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Rincon-Torroella J, Dal Molin M, Mog B, Han G, Watson E, Wyhs N, Ishiyama S, Ahmedna T, Minn I, Azad N, Bettegowda C, Papadopoulos N, Kinzler KW, Zhou S, Vogelstein B, Gabrielson K, Sur S. ME3BP-7 is a targeted cytotoxic agent that rapidly kills pancreatic cancer cells expressing high levels of monocarboxylate transporter MCT1. eLife 2025; 13:RP94488. [PMID: 40391649 PMCID: PMC12092006 DOI: 10.7554/elife.94488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/22/2025] Open
Abstract
Nearly 30% of pancreatic ductal adenocarcinomas (PDACs) exhibit a marked overexpression of monocarboxylate transporter 1 (MCT1) offering a unique opportunity for therapy. However, biochemical inhibitors of MCT1 have proven unsuccessful in clinical trials. In this study, we present an alternative approach using 3-bromopyruvate (3BP) to target MCT1 overexpressing PDACs. 3BP is a cytotoxic agent that is known to be transported into cells via MCT1, but its clinical usefulness has been hampered by difficulties in delivering the drug systemically. We describe here a novel microencapsulated formulation of 3BP (ME3BP-7), which is effective against a variety of PDAC cells in vitro and remains stable in serum. Furthermore, systemically administered ME3BP-7 significantly reduces pancreatic cancer growth and metastatic spread in multiple orthotopic models of pancreatic cancer with manageable toxicity. ME3BP-7 is, therefore, a prototype of a promising new drug, in which the targeting moiety and the cytotoxic moiety are both contained within the same single small molecule.
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Affiliation(s)
- Jordina Rincon-Torroella
- Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Department of Neurosurgery, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Department of Oncology, The Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Marco Dal Molin
- Department of Surgery, The Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Brian Mog
- Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Howard Hughes Medical InstituteChevy ChaseUnited States
- Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Department of Biomedical Engineering, Johns Hopkins UniversityBaltimoreUnited States
| | - Gyuri Han
- Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Evangeline Watson
- Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Nicolas Wyhs
- Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Department of Oncology, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Department of Pathology, The Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Shun Ishiyama
- Department of Molecular and Comparative Pathobiology, The Johns Hopkins University School of Medicine; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins UniversityBaltimoreUnited States
| | - Taha Ahmedna
- Department of Molecular and Comparative Pathobiology, The Johns Hopkins University School of Medicine; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins UniversityBaltimoreUnited States
| | - Il Minn
- Division of Nuclear Medicine and Molecular Imaging, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Nilofer Azad
- Department of Oncology, The Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Chetan Bettegowda
- Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Department of Neurosurgery, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer CenterBaltimoreUnited States
| | - Nickolas Papadopoulos
- Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Department of Oncology, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer CenterBaltimoreUnited States
| | - Kenneth W Kinzler
- Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Department of Oncology, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Department of Pathology, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer CenterBaltimoreUnited States
| | - Shibin Zhou
- Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Department of Oncology, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer CenterBaltimoreUnited States
| | - Bert Vogelstein
- Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Department of Oncology, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Howard Hughes Medical InstituteChevy ChaseUnited States
- Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Department of Pathology, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer CenterBaltimoreUnited States
| | - Kathleen Gabrielson
- Department of Oncology, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Department of Pathology, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Department of Molecular and Comparative Pathobiology, The Johns Hopkins University School of Medicine; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins UniversityBaltimoreUnited States
| | - Surojit Sur
- Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Department of Oncology, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer CenterBaltimoreUnited States
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Wang DW, Ren XH, Ma YJ, Wang FQ, He XW, Li WY, Zhang YK. Dual-template epitope imprinted nanoparticles for anti-glycolytic tumor-targeted treatment. J Colloid Interface Sci 2025; 683:890-905. [PMID: 39755015 DOI: 10.1016/j.jcis.2024.12.227] [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: 09/13/2024] [Revised: 12/28/2024] [Accepted: 12/29/2024] [Indexed: 01/06/2025]
Abstract
Glycolysis provides tumors with abundant nutrients through glucose (Glu) metabolism. As a therapeutic target, precise targeting and effective inhibition of the glycolysis process remains a major challenge in anti-metabolic therapy. In this study, a novel dual-template molecularly imprinted polymer (D-MIP), capable of specifically recognizing glucose transporter member 1 (GLUT1) and hexokinase-2 (HK2) was prepared for anti-glycolytic tumor therapy. The imprinting factors of D-MIP for the recognition of the template molecules, the GLUT1 epitope and the HK2 epitope, were 2.1 and 2.5, respectively, enabling specific recognition of the entire target protein. Targeting GLUT1 with D-MIP could impede its Glu uptake, while simultaneously inhibiting the activity of cytoplasmic HK2, thereby reducing the metabolic rate of Glu. Cell experiments demonstrated that inhibition of HK2 resulted in downregulation of the downstream, products glucose-6-phosphate (6PG) and lactate (LA). In vitro and in vivo experimental results indicated that D-MIP exhibited significant targeting and inhibitory effects on GLUT1 and HK2, respectively, which suppressed tumor glycolysis and induced apoptosis in MCF-7 cells. Furthermore, mouse tumor models and hematoxylin-eosin (H&E) staining confirmed the excellent anti-tumor efficacy and favorable biocompatibility of D-MIP. This work represents the first design and development of a dual-template imprinted polymer targeting key transport channels and metabolic enzymes involved in glycolysis, advancing the research and application of anti-glycolytic tumor therapy.
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Affiliation(s)
- Da-Wei Wang
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Center for Analytical Sciences, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Xing-Hui Ren
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Center for Analytical Sciences, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Yao-Jia Ma
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Center for Analytical Sciences, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Fang-Qi Wang
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Center for Analytical Sciences, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Xi-Wen He
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Center for Analytical Sciences, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Wen-You Li
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Center for Analytical Sciences, College of Chemistry, Nankai University, Tianjin 300071, China.
| | - Yu-Kui Zhang
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Center for Analytical Sciences, College of Chemistry, Nankai University, Tianjin 300071, China; National Chromatographic Research and Analysis Center, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
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3
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Daya T, Breytenbach A, Gu L, Kaur M. Cholesterol metabolism in pancreatic cancer and associated therapeutic strategies. Biochim Biophys Acta Mol Cell Biol Lipids 2025; 1870:159578. [PMID: 39542394 DOI: 10.1016/j.bbalip.2024.159578] [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: 07/24/2024] [Revised: 10/31/2024] [Accepted: 11/10/2024] [Indexed: 11/17/2024]
Abstract
Pancreatic cancer remains one of the most lethal cancers due to late diagnosis and high chemoresistance. Despite recent progression in the development of chemotherapies, immunotherapies, and potential nanoparticles-based approaches, the success rate of therapeutic response is limited which is further compounded by cancer drug resistance. Understanding of emerging biological and molecular pathways causative of pancreatic cancer's aggressive and chemoresistance is vital to improve the effectiveness of existing therapeutics and to develop new therapies. One such under-investigated and relatively less explored area of research is documenting the effect that lipids, specifically cholesterol, and its metabolism, impose on pancreatic cancer. Dysregulated cholesterol metabolism has a profound role in supporting cellular proliferation, survival, and promoting chemoresistance and this has been well established in various other cancers. Thus, we aimed to provide an in-depth review focusing on the significance of cholesterol metabolism in pancreatic cancer and relevant genes at play, molecular processes contributing to cellular cholesterol homeostasis, and current research efforts to develop new cholesterol-targeting therapeutics. We highlight the caveats, weigh in different experimental therapeutic strategies, and provide possible suggestions for future research highlighting cholesterol's importance as a therapeutic target against pancreatic cancer resistance and cancer progression.
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Affiliation(s)
- Tasvi Daya
- School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, WITS, 2050 Johannesburg, South Africa
| | - Andrea Breytenbach
- School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, WITS, 2050 Johannesburg, South Africa
| | - Liang Gu
- School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, WITS, 2050 Johannesburg, South Africa
| | - Mandeep Kaur
- School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, WITS, 2050 Johannesburg, South Africa.
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Rincon-Torroella J, Dal Molin M, Mog B, Han G, Watson E, Wyhs N, Ishiyama S, Ahmedna T, Minn I, Azad NS, Bettegowda C, Papadopoulos N, Kinzler KW, Zhou S, Vogelstein B, Gabrielson K, Sur S. ME3BP-7 is a targeted cytotoxic agent that rapidly kills pancreatic cancer cells expressing high levels of monocarboxylate transporter MCT1. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.07.23.550207. [PMID: 37546808 PMCID: PMC10401962 DOI: 10.1101/2023.07.23.550207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/08/2023]
Abstract
Nearly 30% of Pancreatic ductal adenocarcinoma (PDAC)s exhibit a marked overexpression of Monocarboxylate Transporter 1 (MCT1) offering a unique opportunity for therapy. However, biochemical inhibitors of MCT1 have proven unsuccessful in clinical trials. In this study we present an alternative approach using 3-Bromopyruvate (3BP) to target MCT1 overexpressing PDACs. 3BP is a cytotoxic agent that is known to be transported into cells via MCT1, but its clinical usefulness has been hampered by difficulties in delivering the drug systemically. We describe here a novel microencapsulated formulation of 3BP (ME3BP-7), that is effective against a variety of PDAC cells in vitro and remains stable in serum. Furthermore, systemically administered ME3BP-7 significantly reduces pancreatic cancer growth and metastatic spread in multiple orthotopic models of pancreatic cancer with manageable toxicity. ME3BP-7 is, therefore, a prototype of a promising new drug, in which the targeting moiety and the cytotoxic moiety are both contained within the same single small molecule. One Sentence Summary ME3BP-7 is a novel formulation of 3BP that resists serum degradation and rapidly kills pancreatic cancer cells expressing high levels of MCT1 with tolerable toxicity in mice.
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5
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Barba I, Carrillo-Bosch L, Seoane J. Targeting the Warburg Effect in Cancer: Where Do We Stand? Int J Mol Sci 2024; 25:3142. [PMID: 38542116 PMCID: PMC10970388 DOI: 10.3390/ijms25063142] [Citation(s) in RCA: 38] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 03/06/2024] [Accepted: 03/06/2024] [Indexed: 03/06/2025] Open
Abstract
The Warburg effect, characterized by the preferential conversion of glucose to lactate even in the presence of oxygen and functional mitochondria, is a prominent metabolic hallmark of cancer cells and has emerged as a promising therapeutic target for cancer therapy. Elevated lactate levels and acidic pH within the tumor microenvironment (TME) resulting from glycolytic profoundly impact various cellular populations, including macrophage reprogramming and impairment of T-cell functionality. Altogether, the Warburg effect has been shown to promote tumor progression and immunosuppression through multiple mechanisms. This review provides an overview of the current understanding of the Warburg effect in cancer and its implications. We summarize recent pharmacological strategies aimed at targeting glycolytic enzymes, highlighting the challenges encountered in achieving therapeutic efficacy. Additionally, we examine the utility of the Warburg effect as an early diagnostic tool. Finally, we discuss the multifaceted roles of lactate within the TME, emphasizing its potential as a therapeutic target to disrupt metabolic interactions between tumor and immune cells, thereby enhancing anti-tumor immunity.
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Affiliation(s)
- Ignasi Barba
- Faculty of Medicine, University of Vic-Central University of Catalonia, 08500 Vic, Catalonia, Spain
- Vall d’Hebron Institute of Oncology (VHIO), CIBERONC, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
| | - Laura Carrillo-Bosch
- Vall d’Hebron Institute of Oncology (VHIO), CIBERONC, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
| | - Joan Seoane
- Vall d’Hebron Institute of Oncology (VHIO), CIBERONC, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain
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6
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Sheikh E, Agrawal K, Roy S, Burk D, Donnarumma F, Ko YH, Guttula PK, Biswal NC, Shukla HD, Gartia MR. Multimodal Imaging of Pancreatic Cancer Microenvironment in Response to an Antiglycolytic Drug. Adv Healthc Mater 2023; 12:e2301815. [PMID: 37706285 PMCID: PMC10842640 DOI: 10.1002/adhm.202301815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Indexed: 09/15/2023]
Abstract
Lipid metabolism and glycolysis play crucial roles in the progression and metastasis of cancer, and the use of 3-bromopyruvate (3-BP) as an antiglycolytic agent has shown promise in killing pancreatic cancer cells. However, developing an effective strategy to avoid chemoresistance requires the ability to probe the interaction of cancer drugs with complex tumor-associated microenvironments (TAMs). Unfortunately, no robust and multiplexed molecular imaging technology is currently available to analyze TAMs. In this study, the simultaneous profiling of three protein biomarkers using SERS nanotags and antibody-functionalized nanoparticles in a syngeneic mouse model of pancreatic cancer (PC) is demonstrated. This allows for comprehensive information about biomarkers and TAM alterations before and after treatment. These multimodal imaging techniques include surface-enhanced Raman spectroscopy (SERS), immunohistochemistry (IHC), polarized light microscopy, second harmonic generation (SHG) microscopy, fluorescence lifetime imaging microscopy (FLIM), and untargeted liquid chromatography and mass spectrometry (LC-MS) analysis. The study reveals the efficacy of 3-BP in treating pancreatic cancer and identifies drug treatment-induced lipid species remodeling and associated pathways through bioinformatics analysis.
