Metabolic Reprogramming by Dichloroacetic Acid Potentiates Photodynamic Therapy of Human Breast Adenocarcinoma MCF-7 Cells

Aberrant glycolytic metabolism is one of the hallmarks of carcinogenesis and therefore reversal of metabolic transformation is a promising drug target in cancer treatment strategies. Dichloroacetic acid (DCA) is known to target the glycolytic pathway in cancer cells and facilitates reversal of metabolic transformation from aerobic cytosolic accumulation of pyruvic acid, "the Warburg effect", to mitochondrial oxidative phosphorylation. Recently, combination therapy particularly involving photodynamic therapy (PDT) has received considerable attention in oncology. We hypothesized that if DCA and PDT are combined, they might potentiate mitochondrial dysfunction and induce apoptosis by a reactive oxygen species (ROS) dependent pathway. We used MCF-7 cells as our in vitro model and 5-aminolevulinic acid (5-ALA) dependent PDT therapy to test our hypothesis. We found that combinatorial treatment of MCF-7 cells with PDT and DCA not only increased cell growth inhibition, but also affected mitochondrial membrane integrity perhaps via production of ROS, and enhanced apoptosis. Further, our results on ATP release during the combined treatment demonstrate that immunogenic cell death (ICD) is likely to be a potential mechanism by which PDT and DCA induce cancer cell death. Taken together, our study suggests a novel way of sensitizing MCF-7 cells for accelerated induction of apoptosis and ICD in these cells. The findings included in this study might have direct relevance in breast cancer treatment strategies.