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Zhang YQ, Zhang W, Kong XT, Hai WX, Guo R, Zhang M, Zhang SL, Li B. The therapeutic effect of a novel GAPDH inhibitor in mouse model of breast cancer and efficacy monitoring by molecular imaging. Cancer Cell Int 2024; 24:188. [PMID: 38811918 PMCID: PMC11138053 DOI: 10.1186/s12935-024-03361-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 05/07/2024] [Indexed: 05/31/2024] Open
Abstract
BACKGROUND Breast cancer is a serious threat to women's health with high morbidity and mortality. The development of more effective therapies for the treatment of breast cancer is strongly warranted. Growing evidence suggests that targeting glucose metabolism may be a promising cancer treatment strategy. We previously identified a new glyceraldehyde-3-phosphate dehydrogenase (GAPDH) inhibitor, DC-5163, which shows great potential in inhibiting tumor growth. Here, we evaluated the anticancer potential of DC-5163 in breast cancer cells. METHODS The effects of DC-5163 on breast cancer cells were investigated in vitro and in vivo. Seahorse, glucose uptake, lactate production, and cellular ATP content assays were performed to examine the impact of DC-5163 on cellular glycolysis. Cell viability, colony-forming ability, cell cycle, and apoptosis were assessed by CCK8 assay, colony formation assay, flow cytometry, and immunoblotting respectively. The anticancer activity of DC-5163 in vivo was evaluated in a mouse breast cancer xenograft model. RESULTS DC-5163 suppressed aerobic glycolysis and reduced energy supply of breast cancer cells, thereby inhibiting breast cancer cell growth, inducing cell cycle arrest in the G0/G1 phase, and increasing apoptosis. The therapeutic efficacy was assessed using a breast cancer xenograft mouse model. DC-5163 treatment markedly suppressed tumor growth in vivo without inducing evident systemic toxicity. Micro-PET/CT scans revealed a notable reduction in tumor 18F-FDG and 18F-FLT uptake in the DC-5163 treatment group compared to the DMSO control group. CONCLUSIONS Our results suggest that DC-5163 is a promising GAPDH inhibitor for suppressing breast cancer growth without obvious side effects. 18F-FDG and 18F-FLT PET/CT can noninvasively assess the levels of glycolysis and proliferation in tumors following treatment with DC-5163.
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Affiliation(s)
- Yun-Qi Zhang
- Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Second Road, Shanghai, 200025, China
- Collaborative Innovation Center for Molecular Imaging of Precision Medicine, Shanxi Medical University, Taiyuan, 030000, China
| | - Wei Zhang
- Drug Discovery and Design Canter, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China
| | - Xiang-Tai Kong
- Drug Discovery and Design Canter, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China
| | - Wang-Xi Hai
- Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Second Road, Shanghai, 200025, China
- Collaborative Innovation Center for Molecular Imaging of Precision Medicine, Shanxi Medical University, Taiyuan, 030000, China
| | - Rui Guo
- Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Second Road, Shanghai, 200025, China
- Collaborative Innovation Center for Molecular Imaging of Precision Medicine, Shanxi Medical University, Taiyuan, 030000, China
| | - Min Zhang
- Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Second Road, Shanghai, 200025, China
- Collaborative Innovation Center for Molecular Imaging of Precision Medicine, Shanxi Medical University, Taiyuan, 030000, China
| | - Su-Lin Zhang
- Drug Discovery and Design Canter, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China.
| | - Biao Li
- Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Second Road, Shanghai, 200025, China.
- Collaborative Innovation Center for Molecular Imaging of Precision Medicine, Shanxi Medical University, Taiyuan, 030000, China.
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2
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Przywara K, Adamski R, Książczyk M, Suchodolski J, Cal M. 3-bromopyruvate induces morphological alteration and may initiate programmed cell death in Cryptococcus neoformans cells. Arch Microbiol 2024; 206:153. [PMID: 38472387 DOI: 10.1007/s00203-024-03894-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 02/02/2024] [Accepted: 02/08/2024] [Indexed: 03/14/2024]
Abstract
3-Bromopyruvate (3BP), known for its potent anticancer properties, also exhibits remarkable efficacy against the pathogenic fungus Cryptococcus neoformans. So far it has been proven that the main fungicidal activity of 3BP is based on ATP depletion and a reduction of intracellular level of glutathione. The presented study includes a broad range of methods to further investigate the mechanistic effects of 3BP on C. neoformans cells. The use of flow cytometry allowed a thorough examination of their survival during 3BP treatment, while observations using electron microscopy made it possible to note the changes in cellular morphology. Utilizing ruthenium red, the study suggests a mitochondrial pathway may initiate programmed cell death in response to 3BP. Analysis of free radical generation and gene expression changes supports this hypothesis. These findings enhance comprehension of 3BP's mechanisms in fungal cells, paving the way for its potential application as a therapeutic agent against cryptococcosis.
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Affiliation(s)
- Katarzyna Przywara
- Department of Mycology and Genetics, Faculty of Biological Sciences, University of Wrocław, Wrocław, Poland.
| | - Ryszard Adamski
- Laboratory of Microscopic Techniques, Faculty of Biological Sciences, University of Wrocław, Wrocław, Poland
| | - Marta Książczyk
- Department of Microbiology, Faculty of Biological Sciences, University of Wrocław, Wrocław, Poland
| | - Jakub Suchodolski
- Department of Mycology and Genetics, Faculty of Biological Sciences, University of Wrocław, Wrocław, Poland
| | - Magdalena Cal
- Department of Mycology and Genetics, Faculty of Biological Sciences, University of Wrocław, Wrocław, Poland
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3
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Wang Q, Liu J, Chen Z, Zheng J, Wang Y, Dong J. Targeting metabolic reprogramming in hepatocellular carcinoma to overcome therapeutic resistance: A comprehensive review. Biomed Pharmacother 2024; 170:116021. [PMID: 38128187 DOI: 10.1016/j.biopha.2023.116021] [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: 09/18/2023] [Revised: 11/23/2023] [Accepted: 12/14/2023] [Indexed: 12/23/2023] Open
Abstract
Hepatocellular carcinoma (HCC) poses a heavy burden on human health with high morbidity and mortality rates. Systematic therapy is crucial for advanced and mid-term HCC, but faces a significant challenge from therapeutic resistance, weakening drug effectiveness. Metabolic reprogramming has gained attention as a key contributor to therapeutic resistance. Cells change their metabolism to meet energy demands, adapt to growth needs, or resist environmental pressures. Understanding key enzyme expression patterns and metabolic pathway interactions is vital to comprehend HCC occurrence, development, and treatment resistance. Exploring metabolic enzyme reprogramming and pathways is essential to identify breakthrough points for HCC treatment. Targeting metabolic enzymes with inhibitors is key to addressing these points. Inhibitors, combined with systemic therapeutic drugs, can alleviate resistance, prolong overall survival for advanced HCC, and offer mid-term HCC patients a chance for radical resection. Advances in metabolic research methods, from genomics to metabolomics and cells to organoids, help build the HCC metabolic reprogramming network. Recent progress in biomaterials and nanotechnology impacts drug targeting and effectiveness, providing new solutions for systemic therapeutic drug resistance. This review focuses on metabolic enzyme changes, pathway interactions, enzyme inhibitors, research methods, and drug delivery targeting metabolic reprogramming, offering valuable references for metabolic approaches to HCC treatment.
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Affiliation(s)
- Qi Wang
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Jilin University, Changchun 130021, China
| | - Juan Liu
- Research Unit of Precision Hepatobiliary Surgery Paradigm, Chinese Academy of Medical Sciences, Beijing 100021, China; Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China; Institute for Organ Transplant and Bionic Medicine, Tsinghua University, Beijing 102218, China; Key Laboratory of Digital Intelligence Hepatology (Ministry of Education/Beijing), School of Clinical Medicine, Tsinghua University, Beijing, China.
| | - Ziye Chen
- Clinical Translational Science Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing 102218, China
| | - Jingjing Zheng
- Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
| | - Yunfang Wang
- Research Unit of Precision Hepatobiliary Surgery Paradigm, Chinese Academy of Medical Sciences, Beijing 100021, China; Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China; Institute for Organ Transplant and Bionic Medicine, Tsinghua University, Beijing 102218, China; Clinical Translational Science Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing 102218, China; Key Laboratory of Digital Intelligence Hepatology (Ministry of Education/Beijing), School of Clinical Medicine, Tsinghua University, Beijing, China.
| | - Jiahong Dong
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Jilin University, Changchun 130021, China; Research Unit of Precision Hepatobiliary Surgery Paradigm, Chinese Academy of Medical Sciences, Beijing 100021, China; Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China; Institute for Organ Transplant and Bionic Medicine, Tsinghua University, Beijing 102218, China; Key Laboratory of Digital Intelligence Hepatology (Ministry of Education/Beijing), School of Clinical Medicine, Tsinghua University, Beijing, China.
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4
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Zhang W, Lang R. Succinate metabolism: a promising therapeutic target for inflammation, ischemia/reperfusion injury and cancer. Front Cell Dev Biol 2023; 11:1266973. [PMID: 37808079 PMCID: PMC10556696 DOI: 10.3389/fcell.2023.1266973] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 09/15/2023] [Indexed: 10/10/2023] Open
Abstract
Succinate serves as an essential circulating metabolite within the tricarboxylic acid (TCA) cycle and functions as a substrate for succinate dehydrogenase (SDH), thereby contributing to energy production in fundamental mitochondrial metabolic pathways. Aberrant changes in succinate concentrations have been associated with pathological states, including chronic inflammation, ischemia/reperfusion (IR) injury, and cancer, resulting from the exaggerated response of specific immune cells, thereby rendering it a central area of investigation. Recent studies have elucidated the pivotal involvement of succinate and SDH in immunity beyond metabolic processes, particularly in the context of cancer. Current scientific endeavors are concentrated on comprehending the functional repercussions of metabolic modifications, specifically pertaining to succinate and SDH, in immune cells operating within a hypoxic milieu. The efficacy of targeting succinate and SDH alterations to manipulate immune cell functions in hypoxia-related diseases have been demonstrated. Consequently, a comprehensive understanding of succinate's role in metabolism and the regulation of SDH is crucial for effectively targeting succinate and SDH as therapeutic interventions to influence the progression of specific diseases. This review provides a succinct overview of the latest advancements in comprehending the emerging functions of succinate and SDH in metabolic processes. Furthermore, it explores the involvement of succinate, an intermediary of the TCA cycle, in chronic inflammation, IR injury, and cancer, with particular emphasis on the mechanisms underlying succinate accumulation. This review critically assesses the potential of modulating succinate accumulation and metabolism within the hypoxic milieu as a means to combat various diseases. It explores potential targets for therapeutic interventions by focusing on succinate metabolism and the regulation of SDH in hypoxia-related disorders.
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Affiliation(s)
| | - Ren Lang
- Department of Hepatobiliary Surgery, Beijing Chao-Yang Hospital Affiliated to Capital Medical University, Beijing, China
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5
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Marín-Hernández Á, Saavedra E. Metabolic control analysis as a strategy to identify therapeutic targets, the case of cancer glycolysis. Biosystems 2023; 231:104986. [PMID: 37506818 DOI: 10.1016/j.biosystems.2023.104986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 07/23/2023] [Accepted: 07/25/2023] [Indexed: 07/30/2023]
Abstract
The use of kinetic modeling and metabolic control analysis (MCA) to identify possible therapeutic targets and to investigate the controlling and regulatory mechanisms in cancer glycolysis is here reviewed. The glycolytic pathway has been considered a target to decrease cancer cell growth; however, its occurrence in normal cells makes it difficult to design therapeutic strategies that target this pathway in pathological cells. Notwithstanding, the over-expression of all enzymes and transporters, as well as the expression of isoenzymes with different kinetic and regulatory properties in cancer cells, suggested a different distribution of the control of glycolytic flux than that observed in normal cells. Kinetic models of glycolysis are constructed with enzyme kinetics experimental data, validated with the steady-state metabolite concentrations and glycolytic fluxes; applying MCA, permitted us to identify the steps with the highest control of glycolysis in cancer cells, but low control in normal cells. The cancer glycolysis main controlling steps under several metabolic conditions were: glucose transport, hexokinase and hexose-6-phosphate isomerase (HPI); whereas in normal cells were: the first two and phosphofructokinase-1. HPI is the best therapeutic target because it exerts high control in cancer glycolytic flux, but not in normal cells. Furthermore, kinetic modeling also contributed to identifying new feed-back and feed-forward regulatory loops in cancer cells glycolysis, and to understanding the mode of metabolic action of glycolytic inhibitors. Thus, MCA and metabolic modeling allowed to propose new strategies for inhibiting glycolysis in cancer cells.
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Affiliation(s)
- Álvaro Marín-Hernández
- Departamento de Bioquímica, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, 14080, Mexico.
| | - Emma Saavedra
- Departamento de Bioquímica, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, 14080, Mexico
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Metabolism as a New Avenue for Hepatocellular Carcinoma Therapy. Int J Mol Sci 2023; 24:ijms24043710. [PMID: 36835122 PMCID: PMC9964410 DOI: 10.3390/ijms24043710] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Revised: 02/08/2023] [Accepted: 02/10/2023] [Indexed: 02/16/2023] Open
Abstract
Hepatocellular carcinoma is today the sixth leading cause of cancer-related death worldwide, despite the decreased incidence of chronic hepatitis infections. This is due to the increased diffusion of metabolic diseases such as the metabolic syndrome, diabetes, obesity, and nonalcoholic steatohepatitis (NASH). The current protein kinase inhibitor therapies in HCC are very aggressive and not curative. From this perspective, a shift in strategy toward metabolic therapies may represent a promising option. Here, we review current knowledge on metabolic dysregulation in HCC and therapeutic approaches targeting metabolic pathways. We also propose a multi-target metabolic approach as a possible new option in HCC pharmacology.
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7
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Warren I, Moeller MM, Guiggey D, Chiang A, Maloy M, Ogoke O, Groth T, Mon T, Meamardoost S, Liu X, Thompson S, Szeglowski A, Thompson R, Chen P, Paulmurugan R, Yarmush ML, Kidambi S, Parashurama N. FOXA1/2 depletion drives global reprogramming of differentiation state and metabolism in a human liver cell line and inhibits differentiation of human stem cell-derived hepatic progenitor cells. FASEB J 2023; 37:e22652. [PMID: 36515690 DOI: 10.1096/fj.202101506rrr] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 10/28/2022] [Accepted: 10/31/2022] [Indexed: 12/15/2022]
Abstract
FOXA factors are critical members of the developmental gene regulatory network (GRN) composed of master transcription factors (TF) which regulate murine cell fate and metabolism in the gut and liver. How FOXA factors dictate human liver cell fate, differentiation, and simultaneously regulate metabolic pathways is poorly understood. Here, we aimed to determine the role of FOXA2 (and FOXA1 which is believed to compensate for FOXA2) in controlling hepatic differentiation and cell metabolism in a human hepatic cell line (HepG2). siRNA mediated knockdown of FOXA1/2 in HepG2 cells significantly downregulated albumin (p < .05) and GRN TF gene expression (HNF4α, HEX, HNF1ß, TBX3) (p < .05) and significantly upregulated endoderm/gut/hepatic endoderm markers (goosecoid [GSC], FOXA3, and GATA4), gut TF (CDX2), pluripotent TF (NANOG), and neuroectodermal TF (PAX6) (p < .05), all consistent with partial/transient reprograming. shFOXA1/2 targeting resulted in similar findings and demonstrated evidence of reversibility of phenotype. RNA-seq followed by bioinformatic analysis of shFOXA1/2 knockdown HepG2 cells demonstrated 235 significant downregulated genes and 448 upregulated genes, including upregulation of markers for alternate germ layers lineages (cardiac, endothelial, muscle) and neurectoderm (eye, neural). We found widespread downregulation of glycolysis, citric acid cycle, mitochondrial genes, and alterations in lipid metabolism, pentose phosphate pathway, and ketogenesis. Functional metabolic analysis agreed with these findings, demonstrating significantly diminished glycolysis and mitochondrial respiration, with concomitant accumulation of lipid droplets. We hypothesized that FOXA1/2 inhibit the initiation of human liver differentiation in vitro. During human pluripotent stem cells (hPSC)-hepatic differentiation, siRNA knockdown demonstrated de-differentiation and unexpectedly, activation of pluripotency factors and neuroectoderm. shRNA knockdown demonstrated similar results and activation of SOX9 (hepatobiliary). These results demonstrate that FOXA1/2 controls hepatic and developmental GRN, and their knockdown leads to reprogramming of both differentiation and metabolism, with applications in studies of cancer, differentiation, and organogenesis.