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Affiliation(s)
- Elnaz Sheikh
- Department of Mechanical and Industrial Engineering, Louisiana State University, Baton Rouge, LA, 70803, USA
| | - Kirti Agrawal
- Department of Mechanical and Industrial Engineering, Louisiana State University, Baton Rouge, LA, 70803, USA
| | - Sanjit Roy
- Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
| | - David Burk
- Department of Cell Biology and Bioimaging, Pennington Biomedical Research Center, Baton Rouge, LA, 70808, USA
| | - Fabrizio Donnarumma
- Department of Chemistry, Louisiana State University, Baton Rouge, LA, 70803, USA
| | - Young H Ko
- NewG Lab Pharma, 701 East Pratt Street, Columbus Center, Baltimore, MD, 21202, USA
| | - Praveen Kumar Guttula
- Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada
- Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada
| | - Nrusingh C Biswal
- Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
| | - Hem D Shukla
- Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
| | - Manas Ranjan Gartia
- Department of Mechanical and Industrial Engineering, Louisiana State University, Baton Rouge, LA, 70803, USA
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7
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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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8
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Pourbaghi M, Haghani L, Zhao K, Karimi A, Marinelli B, Erinjeri JP, Geschwind JFH, Yarmohammadi H. Anti-Glycolytic Drugs in the Treatment of Hepatocellular Carcinoma: Systemic and Locoregional Options. Curr Oncol 2023; 30:6609-6622. [PMID: 37504345 PMCID: PMC10377758 DOI: 10.3390/curroncol30070485] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 07/01/2023] [Accepted: 07/04/2023] [Indexed: 07/29/2023] Open
Abstract
Hepatocellular cancer (HCC) is the most common primary liver cancer and the third leading cause of cancer-related death. Locoregional therapies, including transarterial embolization (TAE: bland embolization), chemoembolization (TACE), and radioembolization, have demonstrated survival benefits when treating patients with unresectable HCC. TAE and TACE occlude the tumor's arterial supply, causing hypoxia and nutritional deprivation and ultimately resulting in tumor necrosis. Embolization blocks the aerobic metabolic pathway. However, tumors, including HCC, use the "Warburg effect" and survive hypoxia from embolization. An adaptation to hypoxia through the Warburg effect, which was first described in 1956, is when the cancer cells switch to glycolysis even in the presence of oxygen. Hence, this is also known as aerobic glycolysis. In this article, the adaptation mechanisms of HCC, including glycolysis, are discussed, and anti-glycolytic treatments, including systemic and locoregional options that have been previously reported or have the potential to be utilized in the treatment of HCC, are reviewed.
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Affiliation(s)
- Miles Pourbaghi
- Department of Interventional Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; (M.P.); (K.Z.); (A.K.); (B.M.); (J.P.E.)
| | - Leila Haghani
- Department of Interventional Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; (M.P.); (K.Z.); (A.K.); (B.M.); (J.P.E.)
| | - Ken Zhao
- Department of Interventional Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; (M.P.); (K.Z.); (A.K.); (B.M.); (J.P.E.)
| | - Anita Karimi
- Department of Interventional Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; (M.P.); (K.Z.); (A.K.); (B.M.); (J.P.E.)
| | - Brett Marinelli
- Department of Interventional Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; (M.P.); (K.Z.); (A.K.); (B.M.); (J.P.E.)
| | - Joseph P. Erinjeri
- Department of Interventional Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; (M.P.); (K.Z.); (A.K.); (B.M.); (J.P.E.)
| | | | - Hooman Yarmohammadi
- Department of Interventional Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; (M.P.); (K.Z.); (A.K.); (B.M.); (J.P.E.)
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9
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Bandi DSR, Sarvesh S, Farran B, Nagaraju GP, El-Rayes BF. Targeting the metabolism and immune system in pancreatic ductal adenocarcinoma: Insights and future directions. Cytokine Growth Factor Rev 2023; 71-72:26-39. [PMID: 37407355 DOI: 10.1016/j.cytogfr.2023.06.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 06/29/2023] [Accepted: 06/29/2023] [Indexed: 07/07/2023]
Abstract
Pancreatic cancer, specifically pancreatic ductal adenocarcinoma (PDAC), presents a challenging landscape due to its complex nature and the highly immunosuppressive tumor microenvironment (TME). This immunosuppression severely limits the effectiveness of immune-based therapies. Studies have revealed the critical role of immunometabolism in shaping the TME and influencing PDAC progression. Genetic alterations, lysosomal dysfunction, gut microbiome dysbiosis, and altered metabolic pathways have been shown to modulate immunometabolism in PDAC. These metabolic alterations can significantly impact immune cell functions, including T-cells, myeloid-derived suppressor cells (MDSCs), and macrophages, evading anti-tumor immunity. Advances in immunotherapy offer promising avenues for overcoming immunosuppressive TME and enhancing patient outcomes. This review highlights the challenges and opportunities for future research in this evolving field. By exploring the connections between immunometabolism, genetic alterations, and the microbiome in PDAC, it is possible to tailor novel approaches capable of improving immunotherapy outcomes and addressing the limitations posed by immunosuppressive TME. Ultimately, these insights may pave the way for improved treatment options and better outcomes for PDAC patients.
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Affiliation(s)
- Dhana Sekhar Reddy Bandi
- Department of Hematology and Oncology, Heersink School of Medicine, University of Alabama, Birmingham, AL 35233, USA
| | - Sujith Sarvesh
- Department of Hematology and Oncology, Heersink School of Medicine, University of Alabama, Birmingham, AL 35233, USA
| | - Batoul Farran
- Department of Oncology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Ganji Purnachandra Nagaraju
- Department of Hematology and Oncology, Heersink School of Medicine, University of Alabama, Birmingham, AL 35233, USA.
| | - Bassel F El-Rayes
- Department of Hematology and Oncology, Heersink School of Medicine, University of Alabama, Birmingham, AL 35233, USA.
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10
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The "Superoncogene" Myc at the Crossroad between Metabolism and Gene Expression in Glioblastoma Multiforme. Int J Mol Sci 2023; 24:ijms24044217. [PMID: 36835628 PMCID: PMC9966483 DOI: 10.3390/ijms24044217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 02/10/2023] [Accepted: 02/16/2023] [Indexed: 02/22/2023] Open
Abstract
The concept of the Myc (c-myc, n-myc, l-myc) oncogene as a canonical, DNA-bound transcription factor has consistently changed over the past few years. Indeed, Myc controls gene expression programs at multiple levels: directly binding chromatin and recruiting transcriptional coregulators; modulating the activity of RNA polymerases (RNAPs); and drawing chromatin topology. Therefore, it is evident that Myc deregulation in cancer is a dramatic event. Glioblastoma multiforme (GBM) is the most lethal, still incurable, brain cancer in adults, and it is characterized in most cases by Myc deregulation. Metabolic rewiring typically occurs in cancer cells, and GBM undergoes profound metabolic changes to supply increased energy demand. In nontransformed cells, Myc tightly controls metabolic pathways to maintain cellular homeostasis. Consistently, in Myc-overexpressing cancer cells, including GBM cells, these highly controlled metabolic routes are affected by enhanced Myc activity and show substantial alterations. On the other hand, deregulated cancer metabolism impacts Myc expression and function, placing Myc at the intersection between metabolic pathway activation and gene expression. In this review paper, we summarize the available information on GBM metabolism with a specific focus on the control of the Myc oncogene that, in turn, rules the activation of metabolic signals, ensuring GBM growth.
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11
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Chen G, Wu K, Li H, Xia D, He T. Role of hypoxia in the tumor microenvironment and targeted therapy. Front Oncol 2022; 12:961637. [PMID: 36212414 PMCID: PMC9545774 DOI: 10.3389/fonc.2022.961637] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Accepted: 09/01/2022] [Indexed: 11/21/2022] Open
Abstract
Tumor microenvironment (TME), which is characterized by hypoxia, widely exists in solid tumors. As a current research hotspot in the TME, hypoxia is expected to become a key element to break through the bottleneck of tumor treatment. More and more research results show that a variety of biological behaviors of tumor cells are affected by many factors in TME which are closely related to hypoxia. In order to inhibiting the immune response in TME, hypoxia plays an important role in tumor cell metabolism and anti-apoptosis. Therefore, exploring the molecular mechanism of hypoxia mediated malignant tumor behavior and therapeutic targets is expected to provide new ideas for anti-tumor therapy. In this review, we discussed the effects of hypoxia on tumor behavior and its interaction with TME from the perspectives of immune cells, cell metabolism, oxidative stress and hypoxia inducible factor (HIF), and listed the therapeutic targets or signal pathways found so far. Finally, we summarize the current therapies targeting hypoxia, such as glycolysis inhibitors, anti-angiogenesis drugs, HIF inhibitors, hypoxia-activated prodrugs, and hyperbaric medicine.
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Affiliation(s)
- Gaoqi Chen
- Department of Hepatobiliary Pancreatic Surgery, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Kaiwen Wu
- Department of Gastroenterology, The Third People’s Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, Chengdu, China
| | - Hao Li
- Deparment of Neurology, Affiliated Hospital of Jiangsu University, Jiang Su University, Zhenjiang, China
| | - Demeng Xia
- Luodian Clinical Drug Research Center, Shanghai Baoshan Luodian Hospital, Shanghai University, Shanghai, China
- *Correspondence: Demeng Xia, ; Tianlin He,
| | - Tianlin He
- Department of Hepatobiliary Pancreatic Surgery, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
- *Correspondence: Demeng Xia, ; Tianlin He,
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12
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Wang C, Xu R, Song J, Chen Y, Yin X, Ruze R, Xu Q. Prognostic value of glycolysis markers in pancreatic cancer: A systematic review and meta-analysis. Front Oncol 2022; 12:1004850. [PMID: 36172154 PMCID: PMC9510923 DOI: 10.3389/fonc.2022.1004850] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 08/23/2022] [Indexed: 11/13/2022] Open
Abstract
Introduction Previous studies have investigated the prognostic significance of glycolysis markers in pancreatic cancer; however, conclusions from these studies are still controversial. Methods PubMed, Embase, and Web of Science were systematically searched to investigate the prognostic role of glycolysis markers in pancreatic cancer up to May 2022. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) related to overall survival (OS), disease free survival (DFS), recurrence-free survival (RFS), and distant metastasis-free survival (DMFS) were calculated using the STATA 12.0 software. Results A total of 28 studies comprising 2010 patients were included in this meta-analysis. High expression of the five glycolysis markers was correlated with a poorer OS (HR = 1.72, 95% CI: 1.34-2.22), DFS (HR = 3.09, 95% CI: 1.91-5.01), RFS (HR = 1.73, 95% CI: 1.21-2.48) and DMFS (HR = 2.60, 95% CI: 1.09-6.20) in patients with pancreatic cancer. In subgroup analysis, it was shown that higher expression levels of the five glycolysis markers were related to a poorer OS in Asians (HR = 1.85, 95% CI: 1.46-2.35, P < 0.001) and Caucasians (HR = 1.97, 95% CI: 1.40-2.77, P < 0.001). Besides, analysis based on the expression levels of specific glycolysis markers demonstrated that higher expression levels of GLUT1 (HR = 2.11, 95% CI: 1.58-2.82, P < 0.001), MCT4 (HR = 2.26, 95% CI: 1.36-3.76, P = 0.002), and ENO1 (HR = 2.16, 95% CI: 1.28-3.66, P =0.004) were correlated with a poorer OS in patients with pancreatic cancer. Conclusions High expression of the five glycolysis markers are associated with poorer OS, DFS, RFS and DMFS in patients with pancreatic cancer, indicating that the glycolysis markers could be potential prognostic predictors and therapeutic targets in pancreatic cancer.
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13
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Yeh HC, Su CC, Wu YH, Lee CH, Bao BY, Cheng WC, Wang SC, Liu PL, Chiu CC, Chuu CP, Ke CC, Wu HE, Chen YR, Chung WJ, Huang SP, Li CY. Novel insights into the anti-cancer effects of 3-bromopyruvic acid against castration-resistant prostate cancer. Eur J Pharmacol 2022; 923:174929. [PMID: 35364071 DOI: 10.1016/j.ejphar.2022.174929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 03/14/2022] [Accepted: 03/25/2022] [Indexed: 12/09/2022]
Abstract
3-bromopyruvic acid (3-BP), a small molecule alkylating agent, has been emerged as a glycolytic inhibitor with anticancer activities. However, the effects of 3-BP on the growth and metastasis in prostate cancer have not been well investigated. Here we investigated the anti-cancer effects of 3-BP on prostate cancer in vitro and in vivo. Cell growth, apoptosis, migration, motility, and invasion were examined. The tumor growth ability was determined using a xenograft murine model. Transcriptome analysis using RNA-seq was performed to explore the mechanism of action of 3-BP. Our experimental results showed that 3-BP effectively inhibits prostate cancer cell growth, especially in castration-resistant prostate cancer (CRPC) cells. Moreover, 3-BP induces apoptosis and suppresses cell migration, motility, epithelial-mesenchymal transition (EMT), and invasion in CRPC cells. In addition, 3-BP also attenuates tumor growth in a xenograft murine model. Through transcriptome analysis using RNA-seq, 3-BP significantly regulates the cell cycle pathway and decreases the expression of downstream cycle cycle-associated genes in CRPC cells. The results of cell cycle analysis indicated that 3-BP arrests cell cycle progression at G2/M in CRPC cells. These results suggest that 3-BP has the potential in inhibiting CRPC progression and might be a promising drug for CRPC treatment.
