt
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117, Berlin, Germany
| | - Hartmut Kühn
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117, Berlin, Germany
| | - Kerstin Danker
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117, Berlin, Germany
| | - Andreas Klein
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117, Berlin, Germany
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Schiliro C, Firestein BL. Mechanisms of Metabolic Reprogramming in Cancer Cells Supporting Enhanced Growth and Proliferation. Cells 2021; 10:cells10051056. [PMID: 33946927 PMCID: PMC8146072 DOI: 10.3390/cells10051056] [Citation(s) in RCA: 303] [Impact Index Per Article: 75.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 04/27/2021] [Accepted: 04/28/2021] [Indexed: 02/07/2023] Open
Abstract
Cancer cells alter metabolic processes to sustain their characteristic uncontrolled growth and proliferation. These metabolic alterations include (1) a shift from oxidative phosphorylation to aerobic glycolysis to support the increased need for ATP, (2) increased glutaminolysis for NADPH regeneration, (3) altered flux through the pentose phosphate pathway and the tricarboxylic acid cycle for macromolecule generation, (4) increased lipid uptake, lipogenesis, and cholesterol synthesis, (5) upregulation of one-carbon metabolism for the production of ATP, NADH/NADPH, nucleotides, and glutathione, (6) altered amino acid metabolism, (7) metabolism-based regulation of apoptosis, and (8) the utilization of alternative substrates, such as lactate and acetate. Altered metabolic flux in cancer is controlled by tumor-host cell interactions, key oncogenes, tumor suppressors, and other regulatory molecules, including non-coding RNAs. Changes to metabolic pathways in cancer are dynamic, exhibit plasticity, and are often dependent on the type of tumor and the tumor microenvironment, leading in a shift of thought from the Warburg Effect and the “reverse Warburg Effect” to metabolic plasticity. Understanding the complex nature of altered flux through these multiple pathways in cancer cells can support the development of new therapies.
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Affiliation(s)
- Chelsea Schiliro
- Cell and Developmental Biology Graduate Program and Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, 604 Allison Road, Piscataway, NJ 08854, USA;
| | - Bonnie L. Firestein
- Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, 604 Allison Road, Piscataway, NJ 08854, USA
- Correspondence: ; Tel.: +1-848-445-8045
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Fazal S, Bisserier M, Hadri L. Molecular and Genetic Profiling for Precision Medicines in Pulmonary Arterial Hypertension. Cells 2021; 10:638. [PMID: 33805595 PMCID: PMC7999465 DOI: 10.3390/cells10030638] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 03/10/2021] [Accepted: 03/11/2021] [Indexed: 12/11/2022] Open
Abstract
Pulmonary arterial hypertension (PAH) is a rare and chronic lung disease characterized by progressive occlusion of the small pulmonary arteries, which is associated with structural and functional alteration of the smooth muscle cells and endothelial cells within the pulmonary vasculature. Excessive vascular remodeling is, in part, responsible for high pulmonary vascular resistance and the mean pulmonary arterial pressure, increasing the transpulmonary gradient and the right ventricular "pressure overload", which may result in right ventricular (RV) dysfunction and failure. Current technological advances in multi-omics approaches, high-throughput sequencing, and computational methods have provided valuable tools in molecular profiling and led to the identification of numerous genetic variants in PAH patients. In this review, we summarized the pathogenesis, classification, and current treatments of the PAH disease. Additionally, we outlined the latest next-generation sequencing technologies and the consequences of common genetic variants underlying PAH susceptibility and disease progression. Finally, we discuss the importance of molecular genetic testing for precision medicine in PAH and the future of genomic medicines, including gene-editing technologies and gene therapies, as emerging alternative approaches to overcome genetic disorders in PAH.
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Affiliation(s)
| | | | - Lahouaria Hadri
- Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY 10029, USA; (S.F.); (M.B.)