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Affiliation(s)
- Iyan Warren
- Department of Chemical and Biological Engineering, University at Buffalo (State University of New York), Buffalo, New York, USA
| | - Michael M Moeller
- Department of Chemical and Biomolecular Engineering, University of Nebraska- Lincoln, Lincoln, Nebraska, USA
| | - Daniel Guiggey
- Department of Chemical and Biological Engineering, University at Buffalo (State University of New York), Buffalo, New York, USA
| | - Alexander Chiang
- Department of Chemical and Biological Engineering, University at Buffalo (State University of New York), Buffalo, New York, USA
| | - Mitchell Maloy
- Department of Chemical and Biological Engineering, University at Buffalo (State University of New York), Buffalo, New York, USA
| | - Ogechi Ogoke
- Department of Chemical and Biological Engineering, University at Buffalo (State University of New York), Buffalo, New York, USA
| | - Theodore Groth
- Department of Chemical and Biological Engineering, University at Buffalo (State University of New York), Buffalo, New York, USA
| | - Tala Mon
- Department of Chemical and Biological Engineering, University at Buffalo (State University of New York), Buffalo, New York, USA
| | - Saber Meamardoost
- Department of Chemical and Biological Engineering, University at Buffalo (State University of New York), Buffalo, New York, USA
| | - Xiaojun Liu
- Department of Chemical and Biological Engineering, University at Buffalo (State University of New York), Buffalo, New York, USA
| | - Sarah Thompson
- Department of Chemical and Biological Engineering, University at Buffalo (State University of New York), Buffalo, New York, USA
| | - Antoni Szeglowski
- Department of Chemical and Biological Engineering, University at Buffalo (State University of New York), Buffalo, New York, USA
| | - Ryan Thompson
- Department of Chemical and Biological Engineering, University at Buffalo (State University of New York), Buffalo, New York, USA
| | - Peter Chen
- Department of Biomedical Engineering, University at Buffalo (State University of New York), Buffalo, New York, USA
| | - Ramasamy Paulmurugan
- Department of Radiology, Canary Center for Early Cancer Detection and the Molecular Imaging Program at Stanford, Stanford University, Palo Alto, California, USA
| | - Martin L Yarmush
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.,Department of Biomedical Engineering, Rutgers University, Piscataway, New Jersey, USA
| | - Srivatsan Kidambi
- Department of Chemical and Biomolecular Engineering, University of Nebraska- Lincoln, Lincoln, Nebraska, USA
| | - Natesh Parashurama
- Department of Chemical and Biological Engineering, University at Buffalo (State University of New York), Buffalo, New York, USA.,Department of Biomedical Engineering, University at Buffalo (State University of New York), Buffalo, New York, USA.,Clinical and Translation Research Center (CTRC), University at Buffalo (State University of New York), Buffalo, New York, USA
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8
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Vital PDS, Bonatelli M, Dias MP, de Salis LVV, Pinto MT, Baltazar F, Maria-Engler SS, Pinheiro C. 3-Bromopyruvate Suppresses the Malignant Phenotype of Vemurafenib-Resistant Melanoma Cells. Int J Mol Sci 2022; 23:ijms232415650. [PMID: 36555289 PMCID: PMC9779063 DOI: 10.3390/ijms232415650] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 08/23/2022] [Accepted: 09/02/2022] [Indexed: 12/14/2022] Open
Abstract
(1) BRAF mutations are associated with high mortality and are a substantial factor in therapeutic decisions. Therapies targeting BRAF-mutated tumors, such as vemurafenib (PLX), have significantly improved the overall survival of melanoma patients. However, patient relapse and low response rates remain challenging, even with contemporary therapeutic alternatives. Highly proliferative tumors often rely on glycolysis to sustain their aggressive phenotype. 3-bromopyruvate (3BP) is a promising glycolysis inhibitor reported to mitigate resistance in tumors. This study aimed to evaluate the potential of 3BP as an antineoplastic agent for PLX-resistant melanoma treatment. (2) The effect of 3BP alone or in combination with PLX on viability, proliferation, colony formation, cell death, migration, invasion, epithelial-mesenchymal marker and metabolic protein expression, extracellular glucose and lactate, and reactive species were evaluated in two PLX-resistant melanoma cell lines. (3) 3BP treatment, which was more effective as monotherapy than combined with PLX, disturbed the metabolic and epithelial-mesenchymal profile of PLX-resistant cells, impairing their proliferation, migration, and invasion and triggering cell death. (4) 3BP monotherapy is a potent metabolic-disrupting agent against PLX-resistant melanomas, supporting the suppression of the malignant phenotype in this type of neoplasia.
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Affiliation(s)
- Patrik da Silva Vital
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos 14784-400, SP, Brazil
| | - Murilo Bonatelli
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos 14784-400, SP, Brazil
| | - Marina Pereira Dias
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos 14784-400, SP, Brazil
| | - Larissa Vedovato Vilela de Salis
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos 14784-400, SP, Brazil
- Barretos School of Health Sciences Dr. Paulo Prata—FACISB, Barretos 14785-002, SP, Brazil
| | - Mariana Tomazini Pinto
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos 14784-400, SP, Brazil
| | - Fátima Baltazar
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B’s-PT Government Associate Laboratory, 4710-057 Braga, Portugal
| | - Silvya Stuchi Maria-Engler
- Clinical Chemistry and Toxicology Department, School of Pharmaceutical Sciences, University of São Paulo, São Paulo 04023-901, SP, Brazil
| | - Céline Pinheiro
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos 14784-400, SP, Brazil
- Barretos School of Health Sciences Dr. Paulo Prata—FACISB, Barretos 14785-002, SP, Brazil
- Correspondence: ; Tel.: +55-(17)-3321-3060
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9
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Azevedo-Silva J, Tavares-Valente D, Almeida A, Queirós O, Baltazar F, Ko YH, Pedersen PL, Preto A, Casal M. Cytoskeleton disruption by the metabolic inhibitor 3-bromopyruvate: implications in cancer therapy. Med Oncol 2022; 39:121. [PMID: 35716210 DOI: 10.1007/s12032-022-01712-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 03/15/2022] [Indexed: 11/24/2022]
Abstract
The small molecule 3-bromopyruvate (3BP), is an anticancer molecule that acts by hindering glycolysis and mitochondrial function leading to energy depletion and consequently, to cell death. In this work we have focused on understanding how the glycolytic inhibition affects cancer cell structural features. We showed that 3BP leads to a drastic decrease in the levels of β-actin and α-tubulin followed by disorganization and shrinkage of the cytoskeleton in breast cancer cells. 3BP inhibits cell migration and colony formation independently of the activity of metalloproteinases. To disclose if these structural alterations occurred prior to 3BP toxic effect, non-toxic concentrations of 3BP were used and we could observe that 3BP was able to inhibit energy production and induce loss of β-actin and α-tubulin proteins. This was accompanied with alterations in cytoskeleton organization and an increase in E-cadherin levels which may indicate a decrease in cancer cells aggressiveness. In this study we demonstrate that 3BP glycolytic inhibition of breast cancer cells is accompanied by cytoskeleton disruption and consequently loss of migration ability, suggesting that 3BP can potentially be explored for metastatic breast cancer therapy.
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Affiliation(s)
- J Azevedo-Silva
- Department of Biology, Centre of Molecular and Environmental Biology (CBMA), University of Minho, Portugal, Campus de Gualtar, 4710-057, Braga, Portugal.
| | - D Tavares-Valente
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057, Braga, Portugal.,Department of Sciences, IINFACTS - Institute of Research and Advanced Training in Health Sciences and Technologies, CESPU, CRL, University Institute of Health Sciences (IUCS), Gandra, Portugal
| | - A Almeida
- Department of Biology, Centre of Molecular and Environmental Biology (CBMA), University of Minho, Portugal, Campus de Gualtar, 4710-057, Braga, Portugal
| | - O Queirós
- Department of Sciences, IINFACTS - Institute of Research and Advanced Training in Health Sciences and Technologies, CESPU, CRL, University Institute of Health Sciences (IUCS), Gandra, Portugal
| | - F Baltazar
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057, Braga, Portugal
| | - Y H Ko
- KoDiscovery, LLC, University of Maryland BioPark, Suites 502 E & F, 801 West Baltimore St., Baltimore, MD, 21201, USA
| | - P L Pedersen
- Departments of Biological Chemistry and Oncology, Member at Large, Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, 21205-2185, USA
| | - A Preto
- Department of Biology, Centre of Molecular and Environmental Biology (CBMA), University of Minho, Portugal, Campus de Gualtar, 4710-057, Braga, Portugal
| | - M Casal
- Department of Biology, Centre of Molecular and Environmental Biology (CBMA), University of Minho, Portugal, Campus de Gualtar, 4710-057, Braga, Portugal.
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10
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Beygi F, Mostoufi A, Mojaddami A. Novel Hydrazone Derivatives of 3-Bromopyruvate: Synthesis, Evaluation of the Cytotoxic Effects, Molecular Docking and ADME Studies. Chem Biodivers 2022; 19:e202100754. [PMID: 35427437 DOI: 10.1002/cbdv.202100754] [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: 09/16/2021] [Accepted: 04/14/2022] [Indexed: 11/09/2022]
Abstract
A series of 3-bromopyruvate (3-BP) derivatives were synthesized to develop new potent anticancer agents. The chemical structures of the compounds were characterized using FT-IR, 1 H-, 13 C-NMR spectroscopy, and elemental analysis (CHN). Their cytotoxic activities were investigated against four cancer cell lines, including colon (SW1116), breast (MDA-MB-231), lung (A549), and liver (HepG2) cancer cell lines. Among the synthesized compounds, 3b showed promising cytotoxic activity compared to 3-BP, with IC50 values of 16.3 μM, 19.1 μM, 27.8 μM, and 14.5 μM against A549, MDA-MB-231, SW1116 and, HepG2 cell lines, respectively. Furthermore, the effect of these compounds on MCF-10A (a normal breast cell lines) was investigated to determine their selectivity between tumorigenic and non-tumorigenic cells. Since the 3-BP inhibits hexokinase II (HK II), molecular docking of 3-BP derivatives was carried out using AutoDock 4.2. The binding energies of these derivatives were greater than 3-BP, indicating that they had a higher affinity for HK II. For validation of docking, a 40 ns MD simulation was performed. SwissADME was used to predict pharmacokinetics, drug-likeness, and ADME parameters of the screened compounds. The results demonstrated that these derivatives are suitable candidates for developing orally potent HK II inhibitors.
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Affiliation(s)
- Farzaneh Beygi
- Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.,Department of Medicinal Chemistry, School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Azar Mostoufi
- Toxicology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.,Department of Medicinal Chemistry, School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Ayyub Mojaddami
- Toxicology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.,Department of Medicinal Chemistry, School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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11
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Bottoni P, Pontoglio A, Scarà S, Pieroni L, Urbani A, Scatena R. Mitochondrial Respiratory Complexes as Targets of Drugs: The PPAR Agonist Example. Cells 2022; 11:cells11071169. [PMID: 35406733 PMCID: PMC8997591 DOI: 10.3390/cells11071169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 03/17/2022] [Accepted: 03/24/2022] [Indexed: 12/02/2022] Open
Abstract
Mitochondrial bioenergetics are progressively acquiring significant pathophysiological roles. Specifically, mitochondria in general and Electron Respiratory Chain in particular are gaining importance as unintentional targets of different drugs. The so-called PPAR ligands are a class of drugs which not only link and activate Peroxisome Proliferator-Activated Receptors but also show a myriad of extrareceptorial activities as well. In particular, they were shown to inhibit NADH coenzyme Q reductase. However, the molecular picture of this intriguing bioenergetic derangement has not yet been well defined. Using high resolution respirometry, both in permeabilized and intact HepG2 cells, and a proteomic approach, the mitochondrial bioenergetic damage induced by various PPAR ligands was evaluated. Results show a derangement of mitochondrial oxidative metabolism more complex than one related to a simple perturbation of complex I. In fact, a partial inhibition of mitochondrial NADH oxidation seems to be associated not only with hampered ATP synthesis but also with a significant reduction in respiratory control ratio, spare respiratory capacity, coupling efficiency and, last but not least, serious oxidative stress and structural damage to mitochondria.
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Affiliation(s)
- Patrizia Bottoni
- Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy; (A.P.); (S.S.); (A.U.); (R.S.)
- Correspondence:
| | - Alessandro Pontoglio
- Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy; (A.P.); (S.S.); (A.U.); (R.S.)
| | - Salvatore Scarà
- Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy; (A.P.); (S.S.); (A.U.); (R.S.)
| | | | - Andrea Urbani
- Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy; (A.P.); (S.S.); (A.U.); (R.S.)
- Dipartimento di Medicina di Laboratorio, Fondazione Policlinico Gemelli, Largo Agostino Gemelli 8, 00168 Rome, Italy
| | - Roberto Scatena
- Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy; (A.P.); (S.S.); (A.U.); (R.S.)
- Dipartimento di Medicina di Laboratorio, Madre Giuseppina Vannini Hospital, Via di Acqua Bullicante 4, 00177 Rome, Italy
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12
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Du D, Liu C, Qin M, Zhang X, Xi T, Yuan S, Hao H, Xiong J. Metabolic dysregulation and emerging therapeutical targets for hepatocellular carcinoma. Acta Pharm Sin B 2022; 12:558-580. [PMID: 35256934 PMCID: PMC8897153 DOI: 10.1016/j.apsb.2021.09.019] [Citation(s) in RCA: 333] [Impact Index Per Article: 111.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 08/31/2021] [Accepted: 09/01/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is an aggressive human cancer with increasing incidence worldwide. Multiple efforts have been made to explore pharmaceutical therapies to treat HCC, such as targeted tyrosine kinase inhibitors, immune based therapies and combination of chemotherapy. However, limitations exist in current strategies including chemoresistance for instance. Tumor initiation and progression is driven by reprogramming of metabolism, in particular during HCC development. Recently, metabolic associated fatty liver disease (MAFLD), a reappraisal of new nomenclature for non-alcoholic fatty liver disease (NAFLD), indicates growing appreciation of metabolism in the pathogenesis of liver disease, including HCC, thereby suggesting new strategies by targeting abnormal metabolism for HCC treatment. In this review, we introduce directions by highlighting the metabolic targets in glucose, fatty acid, amino acid and glutamine metabolism, which are suitable for HCC pharmaceutical intervention. We also summarize and discuss current pharmaceutical agents and studies targeting deregulated metabolism during HCC treatment. Furthermore, opportunities and challenges in the discovery and development of HCC therapy targeting metabolism are discussed.
