Metabolic-targeted Combination Therapy With Dichloroacetate and Metformin Suppresses Glioblastoma Cell Line Growth In Vitro and In Vivo.

Abstract

We investigated the hypothesis that dichloroacetate (DCA), a pyruvate dehydrogenase kinase inhibitor, and metformin (MET), an antidiabetic agent and complex I inhibitor, have synergistic cytotoxic effects in glioblastoma cells in vitro and in vivo. We performed dose response experiments and combination index calculation. Apoptotic and necrotic cells were estimated by flow cytometry. Cell metabolism was evaluated by Seahorse analysis and lactate export. Overall survival and tumor volume growth experiments were performed in C57BL/6 mice GL-261 allograft model. DCA and MET showed dose-dependent cytotoxicity and synergistic effects. DCA alleviated the increase in lactate production induced by MET. Seahorse analysis showed that DCA treatment results in increased oxygen consumption rate, which is decreased by MET. DCA and MET significantly inhibited tumor growth and increased overall survival in mice. Compounds targeting tumor cell metabolism could become potential treatment options for glioblastoma multiforme.