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Leow HW, Koscielniak M, Williams L, Saunders PTK, Daniels J, Doust AM, Jones MC, Ferguson GD, Bagger Y, Horne AW, Whitaker LHR. Dichloroacetate as a possible treatment for endometriosis-associated pain: a single-arm open-label exploratory clinical trial (EPiC). Pilot Feasibility Stud 2021; 7:67. [PMID: 33712086 PMCID: PMC7953373 DOI: 10.1186/s40814-021-00797-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 02/15/2021] [Indexed: 01/31/2023] Open
Abstract
BACKGROUND Endometriosis (where endometrial-like tissue is found outside the uterus) affects ~ 176 million women worldwide and can lead to debilitating pelvic pain. There is an unmet need for new medical treatment options for endometriosis. Pelvic peritoneal mesothelial cells of women with endometriosis exhibit detrimental metabolic reprogramming that creates an environment favouring the formation and survival of endometriosis lesions. We have generated powerful preclinical proof-of-concept data to show that it is possible to correct this metabolic phenotype using dichloroacetate (DCA), a non-hormonal compound previously used to treat rare metabolic disorders in children. We plan a single-arm, open-label, single site exploratory clinical trial to inform the design of a future randomised controlled trial (RCT) to determine the efficacy of DCA for the treatment of endometriosis-associated pain. METHODS We will recruit 30 women with endometriosis-associated pain over a 6-month period. All participants will receive approximately 6.25 mg/kg oral DCA capsules twice daily for 6 weeks, with a dose increase to approximately 12.5 mg/kg twice daily for a further 6 weeks if their pain has not been adequately controlled on this dose regime and side-effects are acceptable. If pain is adequately controlled with minimal side-effects, the lower dose will be continued for a further 6 weeks. The primary objective is to determine whether it is possible to achieve acceptable recruitment and retention rates within the defined exclusion and inclusion criteria. Secondary objectives are to determine the acceptability of the trial to participants, including the proposed methods of recruitment, treatment, follow-up frequency and number of questionnaires. The recruitment rate will be determined by the proportion of patients recruited from the pool of eligible women. The retention rate will be determined by the proportion of participants who attended the final trial visit. DISCUSSION This is a feasibility study to explore effectiveness and acceptability of the proposed field methodology (recruitment, retention, study processes and compliance with treatment). The results will be used to inform the design of a future RCT. TRIAL REGISTRATION ClinicalTrials.gov, NCT04046081 Registered 6 August 2019.
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Affiliation(s)
- H. W. Leow
- MRC Centre for Reproductive Health, Queen’s Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ UK
| | - M. Koscielniak
- MRC Centre for Reproductive Health, Queen’s Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ UK
| | - L. Williams
- Usher Institute, NINE Edinburgh BioQuarter, 9 Little France Road, Edinburgh, EH16 4UX UK
| | - P. T. K. Saunders
- Centre for Inflammation Research, Queen’s Medical Research Institue, University of Edinburgh, Edinburgh, EH16 4TJ UK
| | - J. Daniels
- Clinical Trials Unit, University of Nottingham, University Park, Nottingham, NG7 2RD UK
| | - A. M. Doust
- MRC Centre for Reproductive Health, Queen’s Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ UK
| | - M-C Jones
- Institute of Clinical Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT UK
| | - G. D. Ferguson
- Reproductive Medicine and Maternal Health, Ferring Research Institute, San Diego, CA 92121 USA
| | - Y. Bagger
- Reproductive Medicine and Maternal Health, Ferring Research Institute, San Diego, CA 92121 USA
| | - A. W. Horne
- MRC Centre for Reproductive Health, Queen’s Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ UK
| | - L. H. R. Whitaker
- MRC Centre for Reproductive Health, Queen’s Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ UK
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Abildgaard C, Rizza S, Christiansen H, Schmidt S, Dahl C, Abdul-Al A, Christensen A, Filomeni G, Guldberg P. Screening of metabolic modulators identifies new strategies to target metabolic reprogramming in melanoma. Sci Rep 2021; 11:4390. [PMID: 33623106 PMCID: PMC7902673 DOI: 10.1038/s41598-021-83796-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 01/22/2021] [Indexed: 12/13/2022] Open
Abstract
The prognosis of metastatic melanoma remains poor due to de novo or acquired resistance to immune and targeted therapies. Previous studies have shown that melanoma cells have perturbed metabolism and that cellular metabolic pathways represent potential therapeutic targets. To support the discovery of new drug candidates for melanoma, we examined 180 metabolic modulators, including phytochemicals and anti-diabetic compounds, for their growth-inhibitory activities against melanoma cells, alone and in combination with the BRAF inhibitor vemurafenib. Two positive hits from this screen, 4-methylumbelliferone (4-MU) and ursolic acid (UA), were subjected to validation and further characterization. Metabolic analysis showed that 4-MU affected cellular metabolism through inhibition of glycolysis and enhanced the effect of vemurafenib to reduce the growth of melanoma cells. In contrast, UA reduced mitochondrial respiration, accompanied by an increase in the glycolytic rate. This metabolic switch potentiated the growth-inhibitory effect of the pyruvate dehydrogenase kinase inhibitor dichloroacetate. Both drug combinations led to increased production of reactive oxygen species, suggesting the involvement of oxidative stress in the cellular response. These results support the potential use of metabolic modulators for combination therapies in cancer and may encourage preclinical validation and clinical testing of such treatment strategies in patients with metastatic melanoma.