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Key Words
- 1,3-BPG, 1,3-bisphosphoglycerate
- 2-DG, 2-deoxy-d-glucose
- 3-BrPA, 3-bromopyruvic acid
- ACC, acetyl-CoA carboxylase
- ACLY, adenosine triphosphate (ATP) citrate lyase
- ACS, acyl-CoA synthease
- AKT, protein kinase B
- AML, acute myeloblastic leukemia
- AMPK, adenosine mono-phosphate-activated protein kinase
- ASS1, argininosuccinate synthase 1
- ATGL, adipose triacylglycerol lipase
- CANA, canagliflozin
- CPT, carnitine palmitoyl-transferase
- CYP4, cytochrome P450s (CYPs) 4 family
- Cancer therapy
- DNL, de novo lipogenesis
- EMT, epithelial-to-mesenchymal transition
- ER, endoplasmic reticulum
- ERK, extracellular-signal regulated kinase
- FABP1, fatty acid binding protein 1
- FASN, fatty acid synthase
- FBP1, fructose-1,6-bisphosphatase 1
- FFA, free fatty acid
- Fatty acid β-oxidation
- G6PD, glucose-6-phosphate dehydrogenase
- GAPDH, glyceraldehyde-3-phosphate dehydrogenase
- GLS1, renal-type glutaminase
- GLS2, liver-type glutaminase
- GLUT1, glucose transporter 1
- GOT1, glutamate oxaloacetate transaminase 1
- Glutamine metabolism
- Glycolysis
- HCC, hepatocellular carcinoma
- HIF-1α, hypoxia-inducible factor-1 alpha
- HK, hexokinase
- HMGCR, 3-hydroxy-3-methylglutaryl-CoA reductase
- HSCs, hepatic stellate cells
- Hepatocellular carcinoma
- IDH2, isocitrate dehydrogenase 2
- LCAD, long-chain acyl-CoA dehydrogenase
- LDH, lactate dehydrogenase
- LPL, lipid lipase
- LXR, liver X receptor
- MAFLD, metabolic associated fatty liver disease
- MAGL, monoacyglycerol lipase
- MCAD, medium-chain acyl-CoA dehydrogenase
- MEs, malic enzymes
- MMP9, matrix metallopeptidase 9
- Metabolic dysregulation
- NADPH, nicotinamide adenine nucleotide phosphate
- NAFLD, non-alcoholic fatty liver disease
- NASH, non-alcoholic steatohepatitis
- OTC, ornithine transcarbamylase
- PCK1, phosphoenolpyruvate carboxykinase 1
- PFK1, phosphofructokinase 1
- PGAM1, phosphoglycerate mutase 1
- PGK1, phosphoglycerate kinase 1
- PI3K, phosphoinositide 3-kinase
- PKM2, pyruvate kinase M2
- PPARα, peroxisome proliferator-activated receptor alpha
- PPP, pentose phosphate pathway
- Pentose phosphate pathway
- ROS, reactive oxygen species
- SCD1, stearoyl-CoA-desaturase 1
- SGLT2, sodium-glucose cotransporter 2
- SLC1A5/ASCT2, solute carrier family 1 member 5/alanine serine cysteine preferring transporter 2
- SLC7A5/LAT1, solute carrier family 7 member 5/L-type amino acid transporter 1
- SREBP1, sterol regulatory element-binding protein 1
- TAGs, triacylglycerols
- TCA cycle, tricarboxylic acid cycle
- TKIs, tyrosine kinase inhibitors
- TKT, transketolase
- Tricarboxylic acid cycle
- VEGFR, vascular endothelial growth factor receptor
- WD-fed MC4R-KO, Western diet (WD)-fed melanocortin 4 receptor-deficient (MC4R-KO)
- WNT, wingless-type MMTV integration site family
- mIDH, mutant IDH
- mTOR, mammalian target of rapamycin
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Affiliation(s)
- Danyu Du
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Chan Liu
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Mengyao Qin
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Xiao Zhang
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Tao Xi
- Research Center of Biotechnology, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China
| | - Shengtao Yuan
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China
| | - Haiping Hao
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
- Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China
- Corresponding authors.
| | - Jing Xiong
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
- Corresponding authors.
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13
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Wen J, Luo Y, Gao H, Zhang L, Wang X, Huang J, Shang T, Zhou D, Wang D, Wang Z, Li P, Wang Z. Mitochondria-targeted nanoplatforms for enhanced photodynamic therapy against hypoxia tumor. J Nanobiotechnology 2021; 19:440. [PMID: 34930284 PMCID: PMC8686264 DOI: 10.1186/s12951-021-01196-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 12/08/2021] [Indexed: 12/12/2022] Open
Abstract
Background Photodynamic therapy (PDT) is a promising therapeutic modality that can convert oxygen into cytotoxic reactive oxygen species (ROS) via photosensitizers to halt tumor growth. However, hypoxia and the unsatisfactory accumulation of photosensitizers in tumors severely diminish the therapeutic effect of PDT. In this study, a multistage nanoplatform is demonstrated to overcome these limitations by encapsulating photosensitizer IR780 and oxygen regulator 3-bromopyruvate (3BP) in poly (lactic-co-glycolic acid) (PLGA) nanocarriers. Results The as-synthesized nanoplatforms penetrated deeply into the interior region of tumors and preferentially remained in mitochondria due to the intrinsic characteristics of IR780. Meanwhile, 3BP could efficiently suppress oxygen consumption of tumor cells by inhibiting mitochondrial respiratory chain to further improve the generation of ROS. Furthermore, 3BP could abolish the excessive glycolytic capacity of tumor cells and lead to the collapse of ATP production, rendering tumor cells more susceptible to PDT. Successful tumor inhibition in animal models confirmed the therapeutic precision and efficiency. In addition, these nanoplatforms could act as fluorescence (FL) and photoacoustic (PA) imaging contrast agents, effectuating imaging-guided cancer treatment. Conclusions This study provides an ideal strategy for cancer therapy by concurrent oxygen consumption reduction, oxygen-augmented PDT, energy supply reduction, mitochondria-targeted/deep-penetrated nanoplatforms and PA/FL dual-modal imaging guidance/monitoring. It is expected that such strategy will provide a promising alternative to maximize the performance of PDT in preclinical/clinical cancer treatment. Graphical Abstract ![]()
Supplementary Information The online version contains supplementary material available at 10.1186/s12951-021-01196-6.
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Affiliation(s)
- Jiexin Wen
- Department of Ultrasound, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, People's Republic of China
| | - Yong Luo
- Department of Ultrasound, The First People's Hospital of Chongqing Liang Jiang New Area, Chongqing, 401121, People's Republic of China
| | - Hui Gao
- Department of Ultrasound, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, People's Republic of China
| | - Liang Zhang
- Chongqing Key Laboratory of Ultrasound Molecular Imaging, Institute of Ultrasound Imaging, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, People's Republic of China
| | - Xiang Wang
- Department of Ultrasound, The Third Affiliated Hospital, Chongqing Medical University, Chongqing, 401120, People's Republic of China
| | - Ju Huang
- Department of Ultrasound, The Third Affiliated Hospital, Chongqing Medical University, Chongqing, 401120, People's Republic of China
| | - Tingting Shang
- Chongqing Key Laboratory of Ultrasound Molecular Imaging, Institute of Ultrasound Imaging, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, People's Republic of China
| | - Di Zhou
- Department of Radiology, The First Affiliated Hospital, Chongqing Medical University, Chongqing, 400042, People's Republic of China
| | - Dong Wang
- Department of Ultrasound, The First Affiliated Hospital, Chongqing Medical University, Chongqing, 400042, People's Republic of China
| | - Zhigang Wang
- Chongqing Key Laboratory of Ultrasound Molecular Imaging, Institute of Ultrasound Imaging, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, People's Republic of China
| | - Pan Li
- Chongqing Key Laboratory of Ultrasound Molecular Imaging, Institute of Ultrasound Imaging, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, People's Republic of China
| | - Zhaoxia Wang
- Department of Ultrasound, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, People's Republic of China.
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14
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Qiu Q, Zou H, Zou H, Jing T, Li X, Yan G, Geng N, Zhang B, Zhang Z, Zhang S, Yao B, Zhang G, Zou C. 3-Bromopyruvate-induced glycolysis inhibition impacts larval growth and development and carbohydrate homeostasis in fall webworm, Hyphantria cunea Drury. PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY 2021; 179:104961. [PMID: 34802511 DOI: 10.1016/j.pestbp.2021.104961] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 08/26/2021] [Accepted: 08/27/2021] [Indexed: 06/13/2023]
Abstract
As a typical glycolytic inhibitor, 3-bromopyruvate (3-BrPA) has been extensively studied in cancer therapy in recent decades. However, few studies focused on 3-BrPA in regulating the growth and development of insects, and the relationship and regulatory mechanism between glycolysis and chitin biosynthesis remain largely unknown. The Hyphantria cunea, named fall webworm, is a notorious defoliator, which caused a huge economic loss to agriculture and forestry. Here, we investigated the effects of 3-BrPA on the growth and development, glycolysis, carbohydrate homeostasis, as well as chitin synthesis in H. cunea larvae. To elucidate the action mechanism of 3-BrPA on H. cunea will provide a new insight for the control of this pest. The results showed that 3-BrPA dramatically restrained the growth and development of H. cunea larvae and resulted in larval lethality. Meanwhile, we confirmed that 3-BrPA caused a significant decrease in carbohydrate, adenosine triphosphate (ATP), pyruvic acid (PA), and triglyceride (TG) levels by inhibiting glycolysis in H. cunea larvae. Further studies indicated that 3-BrPA significantly affected the activities of hexokinase (HK), phosphofructokinase (PFK), pyruvate kinase (PK), glucose 6-phosphate dehydrogenase (G6PDH) and trehalase, as well as expressions of the genes related to glycolysis, resulting in carbohydrate homeostasis disorder. Moreover, it was found that 3-BrPA enhanced 20-hydroxyecdysone (20E) signaling by upregulating HcCYP306A1 and HcCYP314A1, two critical genes in 20E synthesis pathway, and accelerated chitin synthesis by upregulating transcriptional levels of genes in the chitin synthesis pathway in H. cunea larvae. Taken together, our findings provide a novel insight into the mechanism of glycolytic inhibitor in regulating the growth and development of insects, and lay a foundation for the potential application of glycolytic inhibitors in pest control as well.
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Affiliation(s)
- Qian Qiu
- School of Forestry, Northeast Forestry University, Harbin 150040, PR China
| | - Haifeng Zou
- School of Forestry, Northeast Forestry University, Harbin 150040, PR China
| | - Hang Zou
- School of Forestry, Northeast Forestry University, Harbin 150040, PR China
| | - Tianzhong Jing
- School of Forestry, Northeast Forestry University, Harbin 150040, PR China
| | - XingPeng Li
- School of Forestry, Beihua University, Jilin 132013, PR China
| | - Gaige Yan
- School of Forestry, Northeast Forestry University, Harbin 150040, PR China
| | - Nannan Geng
- School of Forestry, Northeast Forestry University, Harbin 150040, PR China
| | - Bihan Zhang
- School of Forestry, Northeast Forestry University, Harbin 150040, PR China
| | - Zhidong Zhang
- School of Forestry, Northeast Forestry University, Harbin 150040, PR China
| | - Shengyu Zhang
- School of Forestry, Northeast Forestry University, Harbin 150040, PR China
| | - Bin Yao
- School of Forestry, Northeast Forestry University, Harbin 150040, PR China
| | - Guocai Zhang
- School of Forestry, Northeast Forestry University, Harbin 150040, PR China.
| | - Chuanshan Zou
- School of Forestry, Northeast Forestry University, Harbin 150040, PR China.
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15
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Gomes MT, Paes-Vieira L, Gomes-Vieira AL, Cosentino-Gomes D, da Silva APP, Giarola NLL, Da Silva D, Sola-Penna M, Galina A, Meyer-Fernandes JR. 3-Bromopyruvate: A new strategy for inhibition of glycolytic enzymes in Leishmania amazonensis. Exp Parasitol 2021; 229:108154. [PMID: 34481863 DOI: 10.1016/j.exppara.2021.108154] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Revised: 05/14/2021] [Accepted: 08/28/2021] [Indexed: 11/29/2022]
Abstract
The compound 3-bromopyruvate (3-BrPA) is well-known and studies from several researchers have demonstrated its involvement in tumorigenesis. It is an analogue of pyruvic acid that inhibits ATP synthesis by inhibiting enzymes from the glycolytic pathway and oxidative phosphorylation. In this work, we investigated the effect of 3-BrPA on energy metabolism of L. amazonensis. In order to verify the effect of 3-BrPA on L. amazonensis glycolysis, we measured the activity level of three glycolytic enzymes located at different points of the pathway: (i) glucose kinases, step 1, (ii) glyceraldehyde 3-phosphate dehydrogenase (GAPDH), step 6, and (iii) enolase, step 9. 3-BrPA, in a dose-dependent manner, significantly reduced the activity levels of all the enzymes. In addition, 3-BrPA treatment led to a reduction in the levels of phosphofruto-1-kinase (PFK) protein, suggesting that the mode of action of 3-BrPA involves the downregulation of some glycolytic enzymes. Measurement of ATP levels in promastigotes of L. amazonensis showed a significant reduction in ATP generation. The O2 consumption was also significantly inhibited in promastigotes, confirming the energy depletion effect of 3-BrPA. When 3-BrPA was added to the cells at the beginning of growth cycle, it significantly inhibited L. amazonensis proliferation in a dose-dependent manner. Furthermore, the ability to infect macrophages was reduced by approximately 50% when promastigotes were treated with 3-BrPA. Taken together, these studies corroborate with previous reports which suggest 3-BrPA as a potential drug against pathogenic microorganisms that are reliant on glucose catabolism for ATP supply.
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Affiliation(s)
- Marta Teixeira Gomes
- Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Department of Medicine, Indiana University, Indianapolis, IN, USA; Laboratório de Bioquímica Celular, Instituto de Bioquímica Médica Leopoldo de Meis, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
| | - Lisvane Paes-Vieira
- Laboratório de Bioquímica Celular, Instituto de Bioquímica Médica Leopoldo de Meis, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - André Luiz Gomes-Vieira
- Instituto de Química, Departamento de Bioquímica, Universidade Federal Rural do Rio de Janeiro, Seropédica, RJ, Brazil
| | - Daniela Cosentino-Gomes
- Instituto de Química, Departamento de Bioquímica, Universidade Federal Rural do Rio de Janeiro, Seropédica, RJ, Brazil
| | - Ana Paula Pereira da Silva
- Instituto de Química, Departamento de Bioquímica, Universidade Federal Rural do Rio de Janeiro, Seropédica, RJ, Brazil
| | - Naira Ligia Lima Giarola
- Laboratório de Bioquímica Celular, Instituto de Bioquímica Médica Leopoldo de Meis, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Daniel Da Silva
- Laboratório de Enzimologia e Controle do Metabolismo, Departamento de Biotecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Mauro Sola-Penna
- Laboratório de Enzimologia e Controle do Metabolismo, Departamento de Biotecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Antonio Galina
- Laboratorio de Bioenergética e Fisiologia Mitocondrial, Programa de Bioquímica e Biofísica Celular, Instituto de Bioquímica Medica Leopoldo de Meis, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, RJ, Brazil
| | - José Roberto Meyer-Fernandes
- Laboratório de Bioquímica Celular, Instituto de Bioquímica Médica Leopoldo de Meis, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Instituto Nacional de Ciência e Tecnologia em Biologia Estrutural e Bioimagem, Rio de Janeiro, RJ, Brazil.
