Dichloroacetate Radiosensitizes Hypoxic Breast Cancer Cells

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.

Novel insight into metabolic reprogrammming in cancer radioresistance: A promising therapeutic target in radiotherapy

“…Pyruvate dehydrogenase kinases (PDKs) inhibit the activity of PDH, which is a key enzyme regulating the switch between oxidative phosphorylation and glycolysis in cancer cells. Previous studies have indicated that PDK1 and phospho-pyruvate dehydrogenase (p-PDH) are positively associated with radioresistance [53][54][55]. In complex I-deficient mitochondrial cells, there was an increase in the expression of p-PDH, accompanied by radioresistance by reducing histone acetylation and promoting DNA damage repair [53].…”

Chimeric Drug Design with a Noncharged Carrier for Mitochondrial Delivery

“…Increasing the local concentration of the inhibitor through the nanoparticle ensured efficient delivery. Although the doses used for Thio-DCA treatment are still high, they are lower than those employed in recent reports on the use of DCA, usually reaching up to 50 mM [ 44 , 70 , 71 ], and are similar to DCA concentrations used in sensitive cell lines [ 72 ]. The most important observation of our work is, however, that mitochondrial accumulation, promoted by a neutral carrier, enhanced the effect of the drug in several DCA-resistant cell lines.…”

Application of a Dual-Probe Coloading Nanodetection System in the Process Monitoring and Efficacy Assessment of Photodynamic Therapy: An In Vitro Study

“…44,58,59 In hypoxia, DCA enhances cytotoxicity by further inhibiting glycolysis and amplifying oxidative phosphorylation to promote ROS expansion. 60,61 Besides, DCApromoting oxidative phosphorylation can reduce the promoting effect of anaerobic glycolysis on VEGF mRNA expression, thereby reducing the risk of angiogenesis. 62,63 In this work, the H 2 O 2 and VEGF changes during DCA treatment were consistent with the research results.…”