Sensitization of metformin-cytotoxicity by dichloroacetate via reprogramming glucose metabolism in cancer cells.

To investigate sensitization of metformin-cytotoxicity, cancer cells were treated with dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase (PDK). Metformin-cytotoxicity was mainly dependent on glucose availability and reducing power generated by pentose phosphate pathway, whereas DCA cotreatment enhanced metformin-cytotoxicity via reprogramming glucose metabolism by inhibiting PDK and increasing mitochondrial respiration. DCA cotreatment elicited cell death rather than cell survival despite high glucose and high GSH condition. In conclusion, DCA sensitized metformin-cytotoxicity by reprogramming glucose metabolism in part from aerobic glycolysis to mitochondrial oxidation, evidenced by measurements of glucose consumption, lactate release, and the ratio of oxygen consumption rate/extracellular acidification rate.