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Affiliation(s)
- Hsin-Chih Yeh
- Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan; Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan; Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, 80145, Taiwan
| | - Chia-Cheng Su
- Division of Urology, Department of Surgery, Chi-Mei Medical Center, Tainan, 71004, Taiwan; Department of Senior Citizen Service Management, Chia Nan University of Pharmacy and Science, Tainan, 71710, Taiwan
| | - Yen-Hsuan Wu
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Cheng Hsueh Lee
- Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Bo-Ying Bao
- Department of Pharmacy, China Medical University, Taichung, 404333, Taiwan; Sex Hormone Research Center, China Medical University Hospital, Taichung, 404332, Taiwan; Department of Nursing, Asia University, Taichung, 41354, Taiwan
| | - Wei-Chung Cheng
- Graduate Institute of Biomedical Sciences, Research Center for Tumor Medical Science, China Medical University, Taichung, 404333, Taiwan; Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taichung, 404333, Taiwan
| | - Shu-Chi Wang
- Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Po-Len Liu
- Department of Respiratory Therapy, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Chien-Chih Chiu
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Chih-Pin Chuu
- Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, 350401, Taiwan
| | - Chien-Chih Ke
- Department of Medical Imaging and Radiological Sciences, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Hsin-En Wu
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Yuan-Ru Chen
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Wei-Ju Chung
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Shu-Pin Huang
- Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan; Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan; Ph.D. Program in Environmental and Occupational Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan.
| | - Chia-Yang Li
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan.
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14
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Zhang Z, Zhang HJ. Glycometabolic rearrangements-aerobic glycolysis in pancreatic ductal adenocarcinoma (PDAC): roles, regulatory networks, and therapeutic potential. Expert Opin Ther Targets 2021; 25:1077-1093. [PMID: 34874212 DOI: 10.1080/14728222.2021.2015321] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Glycometabolic rearrangements (aerobic glycolysis) is a hallmark of pancreatic ductal adenocarcinoma (PDAC) and contributes to tumorigenesis and progression through numerous mechanisms. The targeting of aerobic glycolysis is recognized as a potential therapeutic strategy which offers the possibility of improving treatment outcomes for PDAC patients. AREAS COVERED In this review, the role of aerobic glycolysis and its regulatory networks in PDAC are discussed. The targeting of aerobic glycolysis in PDAC is examined, and its therapeutic potential is evaluated. The relevant literature published from 2001 to 2021 was searched in databases including PubMed, Scopus, and Embase. EXPERT OPINION Regulatory networks of aerobic glycolysis in PDAC are based on key factors such as c-Myc, hypoxia-inducible factor 1α, the mammalian target of rapamycin pathway, and non-coding RNAs. Experimental evidence suggests that modulators or inhibitors of aerobic glycolysis promote therapeutic effects in preclinical tumor models. Nevertheless, successful clinical translation of drugs that target aerobic glycolysis in PDAC is an obstacle. Moreover, it is necessary to identify the potential targets for future interventions from regulatory networks to design efficacious and safer agents.
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Affiliation(s)
- Zhong Zhang
- Department of Oncology, Zhongda Hospital, Medical School of Southeast University, Nanjing, People's Republic of China
| | - Hai-Jun Zhang
- Department of Oncology, Zhongda Hospital, Medical School of Southeast University, Nanjing, People's Republic of China
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15
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Shi C, Yang EJ, Tao S, Ren G, Mou PK, Shim JS. Natural products targeting cancer cell dependency. J Antibiot (Tokyo) 2021; 74:677-686. [PMID: 34163025 DOI: 10.1038/s41429-021-00438-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 06/03/2021] [Indexed: 02/06/2023]
Abstract
Precision cancer medicine is a tailored treatment approach for individual cancer patients with different genomic characteristics. Mutated or hyperactive oncogenes have served as main drug targets in current precision cancer medicine, while defective or inactivated tumor suppressors in general have not been considered as druggable targets. Synthetic lethality is one of very few approaches that enable to target defective tumor suppressors with pharmacological agents. Synthetic lethality exploits cancer cell dependency on a protein or pathway, which arises when the function of a tumor suppressor is defective. This approach has been proven to be effective in clinical settings since the successful clinical introduction of BRCA-PARP synthetic lethality for the treatment of breast and ovarian cancer with defective BRCA. Subsequently, large-scale screenings with RNAi, CRISPR/Cas9-sgRNAs, and chemical libraries have been applied to identify synthetic lethal partners of tumor suppressors. Natural products are an important source for the discovery of pharmacologically active small molecules. However, little effort has been made in the discovery of synthetic lethal small molecules from natural products. This review introduces recent advances in the discovery of natural products targeting cancer cell dependency and discusses potentials of natural products in the precision cancer medicine.
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Affiliation(s)
- Changxiang Shi
- Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China
| | - Eun Ju Yang
- Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China
| | - Shishi Tao
- Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China
| | - Guowen Ren
- Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China
| | - Pui Kei Mou
- Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China
| | - Joong Sup Shim
- Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China. .,MoE Frontiers Science Center for Precision Oncology, University of Macau, Taipa, Macau SAR, China.
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16
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Mosier JA, Schwager SC, Boyajian DA, Reinhart-King CA. Cancer cell metabolic plasticity in migration and metastasis. Clin Exp Metastasis 2021; 38:343-359. [PMID: 34076787 DOI: 10.1007/s10585-021-10102-1] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Accepted: 05/08/2021] [Indexed: 12/13/2022]
Abstract
Metabolic reprogramming is a hallmark of cancer metastasis in which cancer cells manipulate their metabolic profile to meet the dynamic energetic requirements of the tumor microenvironment. Though cancer cell proliferation and migration through the extracellular matrix are key steps of cancer progression, they are not necessarily fueled by the same metabolites and energy production pathways. The two main metabolic pathways cancer cells use to derive energy from glucose, glycolysis and oxidative phosphorylation, are preferentially and plastically utilized by cancer cells depending on both their intrinsic metabolic properties and their surrounding environment. Mechanical factors in the microenvironment, such as collagen density, pore size, and alignment, and biochemical factors, such as oxygen and glucose availability, have been shown to influence both cell migration and glucose metabolism. As cancer cells have been identified as preferentially utilizing glycolysis or oxidative phosphorylation based on heterogeneous intrinsic or extrinsic factors, the relationship between cancer cell metabolism and metastatic potential is of recent interest. Here, we review current in vitro and in vivo findings in the context of cancer cell metabolism during migration and metastasis and extrapolate potential clinical applications of this work that could aid in diagnosing and tracking cancer progression in vivo by monitoring metabolism. We also review current progress in the development of a variety of metabolically targeted anti-metastatic drugs, both in clinical trials and approved for distribution, and highlight potential routes for incorporating our recent understanding of metabolic plasticity into therapeutic directions. By further understanding cancer cell energy production pathways and metabolic plasticity, more effective and successful clinical imaging and therapeutics can be developed to diagnose, target, and inhibit metastasis.
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Affiliation(s)
- Jenna A Mosier
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA
| | - Samantha C Schwager
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA
| | - David A Boyajian
- Department of Radiology, Weill Cornell Medical College, New York, NY, USA
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17
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Tuerhong A, Xu J, Shi S, Tan Z, Meng Q, Hua J, Liu J, Zhang B, Wang W, Yu X, Liang C. Overcoming chemoresistance by targeting reprogrammed metabolism: the Achilles' heel of pancreatic ductal adenocarcinoma. Cell Mol Life Sci 2021; 78:5505-5526. [PMID: 34131808 PMCID: PMC11072422 DOI: 10.1007/s00018-021-03866-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 05/04/2021] [Accepted: 05/27/2021] [Indexed: 02/07/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related death due to its late diagnosis that removes the opportunity for surgery and metabolic plasticity that leads to resistance to chemotherapy. Metabolic reprogramming related to glucose, lipid, and amino acid metabolism in PDAC not only enables the cancer to thrive and survive under hypovascular, nutrient-poor and hypoxic microenvironments, but also confers chemoresistance, which contributes to the poor prognosis of PDAC. In this review, we systematically elucidate the mechanism of chemotherapy resistance and the relationship of metabolic programming features with resistance to anticancer drugs in PDAC. Targeting the critical enzymes and/or transporters involved in glucose, lipid, and amino acid metabolism may be a promising approach to overcome chemoresistance in PDAC. Consequently, regulating metabolism could be used as a strategy against PDAC and could improve the prognosis of PDAC.
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Affiliation(s)
- Abudureyimu Tuerhong
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong'An Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, People's Republic of China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, People's Republic of China
| | - Jin Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong'An Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, People's Republic of China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, People's Republic of China
| | - Si Shi
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong'An Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, People's Republic of China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, People's Republic of China
| | - Zhen Tan
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong'An Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, People's Republic of China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, People's Republic of China
| | - Qingcai Meng
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong'An Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, People's Republic of China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, People's Republic of China
| | - Jie Hua
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong'An Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, People's Republic of China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, People's Republic of China
| | - Jiang Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong'An Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, People's Republic of China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, People's Republic of China
| | - Bo Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong'An Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, People's Republic of China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, People's Republic of China
| | - Wei Wang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong'An Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, People's Republic of China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, People's Republic of China
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong'An Road, Shanghai, 200032, People's Republic of China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, People's Republic of China.
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, People's Republic of China.
| | - Chen Liang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong'An Road, Shanghai, 200032, People's Republic of China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, People's Republic of China.
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, People's Republic of China.
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Schiliro C, Firestein BL. Mechanisms of Metabolic Reprogramming in Cancer Cells Supporting Enhanced Growth and Proliferation. Cells 2021; 10:cells10051056. [PMID: 33946927 PMCID: PMC8146072 DOI: 10.3390/cells10051056] [Citation(s) in RCA: 291] [Impact Index Per Article: 72.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 04/27/2021] [Accepted: 04/28/2021] [Indexed: 02/07/2023] Open
Abstract
Cancer cells alter metabolic processes to sustain their characteristic uncontrolled growth and proliferation. These metabolic alterations include (1) a shift from oxidative phosphorylation to aerobic glycolysis to support the increased need for ATP, (2) increased glutaminolysis for NADPH regeneration, (3) altered flux through the pentose phosphate pathway and the tricarboxylic acid cycle for macromolecule generation, (4) increased lipid uptake, lipogenesis, and cholesterol synthesis, (5) upregulation of one-carbon metabolism for the production of ATP, NADH/NADPH, nucleotides, and glutathione, (6) altered amino acid metabolism, (7) metabolism-based regulation of apoptosis, and (8) the utilization of alternative substrates, such as lactate and acetate. Altered metabolic flux in cancer is controlled by tumor-host cell interactions, key oncogenes, tumor suppressors, and other regulatory molecules, including non-coding RNAs. Changes to metabolic pathways in cancer are dynamic, exhibit plasticity, and are often dependent on the type of tumor and the tumor microenvironment, leading in a shift of thought from the Warburg Effect and the “reverse Warburg Effect” to metabolic plasticity. Understanding the complex nature of altered flux through these multiple pathways in cancer cells can support the development of new therapies.
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Affiliation(s)
- Chelsea Schiliro
- Cell and Developmental Biology Graduate Program and Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, 604 Allison Road, Piscataway, NJ 08854, USA;
| | - Bonnie L. Firestein
- Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, 604 Allison Road, Piscataway, NJ 08854, USA
- Correspondence: ; Tel.: +1-848-445-8045
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19
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Savic LJ, Schobert IT, Hamm CA, Adam LC, Hyder F, Coman D. A high-throughput imaging platform to characterize extracellular pH in organotypic three-dimensional in vitro models of liver cancer. NMR IN BIOMEDICINE 2021; 34:e4465. [PMID: 33354836 DOI: 10.1002/nbm.4465] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 12/05/2020] [Indexed: 06/12/2023]
Abstract
Given the extraordinary nature of tumor metabolism in hepatocellular carcinoma and its impact on oncologic treatment response, this study introduces a novel high-throughput extracellular pH (pHe ) mapping platform using magnetic resonance spectroscopic imaging in a three-dimensional (3D) in vitro model of liver cancer. pHe mapping was performed using biosensor imaging of redundant deviation in shifts (BIRDS) on 9.4 T and 11.7 T MR scanners for validation purposes. 3D cultures of four liver cancer (HepG2, Huh7, SNU475, VX2) and one hepatocyte (THLE2) cell line were simultaneously analyzed (a) without treatment, (b) supplemented with 4.5 g/L d-glucose, and (c) treated with anti-glycolytic 3-bromopyruvate (6.25, 25, 50, 75, and 100 μM). The MR results were correlated with immunohistochemistry (GLUT-1, LAMP-2) and luminescence-based viability assays. Statistics included the unpaired t-test and ANOVA test. High-throughput pHe imaging with BIRDS for in vitro 3D liver cancer models proved feasible. Compared with non-tumorous hepatocytes (pHe = 7.1 ± 0.1), acidic pHe was revealed in liver cancer (VX2, pHe = 6.7 ± 0.1; HuH7, pHe = 6.8 ± 0.1; HepG2, pHe = 6.9 ± 0.1; SNU475, pHe = 6.9 ± 0.1), in agreement with GLUT-1 upregulation. Glucose addition significantly further decreased pHe in hyperglycolytic cell lines (VX2, HepG2, and Huh7, by 0.28, 0.06, and 0.11, respectively, all p < 0.001), whereas 3-bromopyruvate normalized tumor pHe in a dose-dependent manner without affecting viability. In summary, this study introduces a non-invasive pHe imaging platform for high-yield screening using a translational 3D liver cancer model, which may help reveal and target mechanisms of therapy resistance and inform personalized treatment of patients with hepatocellular carcinoma.