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16
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Faria AVS, Fonseca EMB, Cordeiro HG, Clerici SP, Ferreira-Halder CV. Low molecular weight protein tyrosine phosphatase as signaling hub of cancer hallmarks. Cell Mol Life Sci 2021; 78:1263-1273. [PMID: 33052434 PMCID: PMC11073135 DOI: 10.1007/s00018-020-03657-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 08/21/2020] [Accepted: 09/22/2020] [Indexed: 12/12/2022]
Abstract
In the past decade, significant progress has been made in understanding the role of protein tyrosine phosphatase as a positive regulator of tumor progression. In this scenario, our group was one of the first to report the involvement of the low molecular weight protein tyrosine phosphatase (LMWPTP or ACP1) in the process of resistance and migration of tumor cells. Later, we and others demonstrated a positive correlation between the amount of this enzyme in human tumors and the poor prognosis. With this information in mind, we asked if LMWPTP contribution to metastasis, would it have an action beyond the primary tumor site. We know that the amount of this enzyme in the tumor cell correlates positively with the ability of cancer cells to interact with platelets, an indication that this enzyme is also important for the survival of these cells in the bloodstream. Here, we discuss several molecular aspects that support the idea of LMWPTP as a signaling hub of cancer hallmarks. Chemical and genetic modulation of LMWPTP proved to shut down signaling pathways associated with cancer aggressiveness. Therefore, advances in the development of LMWPTP inhibitors have great applicability in human diseases such as cancer.
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Affiliation(s)
- Alessandra V S Faria
- Department of Biochemistry and Tissue Biology, University of Campinas, Campinas, São Paulo, Brazil
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Emanuella Maria Barreto Fonseca
- Department of Biochemistry and Tissue Biology, University of Campinas, Campinas, São Paulo, Brazil
- Federal Institute of São Paulo, São Roque, São Paulo, Brazil
| | - Helon Guimarães Cordeiro
- Department of Biochemistry and Tissue Biology, University of Campinas, Campinas, São Paulo, Brazil
| | - Stefano Piatto Clerici
- Department of Biochemistry and Tissue Biology, University of Campinas, Campinas, São Paulo, Brazil
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17
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Schmidt CA, McLaughlin KL, Boykov IN, Mojalagbe R, Ranganathan A, Buddo KA, Lin CT, Fisher-Wellman KH, Neufer PD. Aglycemic growth enhances carbohydrate metabolism and induces sensitivity to menadione in cultured tumor-derived cells. Cancer Metab 2021; 9:3. [PMID: 33468237 PMCID: PMC7816515 DOI: 10.1186/s40170-021-00241-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 01/06/2021] [Indexed: 12/19/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) is the most prevalent form of liver malignancy and carries poor prognoses due to late presentation of symptoms. Treatment of late-stage HCC relies heavily on chemotherapeutics, many of which target cellular energy metabolism. A key platform for testing candidate chemotherapeutic compounds is the intrahepatic orthotopic xenograft (IOX) model in rodents. Translational efficacy from the IOX model to clinical use is limited (in part) by variation in the metabolic phenotypes of the tumor-derived cells that can be induced by selective adaptation to subculture conditions. Methods In this study, a detailed multilevel systems approach combining microscopy, respirometry, potentiometry, and extracellular flux analysis (EFA) was utilized to examine metabolic adaptations that occur under aglycemic growth media conditions in HCC-derived (HEPG2) cells. We hypothesized that aglycemic growth would result in adaptive “aerobic poise” characterized by enhanced capacity for oxidative phosphorylation over a range of physiological energetic demand states. Results Aglycemic growth did not invoke adaptive changes in mitochondrial content, network complexity, or intrinsic functional capacity/efficiency. In intact cells, aglycemic growth markedly enhanced fermentative glycolytic substrate-level phosphorylation during glucose refeeding and enhanced responsiveness of both fermentation and oxidative phosphorylation to stimulated energy demand. Additionally, aglycemic growth induced sensitivity of HEPG2 cells to the provitamin menadione at a 25-fold lower dose compared to control cells. Conclusions These findings indicate that growth media conditions have substantial effects on the energy metabolism of subcultured tumor-derived cells, which may have significant implications for chemotherapeutic sensitivity during incorporation in IOX testing panels. Additionally, the metabolic phenotyping approach used in this study provides a practical workflow that can be incorporated with IOX screening practices to aid in deciphering the metabolic underpinnings of chemotherapeutic drug sensitivity. Supplementary Information The online version contains supplementary material available at 10.1186/s40170-021-00241-0.
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Affiliation(s)
- Cameron A Schmidt
- East Carolina Diabetes and Obesity Institute, Greenville, NC, USA.,Dept. of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC, USA
| | - Kelsey L McLaughlin
- East Carolina Diabetes and Obesity Institute, Greenville, NC, USA.,Dept. of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC, USA
| | - Ilya N Boykov
- East Carolina Diabetes and Obesity Institute, Greenville, NC, USA.,Dept. of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC, USA
| | - Rafiq Mojalagbe
- East Carolina Diabetes and Obesity Institute, Greenville, NC, USA
| | | | - Katherine A Buddo
- East Carolina Diabetes and Obesity Institute, Greenville, NC, USA.,Dept. of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC, USA
| | - Chien-Te Lin
- East Carolina Diabetes and Obesity Institute, Greenville, NC, USA.,Dept. of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC, USA
| | - Kelsey H Fisher-Wellman
- East Carolina Diabetes and Obesity Institute, Greenville, NC, USA. .,Dept. of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
| | - P Darrell Neufer
- East Carolina Diabetes and Obesity Institute, Greenville, NC, USA. .,Dept. of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
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18
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Bose S, Zhang C, Le A. Glucose Metabolism in Cancer: The Warburg Effect and Beyond. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1311:3-15. [PMID: 34014531 PMCID: PMC9639450 DOI: 10.1007/978-3-030-65768-0_1] [Citation(s) in RCA: 111] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Otto Warburg observed a peculiar phenomenon in 1924, unknowingly laying the foundation for the field of cancer metabolism. While his contemporaries hypothesized that tumor cells derived the energy required for uncontrolled replication from proteolysis and lipolysis, Warburg instead found them to rapidly consume glucose, converting it to lactate even in the presence of oxygen. The significance of this finding, later termed the Warburg effect, went unnoticed by the broader scientific community at that time. The field of cancer metabolism lay dormant for almost a century awaiting advances in molecular biology and genetics, which would later open the doors to new cancer therapies [2, 3].
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Affiliation(s)
- Sminu Bose
- Division of Hematology and Oncology, Department of Medicine, Columbia University Medical Center, New York, NY, USA
| | - Cissy Zhang
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Biology, Johns Hopkins University Krieger School of Arts and Sciences, Baltimore, MD, USA
| | - Anne Le
- Department of Pathology and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University Whiting School of Engineering, Baltimore, MD, USA.
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19
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Petricciuolo M, Davidescu M, Fettucciari K, Gatticchi L, Brancorsini S, Roberti R, Corazzi L, Macchioni L. The efficacy of the anticancer 3-bromopyruvate is potentiated by antimycin and menadione by unbalancing mitochondrial ROS production and disposal in U118 glioblastoma cells. Heliyon 2020; 6:e05741. [PMID: 33364504 PMCID: PMC7753915 DOI: 10.1016/j.heliyon.2020.e05741] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 11/06/2020] [Accepted: 12/11/2020] [Indexed: 12/14/2022] Open
Abstract
Metabolic reprogramming of tumour cells sustains cancer progression. Similar to other cancer cells, glioblastoma cells exhibit an increased glycolytic flow, which encourages the use of antiglycolytics as an effective complementary therapy. We used the antiglycolytic 3-bromopyruvate (3BP) as a metabolic modifier to treat U118 glioblastoma cells and investigated the toxic effects and the conditions to increase drug effectiveness at the lowest concentration. Cellular vitality was not affected by 3BP concentrations lower than 40 μM, although p-Akt dephosphorylation, p53 degradation, and ATP reduction occurred already at 30 μM 3BP. ROS generated in mitochondria were enhanced at 30 μM 3BP, possibly by unbalancing their generation and their disposal because of glutathione peroxidase inhibition. ROS triggered JNK and ERK phosphorylation, and cyt c release outside mitochondria, not accompanied by caspases-9 and -3 activation, probably due to 3BP-dependent alkylation of cysteine residues at caspase-9 catalytic site. To explore the possibility of sensitizing cells to 3BP treatment, we exploited 3BP effects on mitochondria by using 30 μM 3BP in association with antimycin A or menadione concentrations that in themselves exhibit poor toxicity. 3BP effect on cyt c release and cell vitality loss was potentiated due the greater oxidative stress induced by antimycin or menadione association with 3BP, supporting a preeminent role of mitochondrial ROS in 3BP toxicity. Indeed, the scavenger of mitochondrial superoxide MitoTEMPO counteracted 3BP-induced cyt c release and weakened the potentiating effect of 3BP/antimycin association. In conclusion, the biochemical mechanisms leading U118 glioblastoma cells to viability loss following 3BP treatment rely on mitochondrial ROS-dependent pathways. Their potentiation at low 3BP concentrations is consistent with the goal to minimize the toxic effect of the drug towards non-cancer cells.
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Affiliation(s)
- Maya Petricciuolo
- Department of Experimental Medicine, University of Perugia, 06132, Perugia, Italy
| | - Magdalena Davidescu
- Department of Experimental Medicine, University of Perugia, 06132, Perugia, Italy
| | - Katia Fettucciari
- Department of Experimental Medicine, University of Perugia, 06132, Perugia, Italy
| | - Leonardo Gatticchi
- Department of Experimental Medicine, University of Perugia, 06132, Perugia, Italy
| | - Stefano Brancorsini
- Department of Experimental Medicine, University of Perugia, 06132, Perugia, Italy
| | - Rita Roberti
- Department of Experimental Medicine, University of Perugia, 06132, Perugia, Italy
| | - Lanfranco Corazzi
- Department of Experimental Medicine, University of Perugia, 06132, Perugia, Italy
| | - Lara Macchioni
- Department of Experimental Medicine, University of Perugia, 06132, Perugia, Italy
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20
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Wang G, Yu Y, Wang YZ, Zhu ZM, Yin PH, Xu K. Effects and mechanisms of fatty acid metabolism‑mediated glycolysis regulated by betulinic acid‑loaded nanoliposomes in colorectal cancer. Oncol Rep 2020; 44:2595-2609. [PMID: 33125108 PMCID: PMC7640364 DOI: 10.3892/or.2020.7787] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Accepted: 06/03/2020] [Indexed: 01/05/2023] Open
Abstract
Although previous studies have demonstrated that triterpenoids, such as betulinic acid (BA), can inhibit tumor cell growth, their potential targets in colorectal cancer (CRC) metabolism have not been systematically investigated. In the present study, BA‑loaded nanoliposomes (BA‑NLs) were prepared, and their effects on CRC cell lines were evaluated. The aim of the present study was to determine the anticancer mechanisms of action of BA‑NLs in fatty acid metabolism‑mediated glycolysis, and investigate the role of key targets, such as acyl‑CoA synthetase (ACSL), carnitine palmitoyltransferase (CPT) and acetyl CoA, in promoting glycolysis, which is activated by inducing hexokinase (HK), phosphofructokinase‑1 (PFK‑1), phosphoenolpyruvate (PEP) and pyruvate kinase (PK) expression. The results demonstrated that BA‑NLs significantly suppressed the proliferation and glucose uptake of CRC cells by regulating potential glycolysis and fatty acid metabolism targets and pathways, which forms the basis of the anti‑CRC function of BA‑NLs. Moreover, the effects of BA‑NLs were further validated by demonstrating that the key targets of HK2, PFK‑1, PEP and PK isoenzyme M2 (PKM2) in glycolysis, and of ACSL1, CPT1a and PEP in fatty acid metabolism, were blocked by BA‑NLs, which play key roles in the inhibition of glycolysis and fatty acid‑mediated production of pyruvate and lactate. The results of the present study may provide a deeper understanding supporting the hypothesis that liposomal BA may regulate alternative metabolic pathways implicated in CRC adjuvant therapy.
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Affiliation(s)
- Gang Wang
- Department of Pharmaceutics, Shanghai Eighth People's Hospital, Jiangsu University, Shanghai 200235, P.R. China
| | - Yang Yu
- Jiangsu University School of Pharmacy, Zhenjiang, Jiangsu 212001, P.R. China
| | - Yu-Zhu Wang
- Jiangsu University School of Pharmacy, Zhenjiang, Jiangsu 212001, P.R. China
| | - Zhi-Min Zhu
- Department of Pharmaceutics, Shanghai Eighth People's Hospital, Jiangsu University, Shanghai 200235, P.R. China
| | - Pei-Hao Yin
- Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China
| | - Ke Xu
- Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China
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21
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Galbiati A, Zana A, Conti P. Covalent inhibitors of GAPDH: From unspecific warheads to selective compounds. Eur J Med Chem 2020; 207:112740. [PMID: 32898762 DOI: 10.1016/j.ejmech.2020.112740] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 07/23/2020] [Accepted: 08/05/2020] [Indexed: 11/18/2022]
Abstract
Targeting glycolysis is an attractive approach for the treatment of a wide range of pathologies, such as various tumors and parasitic infections. Due to its pivotal role in the glycolysis, Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) represents a rate-limiting enzyme in those cells that mostly, or exclusively rely on this pathway for energy production. In this context, GAPDH inhibition can be a valuable approach for the development of anticancer and antiparasitic drugs. In addition to its glycolytic role, GAPDH possesses several moonlight functions, whose deregulation is involved in some pathological conditions. Covalent modification on different amino acids of GAPDH, in particular on cysteine residues, can lead to a modulation of the enzyme activity. The selectivity towards specific cysteine residues is essential to achieve a specific phenotypic effect. In this work we report an extensive overview of the latest advances on the numerous compounds able to inhibit GAPDH through the covalent binding to cysteine residues, ranging from endogenous metabolites and xenobiotics, which may serve as pharmacological tools to actual drug-like compounds with promising therapeutic perspectives. Furthermore, we focused on the potentialities of the different warheads, shedding light on the possibility to exploit a combination of a finely tuned electrophilic group with a well-designed recognition moiety. These findings can provide useful information for the rational design of novel covalent inhibitors of GAPDH, with the final goal to expand the current treatment options.
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Affiliation(s)
- Andrea Galbiati
- Department of Pharmaceutical Sciences, Università degli Studi di Milano, Via Mangiagalli 25, 20133, Milano, Italy.
| | - Aureliano Zana
- Department of Pharmaceutical Sciences, Università degli Studi di Milano, Via Mangiagalli 25, 20133, Milano, Italy
| | - Paola Conti
- Department of Pharmaceutical Sciences, Università degli Studi di Milano, Via Mangiagalli 25, 20133, Milano, Italy
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22
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Oliveira GL, Coelho AR, Marques R, Oliveira PJ. Cancer cell metabolism: Rewiring the mitochondrial hub. Biochim Biophys Acta Mol Basis Dis 2020; 1867:166016. [PMID: 33246010 DOI: 10.1016/j.bbadis.2020.166016] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 11/12/2020] [Accepted: 11/15/2020] [Indexed: 12/15/2022]
Abstract
To adapt to tumoral environment conditions or even to escape chemotherapy, cells rapidly reprogram their metabolism to handle adversities and survive. Given the rapid rise of studies uncovering novel insights and therapeutic opportunities based on the role of mitochondria in tumor metabolic programing and therapeutics, this review summarizes most significant developments in the field. Taking in mind the key role of mitochondria on carcinogenesis and tumor progression due to their involvement on tumor plasticity, metabolic remodeling, and signaling re-wiring, those organelles are also potential therapeutic targets. Among other topics, we address the recent data intersecting mitochondria as of prognostic value and staging in cancer, by mitochondrial DNA (mtDNA) determination, and current inhibitors developments targeting mtDNA, OXPHOS machinery and metabolic pathways. We contribute for a holistic view of the role of mitochondria metabolism and directed therapeutics to understand tumor metabolism, to circumvent therapy resistance, and to control tumor development.
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Affiliation(s)
- Gabriela L Oliveira
- CNC-Center for Neuroscience and Cell Biology, UC-Biotech, University of Coimbra, Biocant Park, Cantanhede, Portugal
| | - Ana R Coelho
- CNC-Center for Neuroscience and Cell Biology, UC-Biotech, University of Coimbra, Biocant Park, Cantanhede, Portugal
| | - Ricardo Marques
- CNC-Center for Neuroscience and Cell Biology, UC-Biotech, University of Coimbra, Biocant Park, Cantanhede, Portugal
| | - Paulo J Oliveira
- CNC-Center for Neuroscience and Cell Biology, UC-Biotech, University of Coimbra, Biocant Park, Cantanhede, Portugal.
