Dichloroacetate Radiosensitizes Hypoxic Breast Cancer Cells

Sven de Mey, Inès Dufait, Heng Jiang, Cyril Corbet, Hui Wang, Melissa Van De Gucht, Lisa Kerkhove, Ka Lun Law, Hugo Vandenplas, Thierry Gevaert, Olivier Feron, Mark De Ridder

Research output: Contribution to journalArticle

4 Citations (Scopus)


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.

Original languageEnglish
Article number9367
Pages (from-to)1-20
Number of pages20
JournalInternational Journal of Molecular Sciences
Issue number24
Publication statusPublished - 2 Dec 2020


  • breast cancer
  • dichloroacetate
  • hypoxic radiosensitivity
  • reactive oxygen species


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