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Affiliation(s)
- Lynn Jeanette Savic
- Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA
- Institute of Radiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität, and Berlin Institute of Health, Berlin, Germany
- Berlin Institute of Health (BIH), Berlin, Germany
| | - Isabel Theresa Schobert
- Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA
- Institute of Radiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität, and Berlin Institute of Health, Berlin, Germany
| | - Charlie Alexander Hamm
- Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA
- Institute of Radiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität, and Berlin Institute of Health, Berlin, Germany
- Institute of Diagnostic Radiology and Neuroradiology, Greifswald University Hospital, Greifswald, Germany
| | - Lucas Christoph Adam
- Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA
- Institute of Radiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität, and Berlin Institute of Health, Berlin, Germany
| | - Fahmeed Hyder
- Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA
- Department of Biomedical Engineering, Yale University, New Haven, CT, USA
| | - Daniel Coman
- Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA
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20
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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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Savic LJ, Doemel LA, Schobert IT, Montgomery RR, Joshi N, Walsh JJ, Santana J, Pekurovsky V, Zhang X, Lin M, Adam L, Boustani A, Duncan J, Leng L, Bucala RJ, Goldberg SN, Hyder F, Coman D, Chapiro J. Molecular MRI of the Immuno-Metabolic Interplay in a Rabbit Liver Tumor Model: A Biomarker for Resistance Mechanisms in Tumor-targeted Therapy? Radiology 2020; 296:575-583. [PMID: 32633675 PMCID: PMC7434651 DOI: 10.1148/radiol.2020200373] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Revised: 04/24/2020] [Accepted: 05/05/2020] [Indexed: 02/05/2023]
Abstract
Background The immuno-metabolic interplay has gained interest for determining and targeting immunosuppressive tumor micro-environments that remain a barrier to current immuno-oncologic therapies in hepatocellular carcinoma. Purpose To develop molecular MRI tools to reveal resistance mechanisms to immuno-oncologic therapies caused by the immuno-metabolic interplay in a translational liver cancer model. Materials and Methods A total of 21 VX2 liver tumor-bearing New Zealand white rabbits were used between October 2018 and February 2020. Rabbits were divided into three groups. Group A (n = 3) underwent intra-arterial infusion of gadolinium 160 (160Gd)-labeled anti-human leukocyte antigen-DR isotope (HLA-DR) antibodies to detect antigen-presenting immune cells. Group B (n = 3) received rhodamine-conjugated superparamagnetic iron oxide nanoparticles (SPIONs) intravenously to detect macrophages. These six rabbits underwent 3-T MRI, including T1- and T2-weighted imaging, before and 24 hours after contrast material administration. Group C (n = 15) underwent extracellular pH mapping with use of MR spectroscopy. Of those 15 rabbits, six underwent conventional transarterial chemoembolization (TACE), four underwent conventional TACE with extracellular pH-buffering bicarbonate, and five served as untreated controls. MRI signal intensity distribution was validated by using immunohistochemistry staining of HLA-DR and CD11b, Prussian blue iron staining, fluorescence microscopy of rhodamine, and imaging mass cytometry (IMC) of gadolinium. Statistical analysis included Mann-Whitney U and Kruskal-Wallis tests. Results T1-weighted MRI with 160Gd-labeled antibodies revealed localized peritumoral ring enhancement, which corresponded to gadolinium distribution detected with IMC. T2-weighted MRI with SPIONs showed curvilinear signal intensity representing selective peritumoral deposition in macrophages. Extracellular pH-specific MR spectroscopy of untreated liver tumors showed acidosis (mean extracellular pH, 6.78 ± 0.09) compared with liver parenchyma (mean extracellular pH, 7.18 ± 0.03) (P = .008) and peritumoral immune cell exclusion. Normalization of tumor extracellular pH (mean, 6.96 ± 0.05; P = .02) using bicarbonate during TACE increased peri- and intratumoral immune cell infiltration (P = .002). Conclusion MRI in a rabbit liver tumor model was used to visualize resistance mechanisms mediated by the immuno-metabolic interplay that inform susceptibility and response to immuno-oncologic therapies, providing a therapeutic strategy to restore immune permissiveness in liver cancer. © RSNA, 2020 Online supplemental material is available for this article.
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Affiliation(s)
- Lynn Jeanette Savic
- From the Department of Radiology and Biomedical Imaging (L.J.S., L.A.D., I.T.S., J.J.W., J.S., M.D.L., L.A., A.B., J.D., F.H., D.C., J.C.), Department of Internal Medicine, Section of Rheumatology (R.R.M., L.L., R.J.B.), Department of Immunobiology (N.J.), and Department of Pathology (V.P., X.Z.), Yale University School of Medicine, 300 Cedar St, New Haven, CT 06520; Institute of Radiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität, and Berlin Institute of Health, Berlin, Germany (L.J.S., L.A.D., I.T.S., L.A.); Visage Imaging, San Diego, Calif (M.D.L.); Department of Biomedical Engineering, Yale School of Engineering and Applied Science, New Haven, Conn (J.D.); and Department of Radiology, Hadassah Hebrew University Medical Center, Jerusalem, Israel (S.N.G.)
| | - Luzie A. Doemel
- From the Department of Radiology and Biomedical Imaging (L.J.S., L.A.D., I.T.S., J.J.W., J.S., M.D.L., L.A., A.B., J.D., F.H., D.C., J.C.), Department of Internal Medicine, Section of Rheumatology (R.R.M., L.L., R.J.B.), Department of Immunobiology (N.J.), and Department of Pathology (V.P., X.Z.), Yale University School of Medicine, 300 Cedar St, New Haven, CT 06520; Institute of Radiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität, and Berlin Institute of Health, Berlin, Germany (L.J.S., L.A.D., I.T.S., L.A.); Visage Imaging, San Diego, Calif (M.D.L.); Department of Biomedical Engineering, Yale School of Engineering and Applied Science, New Haven, Conn (J.D.); and Department of Radiology, Hadassah Hebrew University Medical Center, Jerusalem, Israel (S.N.G.)
| | - Isabel Theresa Schobert
- From the Department of Radiology and Biomedical Imaging (L.J.S., L.A.D., I.T.S., J.J.W., J.S., M.D.L., L.A., A.B., J.D., F.H., D.C., J.C.), Department of Internal Medicine, Section of Rheumatology (R.R.M., L.L., R.J.B.), Department of Immunobiology (N.J.), and Department of Pathology (V.P., X.Z.), Yale University School of Medicine, 300 Cedar St, New Haven, CT 06520; Institute of Radiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität, and Berlin Institute of Health, Berlin, Germany (L.J.S., L.A.D., I.T.S., L.A.); Visage Imaging, San Diego, Calif (M.D.L.); Department of Biomedical Engineering, Yale School of Engineering and Applied Science, New Haven, Conn (J.D.); and Department of Radiology, Hadassah Hebrew University Medical Center, Jerusalem, Israel (S.N.G.)
| | - Ruth Rebecca Montgomery
- From the Department of Radiology and Biomedical Imaging (L.J.S., L.A.D., I.T.S., J.J.W., J.S., M.D.L., L.A., A.B., J.D., F.H., D.C., J.C.), Department of Internal Medicine, Section of Rheumatology (R.R.M., L.L., R.J.B.), Department of Immunobiology (N.J.), and Department of Pathology (V.P., X.Z.), Yale University School of Medicine, 300 Cedar St, New Haven, CT 06520; Institute of Radiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität, and Berlin Institute of Health, Berlin, Germany (L.J.S., L.A.D., I.T.S., L.A.); Visage Imaging, San Diego, Calif (M.D.L.); Department of Biomedical Engineering, Yale School of Engineering and Applied Science, New Haven, Conn (J.D.); and Department of Radiology, Hadassah Hebrew University Medical Center, Jerusalem, Israel (S.N.G.)
| | - Nikhil Joshi
- From the Department of Radiology and Biomedical Imaging (L.J.S., L.A.D., I.T.S., J.J.W., J.S., M.D.L., L.A., A.B., J.D., F.H., D.C., J.C.), Department of Internal Medicine, Section of Rheumatology (R.R.M., L.L., R.J.B.), Department of Immunobiology (N.J.), and Department of Pathology (V.P., X.Z.), Yale University School of Medicine, 300 Cedar St, New Haven, CT 06520; Institute of Radiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität, and Berlin Institute of Health, Berlin, Germany (L.J.S., L.A.D., I.T.S., L.A.); Visage Imaging, San Diego, Calif (M.D.L.); Department of Biomedical Engineering, Yale School of Engineering and Applied Science, New Haven, Conn (J.D.); and Department of Radiology, Hadassah Hebrew University Medical Center, Jerusalem, Israel (S.N.G.)
| | - John James Walsh
- From the Department of Radiology and Biomedical Imaging (L.J.S., L.A.D., I.T.S., J.J.W., J.S., M.D.L., L.A., A.B., J.D., F.H., D.C., J.C.), Department of Internal Medicine, Section of Rheumatology (R.R.M., L.L., R.J.B.), Department of Immunobiology (N.J.), and Department of Pathology (V.P., X.Z.), Yale University School of Medicine, 300 Cedar St, New Haven, CT 06520; Institute of Radiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität, and Berlin Institute of Health, Berlin, Germany (L.J.S., L.A.D., I.T.S., L.A.); Visage Imaging, San Diego, Calif (M.D.L.); Department of Biomedical Engineering, Yale School of Engineering and Applied Science, New Haven, Conn (J.D.); and Department of Radiology, Hadassah Hebrew University Medical Center, Jerusalem, Israel (S.N.G.)
| | - Jessica Santana
- From the Department of Radiology and Biomedical Imaging (L.J.S., L.A.D., I.T.S., J.J.W., J.S., M.D.L., L.A., A.B., J.D., F.H., D.C., J.C.), Department of Internal Medicine, Section of Rheumatology (R.R.M., L.L., R.J.B.), Department of Immunobiology (N.J.), and Department of Pathology (V.P., X.Z.), Yale University School of Medicine, 300 Cedar St, New Haven, CT 06520; Institute of Radiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität, and Berlin Institute of Health, Berlin, Germany (L.J.S., L.A.D., I.T.S., L.A.); Visage Imaging, San Diego, Calif (M.D.L.); Department of Biomedical Engineering, Yale School of Engineering and Applied Science, New Haven, Conn (J.D.); and Department of Radiology, Hadassah Hebrew University Medical Center, Jerusalem, Israel (S.N.G.)
| | - Vasily Pekurovsky
- From the Department of Radiology and Biomedical Imaging (L.J.S., L.A.D., I.T.S., J.J.W., J.S., M.D.L., L.A., A.B., J.D., F.H., D.C., J.C.), Department of Internal Medicine, Section of Rheumatology (R.R.M., L.L., R.J.B.), Department of Immunobiology (N.J.), and Department of Pathology (V.P., X.Z.), Yale University School of Medicine, 300 Cedar St, New Haven, CT 06520; Institute of Radiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität, and Berlin Institute of Health, Berlin, Germany (L.J.S., L.A.D., I.T.S., L.A.); Visage Imaging, San Diego, Calif (M.D.L.); Department of Biomedical Engineering, Yale School of Engineering and Applied Science, New Haven, Conn (J.D.); and Department of Radiology, Hadassah Hebrew University Medical Center, Jerusalem, Israel (S.N.G.)
| | - Xuchen Zhang
- From the Department of Radiology and Biomedical Imaging (L.J.S., L.A.D., I.T.S., J.J.W., J.S., M.D.L., L.A., A.B., J.D., F.H., D.C., J.C.), Department of Internal Medicine, Section of Rheumatology (R.R.M., L.L., R.J.B.), Department of Immunobiology (N.J.), and Department of Pathology (V.P., X.Z.), Yale University School of Medicine, 300 Cedar St, New Haven, CT 06520; Institute of Radiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität, and Berlin Institute of Health, Berlin, Germany (L.J.S., L.A.D., I.T.S., L.A.); Visage Imaging, San Diego, Calif (M.D.L.); Department of Biomedical Engineering, Yale School of Engineering and Applied Science, New Haven, Conn (J.D.); and Department of Radiology, Hadassah Hebrew University Medical Center, Jerusalem, Israel (S.N.G.)