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23
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Natural Agents Targeting Mitochondria in Cancer. Int J Mol Sci 2020; 21:ijms21196992. [PMID: 32977472 PMCID: PMC7582837 DOI: 10.3390/ijms21196992] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 09/18/2020] [Accepted: 09/18/2020] [Indexed: 02/07/2023] Open
Abstract
Mitochondria are the key energy provider to highly proliferating cancer cells, and are subsequently considered one of the critical targets in cancer therapeutics. Several compounds have been studied for their mitochondria-targeting ability in cancer cells. These studies’ outcomes have led to the invention of “mitocans”, a category of drug known to precisely target the cancer cells’ mitochondria. Based upon their mode of action, mitocans have been divided into eight classes. To date, different synthetic compounds have been suggested to be potential mitocans, but unfortunately, they are observed to exert adverse effects. Many studies have been published justifying the medicinal significance of large numbers of natural agents for their mitochondria-targeting ability and anticancer activities with minimal or no side effects. However, these natural agents have never been critically analyzed for their mitochondria-targeting activity. This review aims to evaluate the various natural agents affecting mitochondria and categorize them in different classes. Henceforth, our study may further support the potential mitocan behavior of various natural agents and highlight their significance in formulating novel potential anticancer therapeutics.
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24
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Linke C, Wösle M, Harder A. Anti-cancer agent 3-bromopyruvate reduces growth of MPNST and inhibits metabolic pathways in a representative in-vitro model. BMC Cancer 2020; 20:896. [PMID: 32948135 PMCID: PMC7501688 DOI: 10.1186/s12885-020-07397-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Accepted: 09/09/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Anticancer compound 3-bromopyruvate (3-BrPA) suppresses cancer cell growth via targeting glycolytic and mitochondrial metabolism. The malignant peripheral nerve sheath tumor (MPNST), a very aggressive, therapy resistant, and Neurofibromatosis type 1 associated neoplasia, shows a high metabolic activity and affected patients may therefore benefit from 3-BrPA treatment. To elucidate the specific mode of action, we used a controlled cell model overexpressing proteasome activator (PA) 28, subsequently leading to p53 inactivation and oncogenic transformation and therefore reproducing an important pathway in MPNST and overall tumor pathogenesis. METHODS Viability of MPNST cell lines S462, NSF1, and T265 in response to increasing doses (0-120 μM) of 3-BrPA was analyzed by CellTiter-Blue® assay. Additionally, we investigated viability, reactive oxygen species (ROS) production (dihydroethidium assay), nicotinamide adenine dinucleotide dehydrogenase activity (NADH-TR assay) and lactate production (lactate assay) in mouse B8 fibroblasts overexpressing PA28 in response to 3-BrPA application. For all experiments normal and nutrient deficient conditions were tested. MPNST cell lines were furthermore characterized immunohistochemically for Ki67, p53, bcl2, bcl6, cyclin D1, and p21. RESULTS MPNST significantly responded dose dependent to 3-BrPA application, whereby S462 cells were most responsive. Human control cells showed a reduced sensitivity. In PA28 overexpressing cancer cell model 3-BrPA application harmed mitochondrial NADH dehydrogenase activity mildly and significantly failed to inhibit lactate production. PA28 overexpression was associated with a functional glycolysis as well as a partial resistance to stress provoked by nutrient deprivation. 3-BrPA treatment was not associated with an increase of ROS. Starvation sensitized MPNST to treatment. CONCLUSIONS Aggressive MPNST cells are sensitive to 3-BrPA therapy in-vitro with and without starvation. In a PA28 overexpression cancer cell model leading to p53 inactivation, thereby reflecting a key molecular feature in human NF1 associated MPNST, known functions of 3-BrPA to block mitochondrial activity and glycolysis were reproduced, however oncogenic cells displayed a partial resistance. To conclude, 3-BrPA was sufficient to reduce NF1 associated MPNST viability potentially due inhibition of glycolysis which should lead to the initiation of further studies and promises a potential benefit for NF1 patients.
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Affiliation(s)
- Christian Linke
- Faculty of Health Sciences, joint Faculty of the Brandenburg University of Technology Cottbus - Senftenberg, the Brandenburg Medical School Theodor Fontane and the University of Potsdam, Potsdam, Brandenburg an der Havel, Germany
| | - Markus Wösle
- Clinic for Radiotherapy and Radiation Oncology, Dessau City Hospital, Dessau-Roßlau, Germany
| | - Anja Harder
- Faculty of Health Sciences, joint Faculty of the Brandenburg University of Technology Cottbus - Senftenberg, the Brandenburg Medical School Theodor Fontane and the University of Potsdam, Potsdam, Brandenburg an der Havel, Germany. .,Institute of Neuropathology, University Hospital Münster, Münster, Germany. .,Institute of Pathology, Brandenburg Medical School Theodor Fontane, Dessau City Hospital, Auenweg 38, 06847, Dessau-Roßlau, Germany.
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25
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Sun X, Sun G, Huang Y, Hao Y, Tang X, Zhang N, Zhao L, Zhong R, Peng Y. 3-Bromopyruvate regulates the status of glycolysis and BCNU sensitivity in human hepatocellular carcinoma cells. Biochem Pharmacol 2020; 177:113988. [PMID: 32330495 DOI: 10.1016/j.bcp.2020.113988] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Accepted: 04/17/2020] [Indexed: 12/19/2022]
Abstract
Chloroethylnitrosoureas (CENUs) are bifunctional antitumor alkylating agents, which exert their antitumor activity through inducing the formation of dG-dC interstrand crosslinks (ICLs) within DNA double strand. However, the complex process of tumor biology enables tumor cells to escape the killing triggered by CENUs, as for instance with the detoxifying activity of O6-methylguanine DNA methyltransferase (MGMT) to accomplish DNA damage repair. Considering the fact that most tumor cells highly depend on aerobic glycolysis to provide energy for survival even in the presence of oxygen (Warburg effect), inhibition of aerobic glycolysis may be an attractive strategy to overcome the resistance and improve the chemotherapeutic effects of CENUs. Especially, 3-bromopyruvate (3-BrPA), a small molecule alkylating agent, has been emerged as an effective glycolytic inhibitor (energy blocker) in cancer treatment. In view of its tumor specificity and inhibition on cellular multiple targets, it is likely to reduce the chemoresistance when chemotherapeutic drugs are combined with 3-BrPA. In this study, we investigated the effects of 3-BrPA on the chemosensitivity of two human hepatocellular carcinoma (HCC) cell lines to the cytotoxic effects of l,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and the underlying molecular mechanism. The sensitivity of SMMC-7721 and HepG2 cells to BCNU was significantly increased by 2 h pretreatment with micromolar dosage of 3-BrPA. Moreover, 3-BrPA decreased the cellular ATP and GSH levels, and extracellular lactate excreted by tumor cells, and the effects were more effective when 3-BrPA was combined with BCNU. Cellular hexokinase-II (HK-II) activity was also reduced after exposure to the treatment of 3-BrPA plus BCNU. Based on the above results, the effects of 3-BrPA on the formation of dG-dC ICLs induced by BCNU was investigated by stable isotope dilution high-performance liquid chromatography electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS). The results indicated that BCNU produced higher levels of dG-dC ICLs in SMMC-7721 and HepG2 cells pretreated with 3-BrPA compared to that without 3-BrPA pretreatment. Notably, in MGMT-deficient HepG2 cells, the levels of dG-dC ICLs were significantly higher than MGMT-proficient SMMC-7721 cells. In general, these findings revealed that 3-BrPA, as an effective glycolytic inhibitor, may be considered as a potential clinical chemosensitizer to optimize the therapeutic index of CENUs.
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Affiliation(s)
- Xiaodong Sun
- Beijing Key Laboratory of Environmental and Viral Oncology, College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, PR China
| | - Guohui Sun
- Beijing Key Laboratory of Environmental and Viral Oncology, College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, PR China.
| | - Yaxin Huang
- Beijing Key Laboratory of Environmental and Viral Oncology, College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, PR China.
| | - Yuxing Hao
- Beijing Key Laboratory of Environmental and Viral Oncology, College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, PR China.
| | - Xiaoyu Tang
- College of Environmental and Energy Engineering, Beijing University of Technology, Beijing 100124, PR China.
| | - Na Zhang
- Beijing Key Laboratory of Environmental and Viral Oncology, College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, PR China.
| | - Lijiao Zhao
- Beijing Key Laboratory of Environmental and Viral Oncology, College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, PR China.
| | - Rugang Zhong
- Beijing Key Laboratory of Environmental and Viral Oncology, College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, PR China.
| | - Yongzhen Peng
- National Engineering Laboratory for Advanced Municipal Wastewater Treatment and Reuse Technology, Engineering Research Center of Beijing, Beijing University of Technology, Beijing 100124, PR China.
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26
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Sun X, Sun G, Huang Y, Zhang S, Tang X, Zhang N, Zhao L, Zhong R, Peng Y. Glycolytic inhibition by 3-bromopyruvate increases the cytotoxic effects of chloroethylnitrosoureas to human glioma cells and the DNA interstrand cross-links formation. Toxicology 2020; 435:152413. [PMID: 32109525 DOI: 10.1016/j.tox.2020.152413] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 02/19/2020] [Accepted: 02/25/2020] [Indexed: 12/19/2022]
Abstract
DNA interstrand cross-links (ICLs) are essential for the antitumor activity of chloroethylnitrosoureas (CENUs). Commonly, CENUs resistance is mainly considered to be associated with O6-methylguanine-DNA methyltransferase (MGMT) within tumors. Bypassing the MGMT-mediated resistance, to our knowledge, herein, we first utilized a novel glycolytic inhibitor, 3-bromopyruvate (3-BrPA), to increase the cytotoxic effects of l,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) to human glioma cells based on the hypothesis that blocking energy metabolism renders tumor cells more sensitive to chemotherapy. We found 3-BrPA significantly increased the cell killing by BCNU in human glioma SF763 and SF126 cell lines. Significantly decreased levels of extracellular lactate, cellular ATP and glutathione (GSH) were observed after 3-BrPA treatment, and the effects were more remarkable with 3-BrPA in combination with BCNU. Considering that the role of ATP and GSH in drug efflux, DNA damage repair and drug inactivation, we determined the effect of 3-BrPA on the formation of dG-dC ICLs induced by BCNU using stable isotope dilution high-performance liquid chromatography electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS). As expected, the levels of lethal dG-dC ICLs induced by BCNU were obviously enhanced after 3-BrPA pretreatment. Based on these results, 3-BrPA and related glycolytic inhibitors may be promising to enhance the cell killing effect and reverse the clinical chemoresistance of CENUs and related antitumor agents.
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Affiliation(s)
- Xiaodong Sun
- Beijing Key Laboratory of Environmental and Viral Oncology, College of Life Science and Bioengineering, Beijing University of Technology, Beijing, 100124, PR China.
| | - Guohui Sun
- Beijing Key Laboratory of Environmental and Viral Oncology, College of Life Science and Bioengineering, Beijing University of Technology, Beijing, 100124, PR China.
| | - Yaxin Huang
- Beijing Key Laboratory of Environmental and Viral Oncology, College of Life Science and Bioengineering, Beijing University of Technology, Beijing, 100124, PR China.
| | - Shufen Zhang
- Beijing Key Laboratory of Environmental and Viral Oncology, College of Life Science and Bioengineering, Beijing University of Technology, Beijing, 100124, PR China.
| | - Xiaoyu Tang
- College of Environmental and Energy Engineering, Beijing University of Technology, Beijing, 100124, PR China.
| | - Na Zhang
- Beijing Key Laboratory of Environmental and Viral Oncology, College of Life Science and Bioengineering, Beijing University of Technology, Beijing, 100124, PR China.
| | - Lijiao Zhao
- Beijing Key Laboratory of Environmental and Viral Oncology, College of Life Science and Bioengineering, Beijing University of Technology, Beijing, 100124, PR China.
| | - Rugang Zhong
- Beijing Key Laboratory of Environmental and Viral Oncology, College of Life Science and Bioengineering, Beijing University of Technology, Beijing, 100124, PR China.
| | - Yongzhen Peng
- National Engineering Laboratory for Advanced Municipal Wastewater Treatment and Reuse Technology, Engineering Research Center of Beijing, Beijing University of Technology, Beijing, 100124, PR China.
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Effect of methyl jasmonate and 3-bromopyruvate combination therapy on mice bearing the 4 T1 breast cancer cell line. J Bioenerg Biomembr 2020; 52:103-111. [PMID: 31960257 DOI: 10.1007/s10863-019-09811-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2019] [Accepted: 09/24/2019] [Indexed: 12/18/2022]
Abstract
Cancer cells apply the Warburg pathway to meet their increased metabolic demands caused by their rapid growth and proliferation and also creates an acidic environment to promote cancer cell invasion. 3-bromopyruvate (3-BrP) as an anti-cancer agent disrupts glycolytic pathway. Moreover, one of the mechanism of actions of Methyl Jasmonate (MJ) is interference in glycolysis. Hence, the aim of this study was to evaluate MJ and 3-BrP interaction. MTT assay was used to determine IC50 and synergistic concentrations. Combination index was applied to evaluate the drug- drug interaction. Human tumor xenograft breast cancer mice was used to evaluate drug efficacy in vivo. Tumor size was considered as a drug efficacy criterion. In addition to drug efficacy, probable side effects of these drugs including hepatotoxicity, renal failure, immunotoxicity, and losing weight were evaluated. Serum alanine aminotransferase and aspartate aminotransferase for hepatotoxicity, serum urea and creatinine level for the possibility of renal failure and changes in body weight were measured to evaluate drug toxicity. IL10 and TGFβ secretion in supernatant of isolated splenocytes from treated mice were assessed to check immunotoxicity. 3-BrP synergistically augmented the efficacy of MJ in the specific concentrations. This polytherapy was more effective than monotherapy of 3-BrP, MJ, and also surprisingly cyclophosphamide as a routine treatment for breast cancer in the tumor bearing mice. These results have been shown by decrease in tumor volume and increase of tumor growth inhibition percentage. This combination therapy didn't have any noticeable side effects on kidney, liver, and immune system and body weight.
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28
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Abdel-Wahab AF, Mahmoud W, Al-Harizy RM. Targeting glucose metabolism to suppress cancer progression: prospective of anti-glycolytic cancer therapy. Pharmacol Res 2019; 150:104511. [DOI: 10.1016/j.phrs.2019.104511] [Citation(s) in RCA: 358] [Impact Index Per Article: 59.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2019] [Revised: 10/19/2019] [Accepted: 10/23/2019] [Indexed: 12/24/2022]
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Bearham J, Garnett JP, Schroeder V, Biggart MGS, Baines DL. Effective glucose metabolism maintains low intracellular glucose in airway epithelial cells after exposure to hyperglycemia. Am J Physiol Cell Physiol 2019; 317:C983-C992. [PMID: 31433692 PMCID: PMC6879884 DOI: 10.1152/ajpcell.00193.2019] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Revised: 07/26/2019] [Accepted: 08/13/2019] [Indexed: 02/07/2023]
Abstract
The airway epithelium maintains differential glucose concentrations between the airway surface liquid (ASL, ~0.4 mM) and the blood/interstitium (5-6 mM), which is important for defense against infection. Glucose primarily moves from the blood to the ASL via paracellular movement, down its concentration gradient, across the tight junctions. However, there is evidence that glucose can move transcellularly across epithelial cells. Using a Förster resonance energy transfer sensor for glucose, we investigated intracellular glucose concentrations in airway epithelial cells and the role of hexokinases in regulating intracellular glucose concentrations in normoglycemic and hyperglycemic conditions. Our findings indicated that in airway epithelial cells (H441 or primary human bronchial epithelial cells) exposed to 5 mM glucose (normoglycemia), intracellular glucose concentration is in the micromolar range. Inhibition of facilitative glucose transporters (GLUTs) with cytochalasin B reduced intracellular glucose concentration. When cells were exposed to 15 mM glucose (hyperglycemia), intracellular glucose concentration was reduced. Airway cells expressed hexokinases I, II, and III. Inhibition with 3-bromopyruvate decreased hexokinase activity by 25% and elevated intracellular glucose concentration, but levels remained in the micromolar range. Exposure to hyperglycemia increased glycolysis, glycogen, and sorbitol. Thus, glucose enters the airway cell via GLUTs and is then rapidly processed by hexokinase-dependent and hexokinase-independent metabolic pathways to maintain low intracellular glucose concentrations. We propose that this prevents transcellular transport and aids the removal of glucose from the ASL and that the main route of entry for glucose into the ASL is via the paracellular pathway.
