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Dichloroacetate (DCA), pyruvate dehydrogenasekinase (PDK) inhibitor, enhances the cytotoxic effect induced by metformin

Authors
Choi, YongWon; Lim, InKyoung
Department
Department of Biochemistry & Molecular Biology, Ajou University School of Medicine
Abstract
It has been recently reported that metformin, widely used as an antidiabetic drug, reduces risk of cancer development in human and animals based on its inhibitory effects observed in the several cancer cells and mouse tumor models. Metformin shows anti-tumor activity indirectly by enhancing insulin sensitivity and decreasing the level of insulin and IGF in serum. And it was also reported that metformin has direct anti-tumor activity through AMPK activation and mTOR inhibition. We also observed that metformin induces cytotoxicity in several different types of cancer cell lines. However when metformin was treated in high glucose condition, cytotoxic effect of metformin was significantly reduced and mTOR inhibition were not observed. Metformin increased glycolysis by inhibiting mitochondrial respiratory complex I activity weakly and also inhibiting pyruvate dehydrogenase activity more significantly. So cytotoxic effect induced by metformin was dependent on glucose availability. Significant mitochondrial ROS production was observed in metformin treated cancer cells. NADPHs are produced by enhanced glycolysis through the pentose phosphate pathway. Since reducing power of NADPH is important for protection from ROS induced damage, we hypothesized that enhanced glycolysis by inhibition of PDH activity observed in metformin treated cancer cells is a protective role from metformin induced ROS injury. So when PDH activity was enhance by dichloroacetate (DCA), pyruvate dehydrogenase kinase (PDK) inhibitor, ROS production was more increased and resulted in significant cell death.
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