1. Dichloroacetate Radiosensitizes Hypoxic Breast Cancer Cells
- Author
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Hugo Vandenplas, Sven de Mey, Inès Dufait, Olivier Feron, Thierry Gevaert, Mark De Ridder, Lisa Kerkhove, Cyril Corbet, Melissa Van De Gucht, Ka Lun Law, Heng Jiang, Hui Wang, Clinical sciences, Faculty of Medicine and Pharmacy, Radiation Therapy, and Translational Radiation Oncology and Physics
- Subjects
Pyruvate dehydrogenase kinase ,Breast Neoplasms ,Oxidative phosphorylation ,Radiation Tolerance ,Article ,Catalysis ,Cell Line ,Inorganic Chemistry ,lcsh:Chemistry ,breast cancer ,Radioresistance ,Humans ,hypoxic radiosensitivity ,Radiosensitivity ,Enzyme Inhibitors ,Physical and Theoretical Chemistry ,dichloroacetate ,Molecular Biology ,lcsh:QH301-705.5 ,Spectroscopy ,chemistry.chemical_classification ,reactive oxygen species ,Reactive oxygen species ,Dichloroacetic Acid ,Organic Chemistry ,Pyruvate Dehydrogenase Acetyl-Transferring Kinase ,General Medicine ,Metabolism ,Pyruvate dehydrogenase complex ,Computer Science Applications ,chemistry ,lcsh:Biology (General) ,lcsh:QD1-999 ,oncology ,Cancer cell ,Cancer research ,Tumor Hypoxia ,Female - Abstract
Mitochondrial metabolism is an attractive target for cancer therapy. Reprogramming metabolic pathways can potentially sensitize tumors with limited treatment options, such as triple-negative breast cancer (TNBC), to chemo- and/or radiotherapy. Dichloroacetate (DCA) is a specific inhibitor of the pyruvate dehydrogenase kinase (PDK), which leads to enhanced reactive oxygen species (ROS) production. ROS are the primary effector molecules of radiation and an increase hereof will enhance the radioresponse. In this study, we evaluated the effects of DCA and radiotherapy on two TNBC cell lines, namely EMT6 and 4T1, under aerobic and hypoxic conditions. As expected, DCA treatment decreased phosphorylated pyruvate dehydrogenase (PDH) and lowered both extracellular acidification rate (ECAR) and lactate production. Remarkably, DCA treatment led to a significant increase in ROS production (up to 15-fold) in hypoxic cancer cells but not in aerobic cells. Consistently, DCA radiosensitized hypoxic tumor cells and 3D spheroids while leaving the intrinsic radiosensitivity of the tumor cells unchanged. Our results suggest that although described as an oxidative phosphorylation (OXPHOS)-promoting drug, DCA can also increase hypoxic radioresponses. This study therefore paves the way for the targeting of mitochondrial metabolism of hypoxic cancer cells, in particular to combat radioresistance.
- Published
- 2020