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Affiliation(s)
- Jade Bearham
- Institute for Infection and Immunity, St. George's University of London, London, United Kingdom
| | - James P Garnett
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
- Immunology and Respiratory Diseases Research, Boehringer Ingelheim Pharma and Company, Biberach an der Riss, Germany
| | - Victoria Schroeder
- Immunology and Respiratory Diseases Research, Boehringer Ingelheim Pharma and Company, Biberach an der Riss, Germany
| | - Matthew G S Biggart
- Institute for Infection and Immunity, St. George's University of London, London, United Kingdom
| | - Deborah L Baines
- Institute for Infection and Immunity, St. George's University of London, London, United Kingdom
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Niedźwiecka K, Ribas D, Casal M, Ułaszewski S. The Cryptococcus neoformans monocarboxylate transporter Jen4 is responsible for increased 3-bromopyruvate sensitivity. FEMS Yeast Res 2019; 19:5435460. [PMID: 30993332 DOI: 10.1093/femsyr/foz029] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Accepted: 04/06/2019] [Indexed: 12/13/2022] Open
Abstract
In the last decades, 3-bromopyruvate (3BP) has been intensively studied as a promising anticancer and antimicrobial agent. The transport of this drug inside the cell is a critical step for its toxicity in cancer and microorganisms. The Cryptococcus neoformans is the most sensitive species of microorganisms toward 3BP. Its cells exhibit the highest uptake rate of 3BP among all tested fungal strains. In Saccharomyces cerevisiae cells, the Jen1 transporter was found to be responsible for 3BP sensitivity. The deletion of Jen1 resulted in the abolishment of 3BP mediated transport. We functionally characterized the Jen4 protein, a Jen1 homologue of C. neoformans, and its role in the phenotypic 3BP sensitivity. The deletion of the CNAG_04704 gene, which encodes Jen4, was found to impair the mediated transport of 3BP and decrease 3BP sensitivity. Further heterologous expression of Jen4 in the S. cerevisiae jen1Δ ady2Δ strain restored the mediated transport of 3BP. The application of a green fluorescent protein fusion tag with the CNAG_04704, revealed the Jen4 labeled on the plasma membrane. The identification of 3BP transporters in pathogen cells is of great importance for understanding the mechanisms of 3BP action and to anticipate the application of this compound as an antimicrobial drug.
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Affiliation(s)
- Katarzyna Niedźwiecka
- Institute of Genetics and Microbiology, University of Wroclaw, Przybyszewskiego 63/77, 51-148 Wroclaw, Poland
| | - David Ribas
- Centre of Molecular and Environmental Biology (CBMA), Department of Biology, University of Minho, Campus de Gualtar, Braga 4710-057, Portugal
| | - Margarida Casal
- Centre of Molecular and Environmental Biology (CBMA), Department of Biology, University of Minho, Campus de Gualtar, Braga 4710-057, Portugal
| | - Stanisław Ułaszewski
- Institute of Genetics and Microbiology, University of Wroclaw, Przybyszewskiego 63/77, 51-148 Wroclaw, Poland
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Dalla Pozza E, Dando I, Pacchiana R, Liboi E, Scupoli MT, Donadelli M, Palmieri M. Regulation of succinate dehydrogenase and role of succinate in cancer. Semin Cell Dev Biol 2019; 98:4-14. [PMID: 31039394 DOI: 10.1016/j.semcdb.2019.04.013] [Citation(s) in RCA: 130] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 04/17/2019] [Accepted: 04/18/2019] [Indexed: 01/08/2023]
Abstract
Succinate dehydrogenase (SDH) has been classically considered a mitochondrial enzyme with the unique property to participate in both the citric acid cycle and the electron transport chain. However, in recent years, several studies have highlighted the role of the SDH substrate, i.e. succinate, in biological processes other than metabolism, tumorigenesis being the most remarkable. For this reason, SDH has now been defined a tumor suppressor and succinate an oncometabolite. In this review, we discuss recent findings regarding alterations in SDH activity leading to succinate accumulation, which include SDH mutations, regulation of mRNA expression, post-translational modifications and endogenous SDH inhibitors. Further, we report an extensive examination of the role of succinate in cancer development through the induction of epigenetic and metabolic alterations and the effects on epithelial to mesenchymal transition, cell migration and invasion, and angiogenesis. Finally, we have focused on succinate and SDH as diagnostic markers for cancers having altered SDH expression/activity.
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Affiliation(s)
- Elisa Dalla Pozza
- Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biochemistry, University of Verona, Verona, Italy
| | - Ilaria Dando
- Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biochemistry, University of Verona, Verona, Italy
| | - Raffaella Pacchiana
- Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biochemistry, University of Verona, Verona, Italy
| | - Elio Liboi
- Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biochemistry, University of Verona, Verona, Italy
| | - Maria Teresa Scupoli
- Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biochemistry, University of Verona, Verona, Italy; Research Center LURM (Interdepartmental Laboratory of Medical Research), University of Verona, Verona, Italy.
| | - Massimo Donadelli
- Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biochemistry, University of Verona, Verona, Italy.
| | - Marta Palmieri
- Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biochemistry, University of Verona, Verona, Italy
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De Vitto H, Bode AM, Dong Z. The PGC-1/ERR network and its role in precision oncology. NPJ Precis Oncol 2019; 3:9. [PMID: 30911677 PMCID: PMC6428848 DOI: 10.1038/s41698-019-0081-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Accepted: 01/18/2019] [Indexed: 12/13/2022] Open
Abstract
Transcriptional regulators include a superfamily of nuclear proteins referred to as co-activators and co-repressors, both of which are involved in controlling the functions of several nuclear receptors (NRs). The Nuclear Receptor Signaling Atlas (NURSA) has cataloged the composition of NRs, co-regulators, and ligands present in the human cell and their effort has been identified in more than 600 potential molecules. Given the importance of co-regulators in steroid, retinoid, and thyroid hormone signaling networks, hypothesizing that NRs/co-regulators are implicated in a wide range of pathologies are tempting. The co-activators known as peroxisome proliferator-activated receptor gamma co-activator 1 (PGC-1) and their key nuclear partner, the estrogen-related receptor (ERR), are emerging as pivotal transcriptional signatures that regulate an extremely broad repertoire of mitochondrial and metabolic genes, making them very attractive drug targets for cancer. Several studies have provided an increased understanding of the functional and structural biology of nuclear complexes. However, more comprehensive work is needed to create different avenues to explore the therapeutic potential of NRs/co-activators in precision oncology. Here, we discuss the emerging data associated with the structure, function, and molecular biology of the PGC-1/ERR network and address how the concepts evolving from these studies have deepened our understanding of how to develop more effective treatment strategies. We present an overview that underscores new biological insights into PGC-1/ERR to improve cancer outcomes against therapeutic resistance. Finally, we discuss the importance of exploiting new technologies such as single-particle cryo-electron microscopy (cryo-EM) to develop a high-resolution biological structure of PGC-1/ERR, focusing on novel drug discovery for precision oncology.
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Affiliation(s)
- Humberto De Vitto
- The Hormel Institute, University of Minnesota, 801 16th Avenue, Austin, NE 55912 USA
| | - Ann M Bode
- The Hormel Institute, University of Minnesota, 801 16th Avenue, Austin, NE 55912 USA
| | - Zigang Dong
- The Hormel Institute, University of Minnesota, 801 16th Avenue, Austin, NE 55912 USA
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Pulaski L, Jatczak-Pawlik I, Sobalska-Kwapis M, Strapagiel D, Bartosz G, Sadowska-Bartosz I. 3-Bromopyruvate induces expression of antioxidant genes. Free Radic Res 2019; 53:170-178. [PMID: 30362385 DOI: 10.1080/10715762.2018.1541176] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
An alkylating compound, 3-bromopyruvic acid (3-3-bromopyruvic acid (BP)) is a promising anti-cancer agent, potentially able to act on multidrug-resistant cells. Its action has been attributed mainly to inhibition of glycolysis. This compound induces also oxidative stress at a cellular level. The effects of 3-BP on gene expression have not been studied although they may determine the survival of cells exposed to 3-BP. The aim of this paper was to examine the effect 3-BP on gene expression pattern in breast MCF-7 cancer cells. Detection of the differences in gene expression was performed using microarrays and dysregulated genes were validated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Exposure of cells to 100 µM 3-BP for 6, 12 and 24 increased expression and diminished expression of 39 and 6 genes, respectively. Among the induced genes, 22 belong to general cellular stress response genes, maintenance genes involved in redox homeostasis, responding to oxidative stress (among them metallothioneins, low-molecular-weight thiol homeostasis enzymes and genes coding for NAD(P)H-dependent oxidoreductases operating on complex organic substrates, including aldo-keto reductases). These results demonstrate that transient oxidative stress in cells exposed to 3-BP is followed by antioxidant response.
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Affiliation(s)
- Lukasz Pulaski
- a Laboratory of Transcriptional Regulation, Institute of Medical Biology , Polish Academy of Sciences , Lodz , Poland.,b Faculty of Biology and Environmental Protection, Department of Molecular Biophysics , University of Lodz , Lodz , Poland
| | - Izabela Jatczak-Pawlik
- b Faculty of Biology and Environmental Protection, Department of Molecular Biophysics , University of Lodz , Lodz , Poland
| | - Marta Sobalska-Kwapis
- c Biobank Lab, Faculty of Biology and Environmental Protection, Department of Molecular Biophysics , University of Lodz , Lodz , Poland
| | - Dominik Strapagiel
- c Biobank Lab, Faculty of Biology and Environmental Protection, Department of Molecular Biophysics , University of Lodz , Lodz , Poland
| | - Grzegorz Bartosz
- b Faculty of Biology and Environmental Protection, Department of Molecular Biophysics , University of Lodz , Lodz , Poland
| | - Izabela Sadowska-Bartosz
- d Department of Analytical Biochemistry Faculty of Biology and Agriculture , University of Rzeszow , Rzeszow , Poland
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Fan T, Sun G, Sun X, Zhao L, Zhong R, Peng Y. Tumor Energy Metabolism and Potential of 3-Bromopyruvate as an Inhibitor of Aerobic Glycolysis: Implications in Tumor Treatment. Cancers (Basel) 2019; 11:317. [PMID: 30845728 PMCID: PMC6468516 DOI: 10.3390/cancers11030317] [Citation(s) in RCA: 124] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2019] [Revised: 02/28/2019] [Accepted: 03/01/2019] [Indexed: 12/24/2022] Open
Abstract
Tumor formation and growth depend on various biological metabolism processes that are distinctly different with normal tissues. Abnormal energy metabolism is one of the typical characteristics of tumors. It has been proven that most tumor cells highly rely on aerobic glycolysis to obtain energy rather than mitochondrial oxidative phosphorylation (OXPHOS) even in the presence of oxygen, a phenomenon called "Warburg effect". Thus, inhibition of aerobic glycolysis becomes an attractive strategy to specifically kill tumor cells, while normal cells remain unaffected. In recent years, a small molecule alkylating agent, 3-bromopyruvate (3-BrPA), being an effective glycolytic inhibitor, has shown great potential as a promising antitumor drug. Not only it targets glycolysis process, but also inhibits mitochondrial OXPHOS in tumor cells. Excellent antitumor effects of 3-BrPA were observed in cultured cells and tumor-bearing animal models. In this review, we described the energy metabolic pathways of tumor cells, mechanism of action and cellular targets of 3-BrPA, antitumor effects, and the underlying mechanism of 3-BrPA alone or in combination with other antitumor drugs (e.g., cisplatin, doxorubicin, daunorubicin, 5-fluorouracil, etc.) in vitro and in vivo. In addition, few human case studies of 3-BrPA were also involved. Finally, the novel chemotherapeutic strategies of 3-BrPA, including wafer, liposomal nanoparticle, aerosol, and conjugate formulations, were also discussed for future clinical application.
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Affiliation(s)
- Tengjiao Fan
- Beijing Key Laboratory of Environmental & Viral Oncology, College of Life Science & Bioengineering, Beijing University of Technology, Beijing 100124, China.
| | - Guohui Sun
- Beijing Key Laboratory of Environmental & Viral Oncology, College of Life Science & Bioengineering, Beijing University of Technology, Beijing 100124, China.
| | - Xiaodong Sun
- Beijing Key Laboratory of Environmental & Viral Oncology, College of Life Science & Bioengineering, Beijing University of Technology, Beijing 100124, China.
| | - Lijiao Zhao
- Beijing Key Laboratory of Environmental & Viral Oncology, College of Life Science & Bioengineering, Beijing University of Technology, Beijing 100124, China.
| | - Rugang Zhong
- Beijing Key Laboratory of Environmental & Viral Oncology, College of Life Science & Bioengineering, Beijing University of Technology, Beijing 100124, China.
| | - Yongzhen Peng
- National Engineering Laboratory for Advanced Municipal Wastewater Treatment & Reuse Technology, Engineering Research Center of Beijing, Beijing University of Technology, Beijing 100124, China.
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Floberg JM, Schwarz JK. Manipulation of Glucose and Hydroperoxide Metabolism to Improve Radiation Response. Semin Radiat Oncol 2019; 29:33-41. [PMID: 30573182 DOI: 10.1016/j.semradonc.2018.10.007] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Dysregulated glucose and redox metabolism are near universal features of cancers. They therefore represent potential selectively toxic metabolic targets. This review outlines the preclinical and clinical data for targeting glucose and hydroperoxide metabolism in cancer, with a focus on drug strategies that have the most available evidence. In particular, inhibition of glycolysis using 2-deoxyglucose, and inhibition of redox metabolism using the glutathione pathway inhibitor buthionine sulfoximine and the thioredoxin pathway inhibitor auranofin, have shown promise in preclinical studies to increase sensitivity to chemotherapy and radiation by increasing intracellular oxidative stress. Combined inhibition of glycolysis, glutathione, and thioredoxin pathways sensitizes highly glycolytic, radioresistant cancer models in vitro and in vivo. Although the preclinical data support this approach, clinical data are limited to exploratory trials using a single drug in combination with either chemotherapy or radiation. Open research questions include optimizing drug strategies for targeting glycolysis and redox metabolism, determining the appropriate timing for administering this therapy with concurrent chemotherapy and radiation, and identifying biomarkers to determine the cancers that would benefit most from this approach. Given the quality of preclinical evidence, dual targeting of glycolysis and redox metabolism in combination with chemotherapy and radiation should be further evaluated in clinical trials.
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Affiliation(s)
- John M Floberg
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO
| | - Julie K Schwarz
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO; Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO; Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO.