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Affiliation(s)
- Cecilie Abildgaard
- Molecular Diagnostics Group, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark
- Department of Clinical Genetics, Lillebaelt Hospital - University Hospital of Southern Denmark, Vejle, Denmark
| | - Salvatore Rizza
- Redox Biology Group, Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Helle Christiansen
- Lundbeckfonden Center of Excellence NanoCAN, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
- Molecular Oncology, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
- Roche Innovation Center Copenhagen, Hørsholm, Denmark
| | - Steffen Schmidt
- Lundbeckfonden Center of Excellence NanoCAN, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
- Molecular Oncology, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
- Roche Innovation Center Copenhagen, Hørsholm, Denmark
| | - Christina Dahl
- Molecular Diagnostics Group, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark
| | - Ahmad Abdul-Al
- Molecular Diagnostics Group, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark
| | - Annette Christensen
- Molecular Diagnostics Group, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark
| | - Giuseppe Filomeni
- Redox Biology Group, Danish Cancer Society Research Center, Copenhagen, Denmark
- Department of Biology, Tor Vergata University of Rome, Rome, Italy
- Center for Healthy Aging, Copenhagen University, Copenhagen, Denmark
| | - Per Guldberg
- Molecular Diagnostics Group, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark.
- Department of Cancer and Inflammation Research, Institute for Molecular Medicine, University of Southern Denmark, Odense, Denmark.
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Shen H, Yu M, Tsoli M, Chang C, Joshi S, Liu J, Ryall S, Chornenkyy Y, Siddaway R, Hawkins C, Ziegler DS. Targeting reduced mitochondrial DNA quantity as a therapeutic approach in pediatric high-grade gliomas. Neuro Oncol 2021; 22:139-151. [PMID: 31398252 PMCID: PMC6954438 DOI: 10.1093/neuonc/noz140] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Accepted: 08/05/2019] [Indexed: 01/14/2023] Open
Abstract
Background Despite increased understanding of the genetic events underlying pediatric high-grade gliomas (pHGGs), therapeutic progress is static, with poor understanding of nongenomic drivers. We therefore investigated the role of alterations in mitochondrial function and developed an effective combination therapy against pHGGs. Methods Mitochondrial DNA (mtDNA) copy number was measured in a cohort of 60 pHGGs. The implication of mtDNA alteration in pHGG tumorigenesis was studied and followed by an efficacy investigation using patient-derived cultures and orthotopic xenografts. Results Average mtDNA content was significantly lower in tumors versus normal brains. Decreasing mtDNA copy number in normal human astrocytes led to a markedly increased tumorigenicity in vivo. Depletion of mtDNA in pHGG cells promoted cell migration and invasion and therapeutic resistance. Shifting glucose metabolism from glycolysis to mitochondrial oxidation with the adenosine monophosphate–activated protein kinase activator AICAR (5-aminoimidazole-4-carboxamide ribonucleotide) or the pyruvate dehydrogenase kinase inhibitor dichloroacetate (DCA) significantly inhibited pHGG viability. Using DCA to shift glucose metabolism to mitochondrial oxidation and then metformin to simultaneously target mitochondrial function disrupted energy homeostasis of tumor cells, increasing DNA damage and apoptosis. The triple combination with radiation therapy, DCA and metformin led to a more potent therapeutic effect in vitro and in vivo. Conclusions Our results suggest metabolic alterations as an onco-requisite factor of pHGG tumorigenesis. Targeting reduced mtDNA quantity represents a promising therapeutic strategy for pHGG.