| | - MingDe Lin
- From the Department of Radiology and Biomedical Imaging (L.J.S., L.A.D., I.T.S., J.J.W., J.S., M.D.L., L.A., A.B., J.D., F.H., D.C., J.C.), Department of Internal Medicine, Section of Rheumatology (R.R.M., L.L., R.J.B.), Department of Immunobiology (N.J.), and Department of Pathology (V.P., X.Z.), Yale University School of Medicine, 300 Cedar St, New Haven, CT 06520; Institute of Radiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität, and Berlin Institute of Health, Berlin, Germany (L.J.S., L.A.D., I.T.S., L.A.); Visage Imaging, San Diego, Calif (M.D.L.); Department of Biomedical Engineering, Yale School of Engineering and Applied Science, New Haven, Conn (J.D.); and Department of Radiology, Hadassah Hebrew University Medical Center, Jerusalem, Israel (S.N.G.)
| | - Lucas Adam
- From the Department of Radiology and Biomedical Imaging (L.J.S., L.A.D., I.T.S., J.J.W., J.S., M.D.L., L.A., A.B., J.D., F.H., D.C., J.C.), Department of Internal Medicine, Section of Rheumatology (R.R.M., L.L., R.J.B.), Department of Immunobiology (N.J.), and Department of Pathology (V.P., X.Z.), Yale University School of Medicine, 300 Cedar St, New Haven, CT 06520; Institute of Radiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität, and Berlin Institute of Health, Berlin, Germany (L.J.S., L.A.D., I.T.S., L.A.); Visage Imaging, San Diego, Calif (M.D.L.); Department of Biomedical Engineering, Yale School of Engineering and Applied Science, New Haven, Conn (J.D.); and Department of Radiology, Hadassah Hebrew University Medical Center, Jerusalem, Israel (S.N.G.)
| | - Annemarie Boustani
- From the Department of Radiology and Biomedical Imaging (L.J.S., L.A.D., I.T.S., J.J.W., J.S., M.D.L., L.A., A.B., J.D., F.H., D.C., J.C.), Department of Internal Medicine, Section of Rheumatology (R.R.M., L.L., R.J.B.), Department of Immunobiology (N.J.), and Department of Pathology (V.P., X.Z.), Yale University School of Medicine, 300 Cedar St, New Haven, CT 06520; Institute of Radiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität, and Berlin Institute of Health, Berlin, Germany (L.J.S., L.A.D., I.T.S., L.A.); Visage Imaging, San Diego, Calif (M.D.L.); Department of Biomedical Engineering, Yale School of Engineering and Applied Science, New Haven, Conn (J.D.); and Department of Radiology, Hadassah Hebrew University Medical Center, Jerusalem, Israel (S.N.G.)
| | - James Duncan
- From the Department of Radiology and Biomedical Imaging (L.J.S., L.A.D., I.T.S., J.J.W., J.S., M.D.L., L.A., A.B., J.D., F.H., D.C., J.C.), Department of Internal Medicine, Section of Rheumatology (R.R.M., L.L., R.J.B.), Department of Immunobiology (N.J.), and Department of Pathology (V.P., X.Z.), Yale University School of Medicine, 300 Cedar St, New Haven, CT 06520; Institute of Radiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität, and Berlin Institute of Health, Berlin, Germany (L.J.S., L.A.D., I.T.S., L.A.); Visage Imaging, San Diego, Calif (M.D.L.); Department of Biomedical Engineering, Yale School of Engineering and Applied Science, New Haven, Conn (J.D.); and Department of Radiology, Hadassah Hebrew University Medical Center, Jerusalem, Israel (S.N.G.)
| | - Lin Leng
- From the Department of Radiology and Biomedical Imaging (L.J.S., L.A.D., I.T.S., J.J.W., J.S., M.D.L., L.A., A.B., J.D., F.H., D.C., J.C.), Department of Internal Medicine, Section of Rheumatology (R.R.M., L.L., R.J.B.), Department of Immunobiology (N.J.), and Department of Pathology (V.P., X.Z.), Yale University School of Medicine, 300 Cedar St, New Haven, CT 06520; Institute of Radiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität, and Berlin Institute of Health, Berlin, Germany (L.J.S., L.A.D., I.T.S., L.A.); Visage Imaging, San Diego, Calif (M.D.L.); Department of Biomedical Engineering, Yale School of Engineering and Applied Science, New Haven, Conn (J.D.); and Department of Radiology, Hadassah Hebrew University Medical Center, Jerusalem, Israel (S.N.G.)
| | - Richard John Bucala
- From the Department of Radiology and Biomedical Imaging (L.J.S., L.A.D., I.T.S., J.J.W., J.S., M.D.L., L.A., A.B., J.D., F.H., D.C., J.C.), Department of Internal Medicine, Section of Rheumatology (R.R.M., L.L., R.J.B.), Department of Immunobiology (N.J.), and Department of Pathology (V.P., X.Z.), Yale University School of Medicine, 300 Cedar St, New Haven, CT 06520; Institute of Radiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität, and Berlin Institute of Health, Berlin, Germany (L.J.S., L.A.D., I.T.S., L.A.); Visage Imaging, San Diego, Calif (M.D.L.); Department of Biomedical Engineering, Yale School of Engineering and Applied Science, New Haven, Conn (J.D.); and Department of Radiology, Hadassah Hebrew University Medical Center, Jerusalem, Israel (S.N.G.)
| | - S. Nahum Goldberg
- From the Department of Radiology and Biomedical Imaging (L.J.S., L.A.D., I.T.S., J.J.W., J.S., M.D.L., L.A., A.B., J.D., F.H., D.C., J.C.), Department of Internal Medicine, Section of Rheumatology (R.R.M., L.L., R.J.B.), Department of Immunobiology (N.J.), and Department of Pathology (V.P., X.Z.), Yale University School of Medicine, 300 Cedar St, New Haven, CT 06520; Institute of Radiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität, and Berlin Institute of Health, Berlin, Germany (L.J.S., L.A.D., I.T.S., L.A.); Visage Imaging, San Diego, Calif (M.D.L.); Department of Biomedical Engineering, Yale School of Engineering and Applied Science, New Haven, Conn (J.D.); and Department of Radiology, Hadassah Hebrew University Medical Center, Jerusalem, Israel (S.N.G.)
| | - Fahmeed Hyder
- From the Department of Radiology and Biomedical Imaging (L.J.S., L.A.D., I.T.S., J.J.W., J.S., M.D.L., L.A., A.B., J.D., F.H., D.C., J.C.), Department of Internal Medicine, Section of Rheumatology (R.R.M., L.L., R.J.B.), Department of Immunobiology (N.J.), and Department of Pathology (V.P., X.Z.), Yale University School of Medicine, 300 Cedar St, New Haven, CT 06520; Institute of Radiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität, and Berlin Institute of Health, Berlin, Germany (L.J.S., L.A.D., I.T.S., L.A.); Visage Imaging, San Diego, Calif (M.D.L.); Department of Biomedical Engineering, Yale School of Engineering and Applied Science, New Haven, Conn (J.D.); and Department of Radiology, Hadassah Hebrew University Medical Center, Jerusalem, Israel (S.N.G.)
| | - Daniel Coman
- From the Department of Radiology and Biomedical Imaging (L.J.S., L.A.D., I.T.S., J.J.W., J.S., M.D.L., L.A., A.B., J.D., F.H., D.C., J.C.), Department of Internal Medicine, Section of Rheumatology (R.R.M., L.L., R.J.B.), Department of Immunobiology (N.J.), and Department of Pathology (V.P., X.Z.), Yale University School of Medicine, 300 Cedar St, New Haven, CT 06520; Institute of Radiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität, and Berlin Institute of Health, Berlin, Germany (L.J.S., L.A.D., I.T.S., L.A.); Visage Imaging, San Diego, Calif (M.D.L.); Department of Biomedical Engineering, Yale School of Engineering and Applied Science, New Haven, Conn (J.D.); and Department of Radiology, Hadassah Hebrew University Medical Center, Jerusalem, Israel (S.N.G.)
| | - Julius Chapiro
- From the Department of Radiology and Biomedical Imaging (L.J.S., L.A.D., I.T.S., J.J.W., J.S., M.D.L., L.A., A.B., J.D., F.H., D.C., J.C.), Department of Internal Medicine, Section of Rheumatology (R.R.M., L.L., R.J.B.), Department of Immunobiology (N.J.), and Department of Pathology (V.P., X.Z.), Yale University School of Medicine, 300 Cedar St, New Haven, CT 06520; Institute of Radiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität, and Berlin Institute of Health, Berlin, Germany (L.J.S., L.A.D., I.T.S., L.A.); Visage Imaging, San Diego, Calif (M.D.L.); Department of Biomedical Engineering, Yale School of Engineering and Applied Science, New Haven, Conn (J.D.); and Department of Radiology, Hadassah Hebrew University Medical Center, Jerusalem, Israel (S.N.G.)
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Shah VM, Sheppard BC, Sears RC, Alani AW. Hypoxia: Friend or Foe for drug delivery in Pancreatic Cancer. Cancer Lett 2020; 492:63-70. [PMID: 32822815 DOI: 10.1016/j.canlet.2020.07.041] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 07/24/2020] [Accepted: 07/30/2020] [Indexed: 02/07/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal solid tumors with an overall five-year survival rate of that has only just reached 10%. The tumor microenvironment of PDAC is characterized by desmoplasia, which consist of dense stroma of fibroblasts and inflammatory cells, resulting in a hypoxic environment due to limited oxygen diffusion through the tumor. Hypoxia contributes to the aggressive tumor biology by promoting tumor progression, malignancy, and promoting resistance to conventional and targeted therapeutic agents. In depth research in the area has identified that hypoxia modulates the tumor biology through hypoxia inducible factors (HIFs), which not only are the key determinant of pancreatic malignancy but also an important target for therapy. In this review, we summarize the recent advances in understanding hypoxia driven phenotypes, which are responsible for the highly aggressive and metastatic characteristics of pancreatic cancer, and how hypoxia can be exploited as a target for drug delivery.
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Affiliation(s)
- Vidhi M Shah
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University/OHSU, 2730 SW Moody Ave., Portland, OR, 97201, USA; Department of Molecular and Medical Genetics, Oregon Health and Science University, 3181 S. W. Sam Jackson Park Rd., Portland, OR, 97239, USA
| | - Brett C Sheppard
- Department of Surgery, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Road, Portland, OR, 97239, USA; Brenden-Colson Center for Pancreatic Care, Oregon Health and Science University, 3181 S.W Sam Jackson Park Road, Portland, OR, 97239, USA; OHSU Knight Cancer Institute at Oregon Health & Science University, Portland, OR, 97239, USA
| | - Rosalie C Sears
- Brenden-Colson Center for Pancreatic Care, Oregon Health and Science University, 3181 S.W Sam Jackson Park Road, Portland, OR, 97239, USA; Department of Molecular and Medical Genetics, Oregon Health and Science University, 3181 S. W. Sam Jackson Park Rd., Portland, OR, 97239, USA; OHSU Knight Cancer Institute at Oregon Health & Science University, Portland, OR, 97239, USA
| | - Adam Wg Alani
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University/OHSU, 2730 SW Moody Ave., Portland, OR, 97201, USA; OHSU Knight Cancer Institute at Oregon Health & Science University, Portland, OR, 97239, USA; Department of Biomedical Engineering, School of Medicine at Oregon Health & Science University, Portland, OR, 97239, USA.
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Guo Y, Liu X, Zhang Y, Qiu H, Ouyang F, He Y. 3-Bromopyruvate ameliorates pulmonary arterial hypertension by improving mitochondrial metabolism. Life Sci 2020; 256:118009. [PMID: 32603819 DOI: 10.1016/j.lfs.2020.118009] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 06/16/2020] [Accepted: 06/23/2020] [Indexed: 10/24/2022]
Abstract
AIMS Abnormal mitochondrial metabolism is an essential factor for excessive proliferation of pulmonary artery smooth muscle cells (PASMCs), which drives the pathological process of pulmonary arterial hypertension (PAH). 3-Bromopyruvate (3-BrPA) is an effective glycolytic inhibitor that improves mitochondrial metabolism, thereby repressing anomalous cell proliferation. MAIN METHODS An experimental PAH model was established by injection of monocrotaline (MCT) in male Sprague Dawley rats, following which rats were assigned to three groups: control, MCT, and 3-BrPA groups. Three days post injection of MCT, rats were treated with 3-BrPA or vehicle for 4 weeks. At the end of the study, hemodynamic data were measured to confirm PAH condition. Indicators of pulmonary arterial and right ventricular (RV) remodeling as well as the proliferative ability of PASMCs were assayed. Additionally, mitochondrial morphology and function, and antiglycolytic and antiproliferative pathways and genes were analyzed. KEY FINDINGS Treatment with 3-BrPA effectively improved pulmonary vascular remodeling and right ventricular function, inhibited PASMC proliferation, and preserved mitochondrial morphology and function. Besides, 3-BrPA treatment inhibited the PI3K/AKT/mTOR pathway and regulated the expression of antiproliferative genes in PASMCs. However, bloody ascites, bloating, and cirrhosis of organs were observed in some 3-BrPA treated rats. SIGNIFICANCE 3-BrPA acts as an important glycolytic inhibitor to improve energy metabolism and reverse the course of PAH. However, 3-BrPA is associated with side effects in MCT-induced rats, indicating that it should be caution in drug delivery dosage, and further studies are needed to evaluate this toxicological mechanism.