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Ko YH, Niedźwiecka K, Casal M, Pedersen PL, Ułaszewski S. 3-Bromopyruvate as a potent anticancer therapy in honor and memory of the late Professor André Goffeau. Yeast 2018; 36:211-221. [PMID: 30462852 DOI: 10.1002/yea.3367] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Revised: 11/13/2018] [Accepted: 11/14/2018] [Indexed: 01/10/2023] Open
Abstract
3-Bromopyruvate (3BP) is a small, highly reactive molecule formed by bromination of pyruvate. In the year 2000, the antitumor properties of 3BP were discovered. Studies using animal models proved its high efficacy for anticancer therapy with no apparent side effects. This was also found to be the case in a limited number of cancer patients treated with 3BP. Due to the "Warburg effect," most tumor cells exhibit metabolic changes, for example, increased glucose consumption and lactic acid production resulting from mitochondrial-bound overexpressed hexokinase 2. Such alterations promote cell migration, immortality via inhibition of apoptosis, and less dependence on the availability of oxygen. Significantly, these attributes also make cancer cells more sensitive to agents, such as 3BP that inhibits energy production pathways without harming normal cells. This selectivity of 3BP is mainly due to overexpressed monocarboxylate transporters in cancer cells. Furthermore, 3BP is not a substrate for any pumps belonging to the ATP-binding cassette superfamily, which confers resistance to a variety of drugs. Also, 3BP has the capacity to induce multiple forms of cell death, by, for example, ATP depletion resulting from inactivation of both glycolytic and mitochondrial energy production pathways. In addition to its anticancer property, 3BP also exhibits antimicrobial activity. Various species of microorganisms are characterized by different susceptibility to 3BP inhibition. Among tested strains, the most sensitive was found to be the pathogenic yeast-like fungus Cryptococcus neoformans. Significantly, studies carried out in our laboratories have shown that 3BP exhibits a remarkable capacity to eradicate cancer cells, fungi, and algae.
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Affiliation(s)
- Young H Ko
- KoDiscovery, LLC, University of Maryland BioPark, Baltimore, Maryland, USA
| | | | - Margarida Casal
- Centre of Molecular and Environmental Biology (CBMA), Department of Biology, University of Minho, Braga, Portugal
| | - Peter L Pedersen
- Department of Biological Chemistry and Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Darabedian N, Chen TC, Molina H, Pratt MR, Schönthal AH. Bioorthogonal Profiling of a Cancer Cell Proteome Identifies a Large Set of 3-Bromopyruvate Targets beyond Glycolysis. ACS Chem Biol 2018; 13:3054-3058. [PMID: 30395437 DOI: 10.1021/acschembio.8b00743] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
3-Bromopyruvate (3BP) is a potential anticancer agent viewed as a glycolytic inhibitor that preferentially kills cancer cells through inhibition of glyceraldehyde 3-phosphate dehydrogenase (GAPDH), resulting in severe energy depletion. We previously identified four cysteine residues in GAPDH that are alkylated by 3BP, resulting in its inactivation. However, we also showed that addition of excess pyruvate, the final product of glycolysis, was unable to rescue cells from 3BP treatment. This result indicates that GAPDH may not be the only relevant target and is consistent with the chemical reactivity of 3BP that should result in the modification of cysteine residues in many different proteins. To directly test this hypothesis, we first synthesized a probe of 3BP activity bearing an alkyne functionality, termed AO3BP, and then demonstrated that this probe could modify a variety of proteins in living cells. Subsequent competition of AO3BP labeling with pretreatment by 3BP identified 62 statistically significant proteins of various functions as targets of 3BP, confirming that 3BP labeling is indeed widespread. We conclude that 3BP's cytotoxic impact on cancer cells does not only result from selective inhibition of glycolysis but rather from a more widespread effect on cellular proteins that could be driven by the pharmacokinetics of the 3BP. These pleiotropic consequences should be considered when thinking about the potential toxicity of this highly reactive compound.
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Affiliation(s)
| | | | - Henrik Molina
- Proteomics Resource Center, Rockefeller University, New York, New York 10065, United States
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3-Bromopyruvate reverses hypoxia-induced pulmonary arterial hypertension through inhibiting glycolysis: In vitro and in vivo studies. Int J Cardiol 2018; 266:236-241. [DOI: 10.1016/j.ijcard.2018.03.104] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2017] [Revised: 02/12/2018] [Accepted: 03/21/2018] [Indexed: 01/14/2023]
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Anthocyanin-Rich Grape Pomace Extract (Vitis vinifera L.) from Wine Industry Affects Mitochondrial Bioenergetics and Glucose Metabolism in Human Hepatocarcinoma HepG2 Cells. Molecules 2018. [PMID: 29518033 PMCID: PMC6017946 DOI: 10.3390/molecules23030611] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Cancer cells demand high ATP provisions to support proliferation, and targeting of energy metabolism is a good strategy to increase their sensitivity to treatments. In Brazil, wine manufacture is expanding, increasing the amount of pomace that is produced. We determined the phenolic composition and antioxidant properties of a dark skin Grape Pomace Extract and its effects on metabolism and redox state in human hepatocarcinoma HepG2 cells. The material and the methods used represented the industrial process since pomace derived from white wine production and the extract concentrated by pilot plant scale reverse osmosis. Grape pomace extract was rich in polyphenols, mainly anthocyanins, and presented high antioxidant capacity. Short-term metabolic effects, irrespective of any cytotoxicity, involved increased mitochondrial respiration and antioxidant capacity and decreased glycolytic metabolism. Long-term incubation was cytotoxic and cells died by necrosis and GPE was not toxic to non-cancer human fibroblasts. To the best of our knowledge, this is the first report to characterize pomace extract from white wine production from Brazilian winemaking regarding its effects on energy metabolism, suggesting its potential use for pharmaceutical and nutraceutical purposes.
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Anaplerotic Role of Glucose in the Oxidation of Endogenous Fatty Acids during Dengue Virus Infection. mSphere 2018; 3:mSphere00458-17. [PMID: 29404419 PMCID: PMC5793041 DOI: 10.1128/msphere.00458-17] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Accepted: 12/20/2017] [Indexed: 12/21/2022] Open
Abstract
Dengue virus infection is a major cause of human arbovirosis, for which clinical and experimental evidence supports the idea that liver dysfunction and lipid metabolism disorders are characteristics of severe disease. Analyzing mitochondrial bioenergetics, here we show that infection of hepatic cells with dengue virus favors the cellular capacity of metabolizing glucose, impairing the normal metabolic flexibility that allows the oxidative machinery to switch among the main energetic substrates. However, instead of being used as an energy source, glucose performs an anaplerotic role in the oxidation of endogenous fatty acids, which become the main energetic substrate during infection. Taken together, the results shed light on metabolic mechanisms that may explain the profound alterations in lipid metabolism for severe dengue patients, contributing to the understanding of dengue physiopathology. Dengue virus (DENV) is among the most important human arboviruses and is clinically and experimentally associated with lipid metabolism disorders. Using high-resolution respirometry, we analyzed the metabolic switches induced by DENV in a human hepatic cell line. This experimental approach allowed us to determine the contribution of fatty acids, glutamine, glucose, and pyruvate to mitochondrial bioenergetics, shedding light on the mechanisms involved in DENV-induced metabolic alterations. We found that while infection strongly inhibits glutamine oxidation, it increases the cellular capacity of metabolizing glucose; remarkably, though, this substrate, instead being used as an energy source, performs an anaplerotic role in the oxidation of endogenous lipids. Fatty acids become the main energetic substrate in infected cell, and through the pharmacological modulation of β-oxidation we demonstrated that this pathway is essential for virus replication. Interestingly, infected cells were much less susceptible to the Crabtree effect, i.e., the glucose-mediated inhibition of mitochondrial oxygen consumption, suggesting that infection favors cellular respiration by increasing ADP availability. IMPORTANCE Dengue virus infection is a major cause of human arbovirosis, for which clinical and experimental evidence supports the idea that liver dysfunction and lipid metabolism disorders are characteristics of severe disease. Analyzing mitochondrial bioenergetics, here we show that infection of hepatic cells with dengue virus favors the cellular capacity of metabolizing glucose, impairing the normal metabolic flexibility that allows the oxidative machinery to switch among the main energetic substrates. However, instead of being used as an energy source, glucose performs an anaplerotic role in the oxidation of endogenous fatty acids, which become the main energetic substrate during infection. Taken together, the results shed light on metabolic mechanisms that may explain the profound alterations in lipid metabolism for severe dengue patients, contributing to the understanding of dengue physiopathology.
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Hochkogler CM, Lieder B, Schachner D, Heiss E, Schröter A, Hans J, Ley JP, Krammer GE, Somoza V. Capsaicin and nonivamide similarly modulate outcome measures of mitochondrial energy metabolism in HepG2 and 3T3-L1 cells. Food Funct 2018; 9:1123-1132. [DOI: 10.1039/c7fo01626c] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Nonivamide, a less pungent capsaicin analog, has similar effects on the outcome measures of energy metabolism to capsaicin.
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Affiliation(s)
| | - Barbara Lieder
- Christian Doppler Laboratory for Bioactive Aroma Compounds
- University of Vienna
- Vienna
- Austria
- Department of Physiological Chemistry
| | - Daniel Schachner
- Department of Pharmacognosy
- Faculty of Life Sciences
- University of Vienna
- Vienna
- Austria
| | - Elke Heiss
- Department of Pharmacognosy
- Faculty of Life Sciences
- University of Vienna
- Vienna
- Austria
| | - Annett Schröter
- Department of Physiological Chemistry
- Faculty of Chemistry
- University of Vienna
- Vienna
- Austria
| | | | | | | | - Veronika Somoza
- Christian Doppler Laboratory for Bioactive Aroma Compounds
- University of Vienna
- Vienna
- Austria
- Department of Physiological Chemistry
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42
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Nikolaou N, Green CJ, Gunn PJ, Hodson L, Tomlinson JW. Optimizing human hepatocyte models for metabolic phenotype and function: effects of treatment with dimethyl sulfoxide (DMSO). Physiol Rep 2017; 4:4/21/e12944. [PMID: 27803313 PMCID: PMC5112488 DOI: 10.14814/phy2.12944] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Accepted: 08/01/2016] [Indexed: 12/14/2022] Open
Abstract
Primary human hepatocytes are considered to be the "gold standard" cellular model for studying hepatic fatty acid and glucose metabolism; however, they come with limitations. Although the HepG2 cell line retains many of the primary hepatocyte metabolic functions they have a malignant origin and low rates of triglyceride secretion. The aim of this study was to investigate whether dimethyl sulfoxide supplementation in the media of HepG2 cells would enhance metabolic functionality leading to the development of an improved in vitro cell model that closely recapitulates primary human hepatocyte metabolism. HepG2 cells were cultured in media containing 1% dimethyl sulfoxide for 2, 4, 7, 14, and 21 days. Gene expression, protein levels, intracellular triglyceride, and media concentrations of triglyceride, urea, and 3-hydroxybutyrate concentrations were measured. Dimethyl sulfoxide treatment altered the expression of genes involved in lipid (FAS, ACC1, ACC2, DGAT1, DGAT2, SCD) and glucose (PEPCK, G6Pase) metabolism as well as liver functionality (albumin, alpha-1-antitrypsin, AFP). mRNA changes were paralleled by alterations at the protein level. DMSO treatment decreased intracellular triglyceride content and lactate production and increased triglyceride and 3-hydroxybutyrate concentrations in the media in a time-dependent manner. We have demonstrated that the addition of 1% dimethyl sulfoxide to culture media changes the metabolic phenotype of HepG2 cells toward a more primary human hepatocyte phenotype. This will enhance the currently available in vitro model systems for the study of hepatocyte biology related to pathological processes that contribute to disease and their response to specific therapeutic interventions.
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Affiliation(s)
- Nikolaos Nikolaou
- Oxford Centre for Diabetes, Endocrinology & Metabolism and NIHR Biomedical Research Centre, University of Oxford Churchill Hospital, Headington, Oxford, U.K
| | - Charlotte J Green
- Oxford Centre for Diabetes, Endocrinology & Metabolism and NIHR Biomedical Research Centre, University of Oxford Churchill Hospital, Headington, Oxford, U.K
| | - Pippa J Gunn
- Oxford Centre for Diabetes, Endocrinology & Metabolism and NIHR Biomedical Research Centre, University of Oxford Churchill Hospital, Headington, Oxford, U.K
| | - Leanne Hodson
- Oxford Centre for Diabetes, Endocrinology & Metabolism and NIHR Biomedical Research Centre, University of Oxford Churchill Hospital, Headington, Oxford, U.K
| | - Jeremy W Tomlinson
- Oxford Centre for Diabetes, Endocrinology & Metabolism and NIHR Biomedical Research Centre, University of Oxford Churchill Hospital, Headington, Oxford, U.K.
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Santos GC, Zeidler JD, Pérez-Valencia JA, Sant'Anna-Silva ACB, Da Poian AT, El-Bacha T, Almeida FCL. Metabolomic Analysis Reveals Vitamin D-induced Decrease in Polyol Pathway and Subtle Modulation of Glycolysis in HEK293T Cells. Sci Rep 2017; 7:9510. [PMID: 28842639 PMCID: PMC5573350 DOI: 10.1038/s41598-017-10006-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Accepted: 08/02/2017] [Indexed: 12/21/2022] Open
Abstract
We combined 1H NMR metabolomics with functional and molecular biochemical assays to describe the metabolic changes elicited by vitamin D in HEK293T, an embryonic proliferative cell line adapted to high-glucose concentrations. Activation of the polyol pathway, was the most important consequence of cell exposure to high glucose concentration, resembling cells exposed to hyperglycemia. Vitamin D induced alterations in HEK293T cells metabolism, including a decrease in sorbitol, glycine, glutamate, guanine. Vitamin D modulated glycolysis by increasing phosphoglycerate mutase and decreasing enolase activities, changing carbon fate without changing glucose consumption, lactate export and Krebs cycle. The decrease in sorbitol intracellular concentration seems to be related to vitamin D regulated redox homeostasis and protection against oxidative stress, and helped maintaining the high proliferative phenotype, supported by the decrease in glycine and guanine and orotate concentration and increase in choline and phosphocholine concentration. The decrease in orotate and guanine indicated an increased biosynthesis of purine and pyrimidines. Vitamin D elicited metabolic alteration without changing cellular proliferation and mitochondrial respiration, but reclaiming reductive power. Our study may contribute to the understanding of the metabolic mechanism of vitamin D upon exposure to hyperglycemia, suggesting a role of protection against oxidative stress.
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Affiliation(s)
- G C Santos
- Federal University of Rio de Janeiro, Institute of Medical Biochemistry, Leopoldo de Meis, Brazil. .,Federal University of Rio de Janeiro, National Center for Structural Biology and Bioimaging (CENABIO)/National Center for Nuclear Magnetic Resonance (CNRMN), Rio de Janeiro, Brazil.
| | - J D Zeidler
- Federal University of Rio de Janeiro, Institute of Medical Biochemistry, Leopoldo de Meis, Brazil
| | - J A Pérez-Valencia
- Federal University of Rio de Janeiro, Institute of Medical Biochemistry, Leopoldo de Meis, Brazil
| | - A C B Sant'Anna-Silva
- Federal University of Rio de Janeiro, Institute of Medical Biochemistry, Leopoldo de Meis, Brazil
| | - A T Da Poian
- Federal University of Rio de Janeiro, Institute of Medical Biochemistry, Leopoldo de Meis, Brazil
| | - T El-Bacha
- Federal University of Rio de Janeiro, National Center for Structural Biology and Bioimaging (CENABIO)/National Center for Nuclear Magnetic Resonance (CNRMN), Rio de Janeiro, Brazil.,Federal University of Rio de Janeiro, Institute of Nutrition Josué de Castro, Rio de Janeiro, Brazil
| | - F C L Almeida
- Federal University of Rio de Janeiro, Institute of Medical Biochemistry, Leopoldo de Meis, Brazil. .,Federal University of Rio de Janeiro, National Center for Structural Biology and Bioimaging (CENABIO)/National Center for Nuclear Magnetic Resonance (CNRMN), Rio de Janeiro, Brazil.