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Affiliation(s)
- Han Shen
- Children’s Cancer Institute, University of New South Wales, Sydney, New South Wales, Australia
- Current affiliations: Centre for Cancer Research, Westmead Institute for Medical Research, Westmead, New South Wales, Australia
| | - Man Yu
- The Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Maria Tsoli
- Children’s Cancer Institute, University of New South Wales, Sydney, New South Wales, Australia
| | - Cecilia Chang
- Children’s Cancer Institute, University of New South Wales, Sydney, New South Wales, Australia
- Current affiliations: Centre for Cancer Research, Westmead Institute for Medical Research, Westmead, New South Wales, Australia
| | - Swapna Joshi
- Children’s Cancer Institute, University of New South Wales, Sydney, New South Wales, Australia
| | - Jie Liu
- Children’s Cancer Institute, University of New South Wales, Sydney, New South Wales, Australia
| | - Scott Ryall
- The Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Yevgen Chornenkyy
- The Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Robert Siddaway
- The Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Cynthia Hawkins
- The Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
- Division of Pathology, The Hospital for Sick Children, Toronto, Ontario, Canada
- Corresponding Authors: Prof Cynthia Hawkins, Division of Pathology, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, Canada (); A/Prof David Ziegler, Kids Cancer Centre, Sydney Children’s Hospital, High St, Randwick, NSW, 2031, Australia ()
| | - David S Ziegler
- Children’s Cancer Institute, University of New South Wales, Sydney, New South Wales, Australia
- Kids Cancer Centre, Sydney Children’s Hospital, Randwick, New South Wales, Australia
- Corresponding Authors: Prof Cynthia Hawkins, Division of Pathology, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, Canada (); A/Prof David Ziegler, Kids Cancer Centre, Sydney Children’s Hospital, High St, Randwick, NSW, 2031, Australia ()
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Targeting Endothelial Cell Metabolism by Inhibition of Pyruvate Dehydrogenase Kinase and Glutaminase-1. J Clin Med 2020; 9:jcm9103308. [PMID: 33076309 PMCID: PMC7602423 DOI: 10.3390/jcm9103308] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Revised: 10/11/2020] [Accepted: 10/12/2020] [Indexed: 12/30/2022] Open
Abstract
Targeting endothelial cell (EC) metabolism should impair angiogenesis, regardless of how many angiogenic signals are present. The dependency of proliferating ECs on glucose and glutamine for energy and biomass production opens new opportunities for anti-angiogenic therapy in cancer. The aim of the present study was to investigate the role of pyruvate dehydrogenase kinase (PDK) inhibition with dichloroacetate (DCA), alone or in combination with the glutaminase-1 (GLS-1) inhibitor, Bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES), on Human umbilical vein endothelial cells (HUVECs) metabolism, proliferation, apoptosis, migration, and vessel formation. We demonstrated that both drugs normalize HUVECs metabolism by decreasing glycolysis for DCA and by reducing glutamate production for BPTES. DCA and BPTES reduced HUVECs proliferation and migration but have no impact on tube formation. While DCA increased HUVECs respiration, BPTES decreased it. Using both drugs in combination further reduced HUVECs proliferation while normalizing respiration and apoptosis induction. Overall, we demonstrated that DCA, a metabolic drug under study to target cancer cells metabolism, also affects tumor angiogenesis. Combining DCA and BPTES may reduce adverse effect of each drug alone and favor tumor angiogenesis normalization.
