Dichloroacetate Radiosensitizes Hypoxic Breast Cancer Cells.

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.

Inhibition of Phosphoglycerate Dehydrogenase Radiosensitizes Human Colorectal Cancer Cells under Hypoxic Conditions.

Augmented de novo serine synthesis activity is increasingly apparent in distinct types of cancers and has mainly sparked interest by investigation of phosphoglycerate dehydrogenase (PHGDH). Overexpression of PHGDH has been associated with higher tumor grade, shorter relapse time and decreased overall survival. It is well known that therapeutic outcomes in cancer patients can be improved by reprogramming metabolic pathways in combination with standard treatment options, for example, radiotherapy. In this study, possible metabolic changes related to radioresponse were explored upon PHGDH inhibition. Additionally, we evaluated whether PHGDH inhibition could improve radioresponse in human colorectal cancer cell lines in both aerobic and radiobiological relevant hypoxic conditions. Dysregulation of reactive oxygen species (ROS) homeostasis and dysfunction in mitochondrial energy metabolism and oxygen consumption rate were indicative of potential radiomodulatory effects. We demonstrated that PHGDH inhibition radiosensitized hypoxic human colorectal cancer cells while leaving intrinsic radiosensitivity unaffected. In a xenograft model, the first hints of additive effects between PHGDH inhibition and radiotherapy were demonstrated. In conclusion, this study is the first to show that modulation of de novo serine biosynthesis enhances radioresponse in hypoxic colorectal cancer cells, mainly mediated by increased levels of intracellular ROS.

Hypoxic Radioresistance: Can ROS Be the Key to Overcome It?

Radiotherapy is a mainstay treatment for many types of cancer and kills cancer cells via generation of reactive oxygen species (ROS). Incorporating radiation with pharmacological ROS inducers, therefore, has been widely investigated as an approach to enhance aerobic radiosensitization. However, this strategy was overlooked in hypoxic counterpart, one of the most important causes of radiotherapy failure, due to the notion that hypoxic cells are immune to ROS insults because of the shortage of ROS substrate oxygen. Paradoxically, evidence reveals that ROS are produced more in hypoxic than normoxic cells and serve as signaling molecules that render cells adaptive to hypoxia. As a result, hypoxic tumor cells heavily rely on antioxidant systems to sustain the ROS homeostasis. Thereby, they become sensitive to insults that impair the ROS detoxification network, which has been verified in diverse models with or without radiation. Of note, hypoxic radioresistance has been overviewed in different contexts. To the best of our knowledge, this review is the first to systemically summarize the interplay among radiation, hypoxia, and ROS, and to discuss whether perturbation of ROS homeostasis could provide a new avenue to tackle hypoxic radioresistance.