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Affiliation(s)
- Yuan Guo
- Department of Cardiovascular Medicine, The Affiliated Zhuzhou Hospital Xiangya Medical College, Central South University, Zhuzhou, Hunan 412000, China.
| | - Xiangyang Liu
- Department of Cardiovascular Medicine, The Affiliated Zhuzhou Hospital Xiangya Medical College, Central South University, Zhuzhou, Hunan 412000, China
| | - Yibo Zhang
- Department of Ultrasound, The Affiliated Zhuzhou Hospital Xiangya Medical College, Central South University, Zhuzhou, Hunan 412000, China
| | - Haihua Qiu
- Department of Cardiovascular Medicine, The Affiliated Zhuzhou Hospital Xiangya Medical College, Central South University, Zhuzhou, Hunan 412000, China
| | - Fan Ouyang
- Department of Cardiovascular Medicine, The Affiliated Zhuzhou Hospital Xiangya Medical College, Central South University, Zhuzhou, Hunan 412000, China
| | - Yi He
- Department of Cardiovascular Medicine, The Affiliated Zhuzhou Hospital Xiangya Medical College, Central South University, Zhuzhou, Hunan 412000, China
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Yang J, Ren B, Yang G, Wang H, Chen G, You L, Zhang T, Zhao Y. The enhancement of glycolysis regulates pancreatic cancer metastasis. Cell Mol Life Sci 2020; 77:305-321. [PMID: 31432232 PMCID: PMC11104916 DOI: 10.1007/s00018-019-03278-z] [Citation(s) in RCA: 237] [Impact Index Per Article: 47.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 08/10/2019] [Accepted: 08/12/2019] [Indexed: 02/07/2023]
Abstract
Pancreatic ductal adenocarcinoma is prone to distant metastasis and is expected to become the second leading cause of cancer-related death. In an extremely nutrient-deficient and hypoxic environment resulting from uncontrolled growth, vascular disturbances and desmoplastic reactions, pancreatic cancer cells utilize "metabolic reprogramming" to satisfy their energy demand and support malignant behaviors such as metastasis. Notably, pancreatic cancer cells show extensive enhancement of glycolysis, including glycolytic enzyme overexpression and increased lactate production, and this is caused by mitochondrial dysfunction, cancer driver genes, specific transcription factors, a hypoxic tumor microenvironment and stromal cells, such as cancer-associated fibroblasts and tumor-associated macrophages. The metabolic switch from oxidative phosphorylation to glycolysis in pancreatic cancer cells regulates the invasion-metastasis cascade by promoting epithelial-mesenchymal transition, tumor angiogenesis and the metastatic colonization of distant organs. In addition to aerobic glycolysis, oxidative phosphorylation also plays a critical role in pancreatic cancer metastasis in ways that remain unclear. In this review, we expound on the intracellular and extracellular causes of the enhancement of glycolysis in pancreatic cancer and the strong association between glycolysis and cancer metastasis, which we expect will yield new therapeutic approaches targeting cancer metabolism.
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Affiliation(s)
- Jinshou Yang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, People's Republic of China
| | - Bo Ren
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, People's Republic of China
| | - Gang Yang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, People's Republic of China
| | - Huanyu Wang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, People's Republic of China
| | - Guangyu Chen
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, People's Republic of China
| | - Lei You
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, People's Republic of China.
| | - Taiping Zhang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, People's Republic of China.
| | - Yupei Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, People's Republic of China.
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Abdel-Wahab AF, Mahmoud W, Al-Harizy RM. Targeting glucose metabolism to suppress cancer progression: prospective of anti-glycolytic cancer therapy. Pharmacol Res 2019; 150:104511. [DOI: 10.1016/j.phrs.2019.104511] [Citation(s) in RCA: 356] [Impact Index Per Article: 59.3] [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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26
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Coman D, Peters DC, Walsh JJ, Savic LJ, Huber S, Sinusas AJ, Lin M, Chapiro J, Constable RT, Rothman DL, Duncan JS, Hyder F. Extracellular pH mapping of liver cancer on a clinical 3T MRI scanner. Magn Reson Med 2019; 83:1553-1564. [PMID: 31691371 DOI: 10.1002/mrm.28035] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2019] [Revised: 09/13/2019] [Accepted: 09/18/2019] [Indexed: 02/06/2023]
Abstract
PURPOSE To demonstrate feasibility of developing a noninvasive extracellular pH (pHe ) mapping method on a clinical MRI scanner for molecular imaging of liver cancer. METHODS In vivo pHe mapping has been demonstrated on preclinical scanners (e.g., 9.4T, 11.7T) with Biosensor Imaging of Redundant Deviation in Shifts (BIRDS), where the pHe readout by 3D chemical shift imaging (CSI) depends on hyperfine shifts emanating from paramagnetic macrocyclic chelates like TmDOTP5- which upon extravasation from blood resides in the extracellular space. We implemented BIRDS-based pHe mapping on a clinical 3T Siemens scanner, where typically diamagnetic 1 H signals are detected using millisecond-long radiofrequency (RF) pulses, and 1 H shifts span over ±10 ppm with long transverse (T2 , 102 ms) and longitudinal (T1 , 103 ms) relaxation times. We modified this 3D-CSI method for ultra-fast acquisition with microsecond-long RF pulses, because even at 3T the paramagnetic 1 H shifts of TmDOTP5- have millisecond-long T2 and T1 and ultra-wide chemical shifts (±200 ppm) as previously observed in ultra-high magnetic fields. RESULTS We validated BIRDS-based pH in vitro with a pH electrode. We measured pHe in a rabbit model for liver cancer using VX2 tumors, which are highly vascularized and hyperglycolytic. Compared to intratumoral pHe (6.8 ± 0.1; P < 10-9 ) and tumor's edge pHe (6.9 ± 0.1; P < 10-7 ), liver parenchyma pHe was significantly higher (7.2 ± 0.1). Tumor localization was confirmed with histopathological markers of necrosis (hematoxylin and eosin), glucose uptake (glucose transporter 1), and tissue acidosis (lysosome-associated membrane protein 2). CONCLUSION This work demonstrates feasibility and potential clinical translatability of high-resolution pHe mapping to monitor tumor aggressiveness and therapeutic outcome, all to improve personalized cancer treatment planning.
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Affiliation(s)
- Daniel Coman
- Department of Radiology & Biomedical Imaging, Yale University, New Haven, Connecticut
| | - Dana C Peters
- Department of Radiology & Biomedical Imaging, Yale University, New Haven, Connecticut
| | - John J Walsh
- Department of Biomedical Engineering, Yale University, New Haven, Connecticut
| | - Lynn J Savic
- Department of Radiology & Biomedical Imaging, Yale University, New Haven, Connecticut.,Institute of Radiology, Charité-Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität, and Berlin Institute of Health, Berlin, Germany
| | - Steffen Huber
- Department of Radiology & Biomedical Imaging, Yale University, New Haven, Connecticut
| | - Albert J Sinusas
- Department of Radiology & Biomedical Imaging, Yale University, New Haven, Connecticut.,Department of Medicine, Section of Cardiovascular Medicine, Yale University, New Haven, Connecticut
| | - MingDe Lin
- Department of Radiology & Biomedical Imaging, Yale University, New Haven, Connecticut.,Visage Imaging, Inc., San Diego, California
| | - Julius Chapiro
- Department of Radiology & Biomedical Imaging, Yale University, New Haven, Connecticut
| | - R Todd Constable
- Department of Radiology & Biomedical Imaging, Yale University, New Haven, Connecticut
| | - Douglas L Rothman
- Department of Radiology & Biomedical Imaging, Yale University, New Haven, Connecticut.,Department of Biomedical Engineering, Yale University, New Haven, Connecticut
| | - James S Duncan
- Department of Radiology & Biomedical Imaging, Yale University, New Haven, Connecticut.,Department of Biomedical Engineering, Yale University, New Haven, Connecticut
| | - Fahmeed Hyder
- Department of Radiology & Biomedical Imaging, Yale University, New Haven, Connecticut.,Department of Biomedical Engineering, Yale University, New Haven, Connecticut
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27
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Savic LJ, Schobert IT, Peters D, Walsh JJ, Laage-Gaupp FM, Hamm CA, Tritz N, Doemel LA, Lin M, Sinusas A, Schlachter T, Duncan JS, Hyder F, Coman D, Chapiro J. Molecular Imaging of Extracellular Tumor pH to Reveal Effects of Locoregional Therapy on Liver Cancer Microenvironment. Clin Cancer Res 2019; 26:428-438. [PMID: 31582517 DOI: 10.1158/1078-0432.ccr-19-1702] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 07/24/2019] [Accepted: 09/30/2019] [Indexed: 02/06/2023]
Abstract
PURPOSE To establish magnetic resonance (MR)-based molecular imaging paradigms for the noninvasive monitoring of extracellular pH (pHe) as a functional surrogate biomarker for metabolic changes induced by locoregional therapy of liver cancer. EXPERIMENTAL DESIGN Thirty-two VX2 tumor-bearing New Zealand white rabbits underwent longitudinal imaging on clinical 3T-MRI and CT scanners before and up to 2 weeks after complete conventional transarterial chemoembolization (cTACE) using ethiodized oil (lipiodol) and doxorubicin. MR-spectroscopic imaging (MRSI) was employed for pHe mapping. Multiparametric MRI and CT were performed to quantify tumor enhancement, diffusion, and lipiodol coverage of the tumor posttherapy. In addition, incomplete cTACE with reduced chemoembolic doses was applied to mimic undertreatment and exploit pHe mapping to detect viable tumor residuals. Imaging findings were correlated with histopathologic markers indicative of metabolic state (HIF-1α, GLUT-1, and LAMP-2) and viability (proliferating cell nuclear antigen and terminal deoxynucleotidyl-transferase dUTP nick-end labeling). RESULTS Untreated VX2 tumors demonstrated a significantly lower pHe (6.80 ± 0.09) than liver parenchyma (7.19 ± 0.03, P < 0.001). Upregulation of HIF-1α, GLUT-1, and LAMP-2 confirmed a hyperglycolytic tumor phenotype and acidosis. A gradual tumor pHe increase toward normalization similar to parenchyma was revealed within 2 weeks after complete cTACE, which correlated with decreasing detectability of metabolic markers. In contrast, pHe mapping after incomplete cTACE indicated both acidic viable residuals and increased tumor pHe of treated regions. Multimodal imaging revealed durable tumor devascularization immediately after complete cTACE, gradually increasing necrosis, and sustained lipiodol coverage of the tumor. CONCLUSIONS MRSI-based pHe mapping can serve as a longitudinal monitoring tool for viable tumors. As most liver tumors are hyperglycolytic creating microenvironmental acidosis, therapy-induced normalization of tumor pHe may be used as a functional biomarker for positive therapeutic outcome.
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Affiliation(s)
- Lynn Jeanette Savic
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, Connecticut.,Institute of Radiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität, and Berlin Institute of Health, Berlin, Germany
| | - Isabel Theresa Schobert
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, Connecticut.,Institute of Radiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität, and Berlin Institute of Health, Berlin, Germany
| | - Dana Peters
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, Connecticut
| | - John J Walsh
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, Connecticut
| | - Fabian Max Laage-Gaupp
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, Connecticut
| | - Charlie Alexander Hamm
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, Connecticut.,Institute of Radiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität, and Berlin Institute of Health, Berlin, Germany
| | - Nina Tritz
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, Connecticut
| | - Luzie A Doemel
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, Connecticut.,Institute of Radiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität, and Berlin Institute of Health, Berlin, Germany
| | - MingDe Lin
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, Connecticut.,Visage Imaging, Inc., San Diego, California
| | - Albert Sinusas
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, Connecticut.,Department of Internal Medicine (Cardiology), Yale School of Medicine, New Haven, Connecticut
| | - Todd Schlachter
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, Connecticut
| | - James S Duncan
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, Connecticut.,Department of Biomedical Engineering, Yale School of Engineering and Applied Science, New Haven, Connecticut
| | - Fahmeed Hyder
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, Connecticut
| | - Daniel Coman
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, Connecticut
| | - Julius Chapiro
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, Connecticut.