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de Heer EC, Jalving M, Harris AL. HIFs, angiogenesis, and metabolism: elusive enemies in breast cancer. J Clin Invest 2020; 130:5074-5087. [PMID: 32870818 PMCID: PMC7524491 DOI: 10.1172/jci137552] [Citation(s) in RCA: 218] [Impact Index Per Article: 43.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Hypoxia-inducible factors (HIFs) and the HIF-dependent cancer hallmarks angiogenesis and metabolic rewiring are well-established drivers of breast cancer aggressiveness, therapy resistance, and poor prognosis. Targeting of HIF and its downstream targets in angiogenesis and metabolism has been unsuccessful so far in the breast cancer clinical setting, with major unresolved challenges residing in target selection, development of robust biomarkers for response prediction, and understanding and harnessing of escape mechanisms. This Review discusses the pathophysiological role of HIFs, angiogenesis, and metabolism in breast cancer and the challenges of targeting these features in patients with breast cancer. Rational therapeutic combinations, especially with immunotherapy and endocrine therapy, seem most promising in the clinical exploitation of the intricate interplay of HIFs, angiogenesis, and metabolism in breast cancer cells and the tumor microenvironment.
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Affiliation(s)
- Ellen C. de Heer
- University of Groningen, University Medical Center Groningen, Department of Medical Oncology, Groningen, Netherlands
| | - Mathilde Jalving
- University of Groningen, University Medical Center Groningen, Department of Medical Oncology, Groningen, Netherlands
| | - Adrian L. Harris
- Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
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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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Zhu X, Chen HH, Gao CY, Zhang XX, Jiang JX, Zhang Y, Fang J, Zhao F, Chen ZG. Energy metabolism in cancer stem cells. World J Stem Cells 2020; 12:448-461. [PMID: 32742562 PMCID: PMC7360992 DOI: 10.4252/wjsc.v12.i6.448] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 05/09/2020] [Accepted: 05/19/2020] [Indexed: 02/06/2023] Open
Abstract
Normal cells mainly rely on oxidative phosphorylation as an effective energy source in the presence of oxygen. In contrast, most cancer cells use less efficient glycolysis to produce ATP and essential biomolecules. Cancer cells gain the characteristics of metabolic adaptation by reprogramming their metabolic mechanisms to meet the needs of rapid tumor growth. A subset of cancer cells with stem characteristics and the ability to regenerate exist throughout the tumor and are therefore called cancer stem cells (CSCs). New evidence indicates that CSCs have different metabolic phenotypes compared with differentiated cancer cells. CSCs can dynamically transform their metabolic state to favor glycolysis or oxidative metabolism. The mechanism of the metabolic plasticity of CSCs has not been fully elucidated, and existing evidence indicates that the metabolic phenotype of cancer cells is closely related to the tumor microenvironment. Targeting CSC metabolism may provide new and effective methods for the treatment of tumors. In this review, we summarize the metabolic characteristics of cancer cells and CSCs and the mechanisms of the metabolic interplay between the tumor microenvironment and CSCs, and discuss the clinical implications of targeting CSC metabolism.
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Affiliation(s)
- Xuan Zhu
- Department of Radiation Oncology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Hui-Hui Chen
- The Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Hangzhou 310000, Zhejiang Province, China
- Department of Breast Surgery, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Chen-Yi Gao
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou 310000, Zhejiang Province, China
- Department of Breast Surgery, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Xin-Xin Zhang
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou 310000, Zhejiang Province, China
- Department of Breast Surgery, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Jing-Xin Jiang
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou 310000, Zhejiang Province, China
- Department of Breast Surgery, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Yi Zhang
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou 310000, Zhejiang Province, China
- Department of Breast Surgery, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Jun Fang
- Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou 310000, Zhejiang Province, China
| | - Feng Zhao
- Department of Radiation Oncology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Zhi-Gang Chen
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou 310000, Zhejiang Province, China
- Department of Breast Surgery, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China.
