Cancer Lett. 2014 Jan 27. pii: S0304-3835(14)00041-X. doi: 10.1016/j.canlet.2014.01.015. [Epub ahead of print]
Sensitization of metformin-cytotoxicity by dichloroacetate via reprogramming glucose metabolism in cancer cells.
Choi YW1, Lim IK2.
1Department of Biochemistry and Molecular Biology, BK21 Cell Transformation and Restoration Project, Ajou University School of Medicine, Suwon 443-721, Republic of Korea.
2Department of Biochemistry and Molecular Biology, BK21 Cell Transformation and Restoration Project, Ajou University School of Medicine, Suwon 443-721, Republic of Korea. Electronic address: email@example.com.
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.
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