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Cole DW, Svider PF, Shenouda KG, Lee PB, Yoo NG, McLeod TM, Mutchnick SA, Yoo GH, Kaufman RJ, Callaghan MU, Fribley AM. Targeting the unfolded protein response in head and neck and oral cavity cancers. Exp Cell Res 2019; 382:111386. [PMID: 31075256 DOI: 10.1016/j.yexcr.2019.04.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2018] [Revised: 03/25/2019] [Accepted: 04/05/2019] [Indexed: 12/18/2022]
Abstract
Many FDA-approved anti-cancer therapies, targeted toward a wide array of molecular targets and signaling networks, have been demonstrated to activate the unfolded protein response (UPR). Despite a critical role for UPR signaling in the apoptotic execution of cancer cells by many of these compounds, the authors are currently unaware of any instance whereby a cancer drug was developed with the UPR as the intended target. With the essential role of the UPR as a driving force in the genesis and maintenance of the malignant phenotype, a great number of pre-clinical studies have surged into the medical literature describing the ability of dozens of compounds to induce UPR signaling in a myriad of cancer models. The focus of the current work is to review the literature and explore the role of the UPR as a mediator of chemotherapy-induced cell death in squamous cell carcinomas of the head and neck (HNSCC) and oral cavity (OCSCC), with an emphasis on preclinical studies.
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Affiliation(s)
- Daniel W Cole
- Department of Otolaryngology - Head and Neck Surgery, Wayne State University School of Medicine, Detroit, MI, USA
| | - Peter F Svider
- Department of Otolaryngology - Head and Neck Surgery, Wayne State University School of Medicine, Detroit, MI, USA
| | - Kerolos G Shenouda
- Department of Otolaryngology - Head and Neck Surgery, Wayne State University School of Medicine, Detroit, MI, USA
| | - Paul B Lee
- Oakland University William Beaumont School of Medicine, Rochester Hills, Michigan, USA
| | - Nicholas G Yoo
- Department of Otolaryngology - Head and Neck Surgery, Wayne State University School of Medicine, Detroit, MI, USA
| | - Thomas M McLeod
- Department of Otolaryngology - Head and Neck Surgery, Wayne State University School of Medicine, Detroit, MI, USA
| | - Sean A Mutchnick
- Department of Otolaryngology - Head and Neck Surgery, Wayne State University School of Medicine, Detroit, MI, USA
| | - George H Yoo
- Department of Otolaryngology - Head and Neck Surgery, Wayne State University School of Medicine, Detroit, MI, USA; Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA
| | - Randal J Kaufman
- Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Michael U Callaghan
- Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA; Children's Hospital of Michigan, Detroit Medical Center, Detroit, MI, USA
| | - Andrew M Fribley
- Department of Otolaryngology - Head and Neck Surgery, Wayne State University School of Medicine, Detroit, MI, USA; Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA; Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA; Children's Hospital of Michigan, Detroit Medical Center, Detroit, MI, USA; Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA.
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29
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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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Yamada M, Kagaya M, Noguchi N, Ueki S, Hasunuma N, Osada SI, Manabe M. Topical 3-bromopyruvate is a novel targeted therapy for melanoma in a preclinical model. J Dermatol Sci 2018; 92:134-142. [DOI: 10.1016/j.jdermsci.2018.08.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Revised: 08/21/2018] [Accepted: 08/26/2018] [Indexed: 01/10/2023]
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31
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Borsoi C, Leonard F, Lee Y, Zaid M, Elganainy D, Alexander JF, Kai M, Liu YT, Kang Y, Liu X, Koay EJ, Ferrari M, Godin B, Yokoi K. Gemcitabine enhances the transport of nanovector-albumin-bound paclitaxel in gemcitabine-resistant pancreatic ductal adenocarcinoma. Cancer Lett 2017; 403:296-304. [PMID: 28687352 DOI: 10.1016/j.canlet.2017.06.026] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Revised: 06/03/2017] [Accepted: 06/16/2017] [Indexed: 02/06/2023]
Abstract
The mechanism for improved therapeutic efficacy of the combination therapy with nanoparticle albumin-bound paclitaxel (nAb-PTX) and gemcitabine (gem) for pancreatic ductal adenocarcinoma (PDAC) has been ascribed to enhanced gem transport by nAb-PTX. Here, we used an orthotopic mouse model of gem-resistant human PDAC in which increasing gem transport would not improve the efficacy, thus revealing the importance of nAb-PTX transport. We aimed to evaluate therapeutic outcomes and transport of nAb-PTX to PDAC as a result of (1) encapsulating nAb-PTX in multistage nanovectors (MSV); (2) effect of gem on caveolin-1 expression. Treatment with MSV/nAb-PTX + gem was highly efficient in prolonging animal survival in comparison to other therapeutic regimens. MSV/nAb-PTX + gem also caused a substantial increase in tumor PTX accumulation, significantly reduced tumor growth and tumor cell proliferation, and increased apoptosis. Moreover, gem enhanced caveolin-1 expression in vitro and in vivo, thereby improving transport of nAb-PTX to PDAC. This data was confirmed by analysis of PDACs from patients who received gem-based neo-adjuvant chemotherapy. In conclusion, we found that nAb-PTX treatment of gem-resistant PDAC can be enhanced by (1) gem through up-regulation of caveolin-1 and (2) MSV through increasing accumulation of nAb-PTX in the tumor.
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Affiliation(s)
- Carlotta Borsoi
- Department of Nanomedicine, Houston Methodist Research Institute, 6700 Bertner Ave., Houston, TX 77030, USA
| | - Fransisca Leonard
- Department of Nanomedicine, Houston Methodist Research Institute, 6700 Bertner Ave., Houston, TX 77030, USA
| | - Yeonju Lee
- Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA
| | - Mohamed Zaid
- Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA
| | - Dalia Elganainy
- Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA
| | | | - Megumi Kai
- Department of Nanomedicine, Houston Methodist Research Institute, 6700 Bertner Ave., Houston, TX 77030, USA
| | - Yan Ting Liu
- Department of Nanomedicine, Houston Methodist Research Institute, 6700 Bertner Ave., Houston, TX 77030, USA
| | - Yaan Kang
- Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA
| | - Xuewu Liu
- Department of Nanomedicine, Houston Methodist Research Institute, 6700 Bertner Ave., Houston, TX 77030, USA
| | - Eugene J Koay
- Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA
| | - Mauro Ferrari
- Department of Nanomedicine, Houston Methodist Research Institute, 6700 Bertner Ave., Houston, TX 77030, USA; Department of Medicine, Weill Cornell Medicine, 1300 York Ave., New York, NY 10065, USA.
| | - Biana Godin
- Department of Nanomedicine, Houston Methodist Research Institute, 6700 Bertner Ave., Houston, TX 77030, USA.
| | - Kenji Yokoi
- Department of Nanomedicine, Houston Methodist Research Institute, 6700 Bertner Ave., Houston, TX 77030, USA.
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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: 24] [Impact Index Per Article: 3.0] [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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Erkan M, Kurtoglu M, Kleeff J. The role of hypoxia in pancreatic cancer: a potential therapeutic target? Expert Rev Gastroenterol Hepatol 2016; 10:301-16. [PMID: 26560854 DOI: 10.1586/17474124.2016.1117386] [Citation(s) in RCA: 100] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
One of the key factors that correlates with poor survival of patients with pancreatic cancer is the extent of hypoxic areas within the tumor tissue. The adaptation of pancreatic cancer cells to limited oxygen delivery promotes the induction of an invasive and treatment-resistant phenotype, triggering metastases at an early stage of tumor development, which resist in most cases adjuvant therapies following tumor resection. In this article, the authors summarize the evidence demonstrating the significance of hypoxia in pancreatic cancer pathogenesis and discuss the possible hypoxia-induced mechanisms underlying its aggressive nature. We then conclude with promising strategies that target hypoxia-adapted pancreatic cancer cells.
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Affiliation(s)
- Mert Erkan
- a Department of Surgery , Koç University School of Medicine , Istanbul , Turkey
| | - Metin Kurtoglu
- b Department of Oncology , Koç University School of Medicine , Istanbul , Turkey
| | - Jorg Kleeff
- c Department of Surgery , The Royal Liverpool and Broadgreen University Hospitals , Liverpool , UK.,d Department of General-, Visceral- and Pediatric Surgery , University Hospital Düsseldorf, Heinrich Heine University Düsseldorf , Düsseldorf , Germany
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Pan Q, Sun Y, Jin Q, Li Q, Wang Q, Liu H, Zhao S. Hepatotoxicity and nephrotoxicity of 3-bromopyruvate in mice. Acta Cir Bras 2016; 31:724-729. [DOI: 10.1590/s0102-865020160110000004] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2016] [Accepted: 10/10/2016] [Indexed: 11/22/2022] Open
Affiliation(s)
| | | | | | | | | | - Hao Liu
- Department of Pharmacy, China
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35
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Emile O, Emile J, Ghoufi A. Influence of the interface on the optical activity of confined glucose films. J Colloid Interface Sci 2016; 477:103-8. [PMID: 27254252 DOI: 10.1016/j.jcis.2016.05.047] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Revised: 05/23/2016] [Accepted: 05/23/2016] [Indexed: 10/21/2022]
Abstract
We report on the time evolution of the optical activity of a thinning liquid film containing glucose, and confined between two glass slides. This dynamics strongly depends on the presence of surfactant molecules. With sodium dodecyl sulfate (SDS), we evidence favorable interactions of sugar molecules with the sulfate group. As previously observed for a freely suspended soap film in the air (see Emile et al., 2013), this corresponds to an anchoring of glucose molecules at the interface. For glucose alone, we also highlight a molecular rearrangement that is not instantaneous and occurs after several minutes. This interfacial organization leads to an unusual giant optical activity that is different with or without SDS. Molecular simulations confirm the anchoring of the glucose molecules at the glass/liquid interface, and show a different molecular orientation in each case.
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Affiliation(s)
- Olivier Emile
- Université de Rennes 1, Campus de Beaulieu, 35042 Rennes, France.
| | - Janine Emile
- Institut de Physique de Rennes, CNRS UMR 6521, Université de Rennes 1, Campus de Beaulieu, 35042 Rennes, France
| | - Aziz Ghoufi
- Institut de Physique de Rennes, CNRS UMR 6521, Université de Rennes 1, Campus de Beaulieu, 35042 Rennes, France
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The anticancer agent 3-bromopyruvate: a simple but powerful molecule taken from the lab to the bedside. J Bioenerg Biomembr 2016; 48:349-62. [PMID: 27457582 DOI: 10.1007/s10863-016-9670-z] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2016] [Accepted: 07/18/2016] [Indexed: 12/13/2022]
Abstract
At the beginning of the twenty-first century, 3-bromopyruvate (3BP), a simple alkylating chemical compound was presented to the scientific community as a potent anticancer agent, able to cause rapid toxicity to cancer cells without bystander effects on normal tissues. The altered metabolism of cancers, an essential hallmark for their progression, also became their Achilles heel by facilitating 3BP's selective entry and specific targeting. Treatment with 3BP has been administered in several cancer type models both in vitro and in vivo, either alone or in combination with other anticancer therapeutic approaches. These studies clearly demonstrate 3BP's broad action against multiple cancer types. Clinical trials using 3BP are needed to further support its anticancer efficacy against multiple cancer types thus making it available to more than 30 million patients living with cancer worldwide. This review discusses current knowledge about 3BP related to cancer and discusses also the possibility of its use in future clinical applications as it relates to safety and treatment issues.
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Haider S, McIntyre A, van Stiphout RGPM, Winchester LM, Wigfield S, Harris AL, Buffa FM. Genomic alterations underlie a pan-cancer metabolic shift associated with tumour hypoxia. Genome Biol 2016; 17:140. [PMID: 27358048 PMCID: PMC4926297 DOI: 10.1186/s13059-016-0999-8] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Accepted: 06/06/2016] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Altered metabolism is a hallmark of cancer. However, the role of genomic changes in metabolic genes driving the tumour metabolic shift remains to be elucidated. Here, we have investigated the genomic and transcriptomic changes underlying this shift across ten different cancer types. RESULTS A systematic pan-cancer analysis of 6538 tumour/normal samples covering ten major cancer types identified a core metabolic signature of 44 genes that exhibit high frequency somatic copy number gains/amplifications (>20 % cases) associated with increased mRNA expression (ρ > 0.3, q < 10(-3)). Prognostic classifiers using these genes were confirmed in independent datasets for breast and kidney cancers. Interestingly, this signature is strongly associated with hypoxia, with nine out of ten cancer types showing increased expression and five out of ten cancer types showing increased gain/amplification of these genes in hypoxic tumours (P ≤ 0.01). Further validation in breast and colorectal cancer cell lines highlighted squalene epoxidase, an oxygen-requiring enzyme in cholesterol biosynthesis, as a driver of dysregulated metabolism and a key player in maintaining cell survival under hypoxia. CONCLUSIONS This study reveals somatic genomic alterations underlying a pan-cancer metabolic shift and suggests genomic adaptation of these genes as a survival mechanism in hypoxic tumours.