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Combination of Dichloroacetate and Atorvastatin Regulates Excessive Proliferation and Oxidative Stress in Pulmonary Arterial Hypertension Development via p38 Signaling. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:6973636. [PMID: 32617141 PMCID: PMC7306075 DOI: 10.1155/2020/6973636] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Accepted: 05/19/2020] [Indexed: 11/18/2022]
Abstract
Pulmonary arterial hypertension (PAH) is a lethal disease generally characterized by pulmonary artery remodeling. Mitochondrial metabolic disorders have been implicated as a critical regulator of excessively proliferative- and apoptosis-resistant phenotypes in pulmonary artery smooth muscle cells (PASMCs). Dichloroacetate (DCA) is an emerging drug that targets aerobic glycolysis in tumor cells. Atorvastatin (ATO) is widely used for hyperlipemia in various cardiovascular diseases. Considering that DCA and ATO regulate glucose and lipid metabolism, respectively, we hypothesized that the combination of DCA and ATO could be a potential treatment for PAH. A notable decrease in the right ventricular systolic pressure accompanied by reduced right heart hypertrophy was observed in the DCA/ATO combination treatment group compared with the monocrotaline treatment group. The DCA/ATO combination treatment alleviated vascular remodeling, thereby suppressing excessive PASMC proliferation and macrophage infiltration. In vitro, both DCA and ATO alone reduced PASMC viability by upregulating oxidative stress and lowering mitochondrial membrane potential. Surprisingly, when combined, DCA/ATO was able to decrease the levels of reactive oxygen species and cell apoptosis without compromising PASMC proliferation. Furthermore, suppression of the p38 pathway through the specific inhibitor SB203580 attenuated cell death and oxidative stress at a level consistent with that of DCA/ATO combination treatment. These observations suggested a complementary effect of DCA and ATO on rescuing PASMCs from a PAH phenotype through p38 activation via the regulation of mitochondrial-related cell death and oxidative stress. DCA in combination with ATO may represent a novel therapeutic strategy for PAH treatment.
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Diaz-Vegas A, Sanchez-Aguilera P, Krycer JR, Morales PE, Monsalves-Alvarez M, Cifuentes M, Rothermel BA, Lavandero S. Is Mitochondrial Dysfunction a Common Root of Noncommunicable Chronic Diseases? Endocr Rev 2020; 41:5807952. [PMID: 32179913 PMCID: PMC7255501 DOI: 10.1210/endrev/bnaa005] [Citation(s) in RCA: 94] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2019] [Accepted: 03/12/2020] [Indexed: 12/19/2022]
Abstract
Mitochondrial damage is implicated as a major contributing factor for a number of noncommunicable chronic diseases such as cardiovascular diseases, cancer, obesity, and insulin resistance/type 2 diabetes. Here, we discuss the role of mitochondria in maintaining cellular and whole-organism homeostasis, the mechanisms that promote mitochondrial dysfunction, and the role of this phenomenon in noncommunicable chronic diseases. We also review the state of the art regarding the preclinical evidence associated with the regulation of mitochondrial function and the development of current mitochondria-targeted therapeutics to treat noncommunicable chronic diseases. Finally, we give an integrated vision of how mitochondrial damage is implicated in these metabolic diseases.
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Affiliation(s)
- Alexis Diaz-Vegas
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile.,Charles Perkins Centre, School of Life and Environmental Sciences, The University of Sydney, Camperdown, Sydney, NSW, Australia
| | - Pablo Sanchez-Aguilera
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - James R Krycer
- Charles Perkins Centre, School of Life and Environmental Sciences, The University of Sydney, Camperdown, Sydney, NSW, Australia
| | - Pablo E Morales
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Matías Monsalves-Alvarez
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile.,Institute of Nutrition and Food Technology (INTA), Universidad de Chile, Santiago, Chile
| | - Mariana Cifuentes
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile.,Institute of Nutrition and Food Technology (INTA), Universidad de Chile, Santiago, Chile.,Center for Studies of Exercise, Metabolism and Cancer (CEMC), Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Beverly A Rothermel
- Department of Internal Medicine (Cardiology Division), University of Texas Southwestern Medical Center, Dallas, Texas
| | - Sergio Lavandero
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile.,Department of Internal Medicine (Cardiology Division), University of Texas Southwestern Medical Center, Dallas, Texas.,Center for Studies of Exercise, Metabolism and Cancer (CEMC), Facultad de Medicina, Universidad de Chile, Santiago, Chile
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