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Zeidler JD, Fernandes-Siqueira LO, Carvalho AS, Cararo-Lopes E, Dias MH, Ketzer LA, Galina A, Da Poian AT. Short-term starvation is a strategy to unravel the cellular capacity of oxidizing specific exogenous/endogenous substrates in mitochondria. J Biol Chem 2017; 292:14176-14187. [PMID: 28663370 DOI: 10.1074/jbc.m117.786582] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Revised: 06/28/2017] [Indexed: 11/06/2022] Open
Abstract
Mitochondrial oxidation of nutrients is tightly regulated in response to the cellular environment and changes in energy demands. In vitro studies evaluating the mitochondrial capacity of oxidizing different substrates are important for understanding metabolic shifts in physiological adaptations and pathological conditions, but may be influenced by the nutrients present in the culture medium or by the utilization of endogenous stores. One such influence is exemplified by the Crabtree effect (the glucose-mediated inhibition of mitochondrial respiration) as most in vitro experiments are performed in glucose-containing media. Here, using high-resolution respirometry, we evaluated the oxidation of endogenous or exogenous substrates by cell lines harboring different metabolic profiles. We found that a 1-h deprivation of the main energetic nutrients is an appropriate strategy to abolish interference of endogenous or undesirable exogenous substrates with the cellular capacity of oxidizing specific substrates, namely glutamine, pyruvate, glucose, or palmitate, in mitochondria. This approach primed mitochondria to immediately increase their oxygen consumption after the addition of the exogenous nutrients. All starved cells could oxidize exogenous glutamine, whereas the capacity for oxidizing palmitate was limited to human hepatocarcinoma Huh7 cells and to C2C12 mouse myoblasts that differentiated into myotubes. In the presence of exogenous glucose, starvation decreased the Crabtree effect in Huh7 and C2C12 cells and abrogated it in mouse neuroblastoma N2A cells. Interestingly, the fact that the Crabtree effect was observed only for mitochondrial basal respiration but not for the maximum respiratory capacity suggests it is not caused by a direct effect on the electron transport system.
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Affiliation(s)
- Julianna D Zeidler
- From the Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil,.
| | - Lorena O Fernandes-Siqueira
- From the Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Ana S Carvalho
- From the Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Eduardo Cararo-Lopes
- Center of Toxins, Immune-Response and Cell Signaling, Instituto Butantan, São Paulo 05503-900, Brazil; Instituto de Química, Universidade de São Paulo, São Paulo 05508-000, Brazil
| | - Matheus H Dias
- Center of Toxins, Immune-Response and Cell Signaling, Instituto Butantan, São Paulo 05503-900, Brazil
| | - Luisa A Ketzer
- Universidade Federal do Rio de Janeiro, Pólo de Xerém, Duque de Caxias 25245-390, Brazil
| | - Antonio Galina
- From the Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Andrea T Da Poian
- From the Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil,.
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45
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李 其, 张 配, 刘 芳, 王 先, 李 璐, 王 仲, 蒋 琛, 郑 海, 刘 浩. [Monocarboxylate transporter 1 enhances the sensitivity of breast cancer cells to 3-bromopyruvate in vitro]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2017; 37:588-593. [PMID: 28539279 PMCID: PMC6780470 DOI: 10.3969/j.issn.1673-4254.2017.05.04] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Indexed: 06/07/2023]
Abstract
OBJECTIVE To investigate the role of monocarboxylate transporter 1 (MCT1) in enhancing the sensitivity of breast cancer cells to 3-bromopyruvate (3-BrPA). METHODS The inhibitory effect of 3-BrPA on the proliferation of breast cancer cells was assessed with MTT assay, and brominated propidium bromide single staining flow cytometry was used for detecting the cell apoptosis. An ELISA kit was used to detect the intracellular levels of hexokinase II, lactate dehydrogenase, lactate, and adenosine triphosphate, and Western blotting was performed to detect the expression of MCT1. MDA-MB-231 cells were transiently transfected with MCT1 cDNA for over-expressing MCT1, and the effect of 3-BrPA on the cell proliferation and adenosine triphosphate level was deteced. RESULTS 3-BrPA did not produce significant effects on the proliferation and apoptosis of MDA-MB-231 cells, and the cells treated with 200 µmol/L 3-BrPA for 24 h showed an inhibition rate and an apoptosis rate of only 8.72% and 7.8%, respectively. The same treatment, however, produced an inhibition rate and an apoptosis rate of 84.6% and 82.3% in MCF-7 cells, respectively. In MDA-MB-231 cells with MCT1 overexpression, 200 µmol/L 3-BrPA resulted in an inhibition rate of 72.44%, significantly higher than that in the control cells (P<0.05); treatment of the cells with 25, 50, 100, and 200 µmol/L 3-BrPA for 6 h resulted in intracellular adenosine triphosphate levels of 96.98%, 88.44%, 43.3% and 27.56% relative to the control level respectively. CONCLUSION MCT1 can enhance the sensitivity of breast cancer cells to 3-BrPA possibly by transporting 3-BrPA into cells to inhibit cell glycolysis.
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Affiliation(s)
- 其响 李
- 蚌埠医学院药学院，安徽 蚌埠 233030School of Pharmacy , Bengbu Medical College, Bengbu 233030, China
| | - 配 张
- 蚌埠医学院药学院，安徽 蚌埠 233030School of Pharmacy , Bengbu Medical College, Bengbu 233030, China
| | - 芳 刘
- 蚌埠医学院药学院，安徽 蚌埠 233030School of Pharmacy , Bengbu Medical College, Bengbu 233030, China
| | - 先知 王
- 蚌埠医学院药学院，安徽 蚌埠 233030School of Pharmacy , Bengbu Medical College, Bengbu 233030, China
| | - 璐 李
- 蚌埠医学院药学院，安徽 蚌埠 233030School of Pharmacy , Bengbu Medical College, Bengbu 233030, China
| | - 仲崑 王
- 蚌埠医学院药学院，安徽 蚌埠 233030School of Pharmacy , Bengbu Medical College, Bengbu 233030, China
| | - 琛琛 蒋
- 蚌埠医学院药学院，安徽 蚌埠 233030School of Pharmacy , Bengbu Medical College, Bengbu 233030, China
| | - 海伦 郑
- 蚌埠医学院第一附属医院消化科，安徽 蚌埠 233030 Department of Gastroenterology, First Affiliated Hospital, Bengbu Medical College, Bengbu 233030, China
| | - 浩 刘
- 蚌埠医学院药学院，安徽 蚌埠 233030School of Pharmacy , Bengbu Medical College, Bengbu 233030, China
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Yadav S, Pandey SK, Kumar A, Kujur PK, Singh RP, Singh SM. Antitumor and chemosensitizing action of 3-bromopyruvate: Implication of deregulated metabolism. Chem Biol Interact 2017; 270:73-89. [DOI: 10.1016/j.cbi.2017.04.015] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Revised: 04/04/2017] [Accepted: 04/18/2017] [Indexed: 01/22/2023]
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47
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Chen TC, Yu J, Nouri Nigjeh E, Wang W, Myint PT, Zandi E, Hofman FM, Schönthal AH. A perillyl alcohol-conjugated analog of 3-bromopyruvate without cellular uptake dependency on monocarboxylate transporter 1 and with activity in 3-BP-resistant tumor cells. Cancer Lett 2017; 400:161-174. [PMID: 28450161 DOI: 10.1016/j.canlet.2017.04.015] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2016] [Revised: 03/07/2017] [Accepted: 04/17/2017] [Indexed: 02/08/2023]
Abstract
The anticancer agent 3-bromopyruvate (3-BP) is viewed as a glycolytic inhibitor that preferentially kills glycolytic cancer cells through energy depletion. However, its cytotoxic activity is dependent on cellular drug import through transmembrane monocarboxylate transporter 1 (MCT-1), which restricts its anticancer potential to MCT-1-positive tumor cells. We created and characterized an MCT-1-independent analog of 3-BP, called NEO218. NEO218 was synthesized by covalently conjugating 3-BP to perillyl alcohol (POH), a natural monoterpene. The responses of various tumor cell lines to treatment with either compound were characterized in the presence or absence of supplemental pyruvate or antioxidants N-acetyl-cysteine (NAC) and glutathione (GSH). Drug effects on glyceraldehyde 3-phosphate dehydrogenase (GAPDH) enzyme activity were investigated by mass spectrometric analysis. The development of 3-BP resistance was investigated in MCT-1-positive HCT116 colon carcinoma cells in vitro. Our results show that NEO218: (i) pyruvylated GAPDH on all 4 of its cysteine residues and shut down enzymatic activity; (ii) severely lowered cellular ATP content below life-sustaining levels, and (iii) triggered rapid necrosis. Intriguingly, supplemental antioxidants effectively prevented cytotoxic activity of NEO218 as well as 3-BP, but supplemental pyruvate powerfully protected cells only from 3-BP, not from NEO218. Unlike 3-BP, NEO218 exerted its potent cytotoxic activity irrespective of cellular MCT-1 status. Treatment of HCT116 cells with 3-BP resulted in prompt development of resistance, based on the emergence of MCT-1-negative cells. This was not the case with NEO218, and highly 3-BP-resistant cells remained exquisitely sensitive to NEO218. Thus, our study identifies a mechanism by which tumor cells develop rapid resistance to 3-BP, and presents NEO218 as a superior agent not subject to this cellular defense. Furthermore, our results offer alternative interpretations of previously published models on the role of supplemental antioxidants: Rather than quenching reactive oxygen species (ROS), supplemental NAC or GSH directly interact with 3-BP, thereby neutralizing the drug's cytotoxic potential before it can trigger ROS production. Altogether, our study introduces new aspects of the cytotoxic mechanism of 3-BP, and characterizes NEO218 as an analog able to overcome a key cellular defense mechanism towards this drug.
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Affiliation(s)
- Thomas C Chen
- Department of Neurosurgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
| | - Jiali Yu
- Department of Neurosurgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - Eslam Nouri Nigjeh
- Research Center for Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - Weijun Wang
- Department of Neurosurgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - Phyo Thazin Myint
- Department of Molecular Microbiology & Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - Ebrahim Zandi
- Department of Molecular Microbiology & Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - Florence M Hofman
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - Axel H Schönthal
- Department of Molecular Microbiology & Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
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Roy M, Finley SD. Computational Model Predicts the Effects of Targeting Cellular Metabolism in Pancreatic Cancer. Front Physiol 2017; 8:217. [PMID: 28446878 PMCID: PMC5388762 DOI: 10.3389/fphys.2017.00217] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Accepted: 03/27/2017] [Indexed: 12/13/2022] Open
Abstract
Reprogramming of energy metabolism is a hallmark of cancer that enables the cancer cells to meet the increased energetic requirements due to uncontrolled proliferation. One prominent example is pancreatic ductal adenocarcinoma, an aggressive form of cancer with an overall 5-year survival rate of 5%. The reprogramming mechanism in pancreatic cancer involves deregulated uptake of glucose and glutamine and other opportunistic modes of satisfying energetic demands in a hypoxic and nutrient-poor environment. In the current study, we apply systems biology approaches to enable a better understanding of the dynamics of the distinct metabolic alterations in KRAS-mediated pancreatic cancer, with the goal of impeding early cell proliferation by identifying the optimal metabolic enzymes to target. We have constructed a kinetic model of metabolism represented as a set of ordinary differential equations that describe time evolution of the metabolite concentrations in glycolysis, glutaminolysis, tricarboxylic acid cycle and the pentose phosphate pathway. The model is comprised of 46 metabolites and 53 reactions. The mathematical model is fit to published enzyme knockdown experimental data. We then applied the model to perform in silico enzyme modulations and evaluate the effects on cell proliferation. Our work identifies potential combinations of enzyme knockdown, metabolite inhibition, and extracellular conditions that impede cell proliferation. Excitingly, the model predicts novel targets that can be tested experimentally. Therefore, the model is a tool to predict the effects of inhibiting specific metabolic reactions within pancreatic cancer cells, which is difficult to measure experimentally, as well as test further hypotheses toward targeted therapies.
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Affiliation(s)
- Mahua Roy
- Biomedical Engineering, University of Southern CaliforniaLos Angeles, CA, USA
| | - Stacey D Finley
- Biomedical Engineering, University of Southern CaliforniaLos Angeles, CA, USA.,Chemical Engineering, University of Southern CaliforniaLos Angeles, CA, USA
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Feinberg T, Herbig J, Kohl I, Las G, Cancilla JC, Torrecilla JS, Ilouze M, Haick H, Peled N. Cancer metabolism: the volatile signature of glycolysis-in vitro model in lung cancer cells. J Breath Res 2017; 11:016008. [PMID: 28068289 DOI: 10.1088/1752-7163/aa51d6] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Discovering the volatile signature of cancer cells is an emerging approach in cancer research, as it may contribute to a fast and simple diagnosis of tumors in vivo and in vitro. One of the main contributors to such a volatile signature is hyperglycolysis, which characterizes the cancerous cell. The metabolic perturbation in cancer cells is known as the Warburg effect; glycolysis is preferred over oxidative phosphorylation (OXPHOS), even in the presence of oxygen. The precise mitochondrial alterations that underlie the increased dependence of cancer cells on aerobic glycolysis for energy generation have remained a mystery. We aimed to profile the volatile signature of the glycolysis activity in lung cancer cells. For that an in vitro model, using lung cancer cell line cultures (A549, H2030, H358, H322), was developed. The volatile signature was measured by proton transfer reaction mass spectrometry under normal conditions and glycolysis inhibition. Glycolysis inhibition and mitochondrial activity were also assessed by mitochondrial respiration capacity measurements. Cells were divided into two groups upon their glycolytic profile (PET positive and PET negative). Glycolysis blockade had a unique characteristic that was shared by all cells. Furthermore, each group had a characteristic volatile signature that enabled us to discriminate between those sub-groups of cells. In conclusion, lung cancer cells may have different subpopulations of cells upon low and high mitochondrial capacity. In both groups, glycolysis blockade induced a unique volatile signature.
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Affiliation(s)
- Tali Feinberg
- Thoracic Cancer Research and Detection Center, Sheba Medical Center, Tel-Aviv University, Israel
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50
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Su X, Li R, Kong KF, Tsang JSH. Transport of haloacids across biological membranes. BIOCHIMICA ET BIOPHYSICA ACTA 2016; 1858:3061-3070. [PMID: 27668346 DOI: 10.1016/j.bbamem.2016.09.017] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Revised: 09/20/2016] [Accepted: 09/21/2016] [Indexed: 12/28/2022]
Abstract
Haloacids are considered to be environmental pollutants, but some of them have also been tested in clinical research. The way that haloacids are transported across biological membranes is important for both biodegradation and drug delivery purposes. In this review, we will first summarize putative haloacids transporters and the information about haloacids transport when studying carboxylates transporters. We will then introduce MCT1 and SLC5A8, which are respective transporter for antitumor agent 3-bromopyruvic acid and dichloroacetic acid, and monochloroacetic acid transporters Deh4p and Dehp2 from a haloacids-degrading bacterium. Phylogenetic analysis of these haloacids transporters and other monocarboxylate transporters reveals their evolutionary relationships. Haloacids transporters are not studied to the extent that they deserve compared with their great application potentials, thus future inter-discipline research are desired to better characterize their transport mechanisms for potential applications in both environmental and clinical fields.
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Affiliation(s)
- Xianbin Su
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, PR China.
| | - Ruihong Li
- Shanghai Quality Safety Centre of Agricultural Products, Shanghai 200335, PR China.
| | - Ka-Fai Kong
- Molecular Microbiology Laboratory, School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong.
| | - Jimmy S H Tsang
- Molecular Microbiology Laboratory, School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong.
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