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Affiliation(s)
- Syed Haider
- />Computational Biology and Integrative Genomics, Department of Oncology, University of Oxford, Oxford, UK
- />Molecular Oncology Laboratories, Department of Oncology, The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
| | - Alan McIntyre
- />Molecular Oncology Laboratories, Department of Oncology, The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
| | - Ruud G. P. M. van Stiphout
- />Computational Biology and Integrative Genomics, Department of Oncology, University of Oxford, Oxford, UK
| | - Laura M. Winchester
- />Computational Biology and Integrative Genomics, Department of Oncology, University of Oxford, Oxford, UK
- />Molecular Oncology Laboratories, Department of Oncology, The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
| | - Simon Wigfield
- />Molecular Oncology Laboratories, Department of Oncology, The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
| | - Adrian L. Harris
- />Molecular Oncology Laboratories, Department of Oncology, The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
| | - Francesca M. Buffa
- />Computational Biology and Integrative Genomics, Department of Oncology, University of Oxford, Oxford, UK
- />Molecular Oncology Laboratories, Department of Oncology, The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
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Pancreatic Cancer Epidemiology, Detection, and Management. Gastroenterol Res Pract 2016; 2016:8962321. [PMID: 26941789 PMCID: PMC4749824 DOI: 10.1155/2016/8962321] [Citation(s) in RCA: 113] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2015] [Accepted: 01/05/2016] [Indexed: 02/07/2023] Open
Abstract
PC (pancreatic cancer) is the fourth most common cause of death due to cancer worldwide. The incidence and mortality rates have been increasing year by year worldwide, and this review has analyzed the most recent incidence and mortality data for pancreatic cancer occurrence in China. Several possible risk factors have been discussed here, involving known established risk factors and novel possible risk factors. The development of this cancer is a stepwise progression through intraepithelial neoplasia to carcinoma. Though early and accurate diagnosis is promising based on a combination of recent techniques including tumor markers and imaging modalities, lacking early clinical symptoms makes the diagnosis late. Correct staging is critical because treatment is generally based on this parameter. Treatment options have improved throughout the last decades. However, surgical excision remains the primary therapy and efficacy of conventional chemoradiotherapy for PC is limited. Recently, some novel new therapies have been developed and will be applied in clinics soon. This review will provide an overview of pancreatic cancer, including an understanding of the developments and controversies.
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Savic LJ, Chapiro J, Duwe G, Geschwind JF. Targeting glucose metabolism in cancer: new class of agents for loco-regional and systemic therapy of liver cancer and beyond? Hepat Oncol 2016; 3:19-28. [PMID: 26989470 DOI: 10.2217/hep.15.36] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent cancers and the third leading cause of cancer-related deaths worldwide. In patients with unresectable disease, loco-regional catheter-based intra-arterial therapies (IAT) can achieve selective tumor control while minimizing systemic toxicity. As molecular features of tumor growth and microenvironment are better understood, new targets arise for selective anticancer therapy. Particularly, antiglycolytic drugs that exploit the hyperglycolytic cancer cell metabolism - also known as the 'Warburg effect' - have emerged as promising therapeutic options. Thus, future developments will combine the selective character of loco-regional drug delivery platforms with highly specific molecular targeted antiglycolytic agents. This review will exemplify literature on antiglycolytic approaches and particularly focus on intra-arterial delivery methods.
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Affiliation(s)
- Lynn Jeanette Savic
- Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, CT, US; Department of Diagnostic & Interventional Radiology, Universitätsmedizin Charité Berlin, Berlin, Germany
| | - Julius Chapiro
- Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, CT, US; Department of Diagnostic & Interventional Radiology, Universitätsmedizin Charité Berlin, Berlin, Germany
| | - Gregor Duwe
- Department of Diagnostic & Interventional Radiology, Universitätsmedizin Charité Berlin, Berlin, Germany
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Akhenblit PJ, Pagel MD. Recent Advances in Targeting Tumor Energy Metabolism with Tumor Acidosis as a Biomarker of Drug Efficacy. ACTA ACUST UNITED AC 2016; 8:20-29. [PMID: 26962408 PMCID: PMC4780427 DOI: 10.4172/1948-5956.1000382] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Cancer cells employ a deregulated cellular metabolism to leverage survival and growth advantages. The unique tumor energy metabolism presents itself as a promising target for chemotherapy. A pool of tumor energy metabolism targeting agents has been developed after several decades of efforts. This review will cover glucose and fatty acid metabolism, PI3K/AKT/mTOR, HIF-1 and glutamine pathways in tumor energy metabolism, and how they are being exploited for treatments and therapies by promising pre-clinical or clinical drugs being developed or investigated. Additionally, acidification of the tumor extracellular microenvironment is hypothesized to be the result of active tumor metabolism. This implies that tumor extracellular pH (pHe) can be a biomarker for assessing the efficacy of therapies that target tumor metabolism. Several translational molecular imaging methods (PET, MRI) for interrogating tumor acidification and its suppression are discussed as well.
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Affiliation(s)
- Paul J Akhenblit
- Cancer Biology Graduate Interdisciplinary Program, University of Arizona, Tucson, AZ, USA
| | - Mark D Pagel
- Cancer Biology Graduate Interdisciplinary Program, University of Arizona, Tucson, AZ, USA; Department of Medical Imaging, University of Arizona, Tucson, AZ, USA
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41
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Diedrich J, Gusky HC, Podgorski I. Adipose tissue dysfunction and its effects on tumor metabolism. Horm Mol Biol Clin Investig 2015; 21:17-41. [PMID: 25781550 DOI: 10.1515/hmbci-2014-0045] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Accepted: 01/14/2015] [Indexed: 12/12/2022]
Abstract
Growing by an alarming rate in the Western world, obesity has become a condition associated with a multitude of diseases such as diabetes, metabolic syndrome and various cancers. Generally viewed as an abnormal accumulation of hypertrophied adipocytes, obesity is also a poor prognostic factor for recurrence and chemoresistance in cancer patients. With more than two-thirds of the adult population in the United States considered clinically overweight or obese, it is critical that the relationship between obesity and cancer is further emphasized and elucidated. Adipocytes are highly metabolically active cells, which, through release of adipokines and cytokines and activation of endocrine and paracrine pathways, affect processes in neighboring and distant cells, altering their normal homeostasis. This work will examine specifically how adipocyte-derived factors regulate the cellular metabolism of malignant cells within the tumor niche. Briefly, tumor cells undergo metabolic pressure towards a more glycolytic and hypoxic state through a variety of metabolic regulators and signaling pathways, i.e., phosphoinositol-3 kinase (PI3K), hypoxia-inducible factor-1 alpha (HIF-1α), and c-MYC signaling. Enhanced glycolysis and high lactate production are hallmarks of tumor progression largely because of a process known as the Warburg effect. Herein, we review the latest literature pertaining to the body of work on the interactions between adipose and tumor cells, and underlining the changes in cancer cell metabolism that have been targeted by the currently available treatments.
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Karthikeyan S, Potter JJ, Geschwind JF, Sur S, Hamilton JP, Vogelstein B, Kinzler KW, Mezey E, Ganapathy-Kanniappan S. Deregulation of energy metabolism promotes antifibrotic effects in human hepatic stellate cells and prevents liver fibrosis in a mouse model. Biochem Biophys Res Commun 2015; 469:463-9. [PMID: 26525850 DOI: 10.1016/j.bbrc.2015.10.101] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2015] [Accepted: 10/20/2015] [Indexed: 12/21/2022]
Abstract
Liver fibrosis and cirrhosis result from uncontrolled secretion and accumulation of extracellular matrix (ECM) proteins by hepatic stellate cells (HSCs) that are activated by liver injury and inflammation. Despite the progress in understanding the biology liver fibrogenesis and the identification of potential targets for treating fibrosis, development of an effective therapy remains elusive. Since an uninterrupted supply of intracellular energy is critical for the activated-HSCs to maintain constant synthesis and secretion of ECM, we hypothesized that interfering with energy metabolism could affect ECM secretion. Here we report that a sublethal dose of the energy blocker, 3-bromopyruvate (3-BrPA) facilitates phenotypic alteration of activated LX-2 (a human hepatic stellate cell line), into a less-active form. This treatment-dependent reversal of activated-LX2 cells was evidenced by a reduction in α-smooth muscle actin (α-SMA) and collagen secretion, and an increase in activity of matrix metalloproteases. Mechanistically, 3-BrPA-dependent antifibrotic effects involved down-regulation of the mitochondrial metabolic enzyme, ATP5E, and up-regulation of glycolysis, as evident by elevated levels of lactate dehydrogenase, lactate production and its transporter, MCT4. Finally, the antifibrotic effects of 3-BrPA were validated in vivo in a mouse model of carbon tetrachloride-induced liver fibrosis. Results from histopathology & histochemical staining for collagen and α-SMA substantiated that 3-BrPA promotes antifibrotic effects in vivo. Taken together, our data indicate that sublethal, metronomic treatment with 3-BrPA blocks the progression of liver fibrosis suggesting its potential as a novel therapeutic for treating liver fibrosis.
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Affiliation(s)
- Swathi Karthikeyan
- Division of Interventional Radiology, Russell H. Morgan Department of Radiology & Radiological Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - James J Potter
- Division of Gastroenterology and Hepatology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jean-Francois Geschwind
- Division of Interventional Radiology, Russell H. Morgan Department of Radiology & Radiological Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
| | - Surojit Sur
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - James P Hamilton
- Division of Gastroenterology and Hepatology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Bert Vogelstein
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - Kenneth W Kinzler
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - Esteban Mezey
- Division of Gastroenterology and Hepatology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Shanmugasundaram Ganapathy-Kanniappan
- Division of Interventional Radiology, Russell H. Morgan Department of Radiology & Radiological Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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Gan L, Xiu R, Ren P, Yue M, Su H, Guo G, Xiao D, Yu J, Jiang H, Liu H, Hu G, Qing G. Metabolic targeting of oncogene MYC by selective activation of the proton-coupled monocarboxylate family of transporters. Oncogene 2015; 35:3037-48. [PMID: 26434591 DOI: 10.1038/onc.2015.360] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2015] [Revised: 08/14/2015] [Accepted: 08/24/2015] [Indexed: 12/23/2022]
Abstract
Deregulation of the MYC oncogene produces Myc protein that regulates multiple aspects of cancer cell metabolism, contributing to the acquisition of building blocks essential for cancer cell growth and proliferation. Therefore, disabling Myc function represents an attractive therapeutic option for cancer treatment. However, pharmacological strategies capable of directly targeting Myc remain elusive. Here, we identified that 3-bromopyruvate (3-BrPA), a drug candidate that primarily inhibits glycolysis, preferentially induced massive cell death in human cancer cells overexpressing the MYC oncogene, in vitro and in vivo, without appreciable effects on those exhibiting low MYC levels. Importantly, pharmacological inhibition of glutamine metabolism synergistically potentiated the synthetic lethal targeting of MYC by 3-BrPA due in part to the metabolic disturbance caused by this combination. Mechanistically, we identified that the proton-coupled monocarboxylate transporter 1 (MCT1) and MCT2, which enable efficient 3-BrPA uptake by cancer cells, were selectively activated by Myc. Two regulatory mechanisms were involved: first, Myc directly activated MCT1 and MCT2 transcription by binding to specific recognition sites of both genes; second, Myc transcriptionally repressed miR29a and miR29c, resulting in enhanced expression of their target protein MCT1. Of note, expressions of MCT1 and MCT2 were each significantly elevated in MYCN-amplified neuroblastomas and C-MYC-overexpressing lymphomas than in tumors without MYC overexpression, correlating with poor prognosis and unfavorable patient survival. These results identify a novel mechanism by which Myc sensitizes cells to metabolic inhibitors and validate 3-BrPA as potential Myc-selective cancer therapeutics.
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Affiliation(s)
- L Gan
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.,School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - R Xiu
- School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - P Ren
- School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - M Yue
- School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - H Su
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - G Guo
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - D Xiao
- School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - J Yu
- Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, People's Republic of China
| | - H Jiang
- Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, People's Republic of China
| | - H Liu
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - G Hu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - G Qing
- School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.,Medical Research Institute, Wuhan University, Wuhan, People's Republic of China
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44
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Lee M, Yoon JH. Metabolic interplay between glycolysis and mitochondrial oxidation: The reverse Warburg effect and its therapeutic implication. World J Biol Chem 2015; 6:148-61. [PMID: 26322173 PMCID: PMC4549759 DOI: 10.4331/wjbc.v6.i3.148] [Citation(s) in RCA: 107] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2015] [Revised: 05/26/2015] [Accepted: 07/21/2015] [Indexed: 02/05/2023] Open
Abstract
Aerobic glycolysis, i.e., the Warburg effect, may contribute to the aggressive phenotype of hepatocellular carcinoma. However, increasing evidence highlights the limitations of the Warburg effect, such as high mitochondrial respiration and low glycolysis rates in cancer cells. To explain such contradictory phenomena with regard to the Warburg effect, a metabolic interplay between glycolytic and oxidative cells was proposed, i.e., the "reverse Warburg effect". Aerobic glycolysis may also occur in the stromal compartment that surrounds the tumor; thus, the stromal cells feed the cancer cells with lactate and this interaction prevents the creation of an acidic condition in the tumor microenvironment. This concept provides great heterogeneity in tumors, which makes the disease difficult to cure using a single agent. Understanding metabolic flexibility by lactate shuttles offers new perspectives to develop treatments that target the hypoxic tumor microenvironment and overcome the limitations of glycolytic inhibitors.
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