Abstract 1869: DCA and metformin synergistically induce apoptosis in breast cancer cells.

Abstract

The unusual metabolism of aerobic glycolysis in cancer cells suggests that this phenomenon can be exploited for improved therapies. Metformin, a drug used to treat type 2 diabetics, has clinical evidence of cancer prevention, and some studies show that cancer patients have a better response when it is used with neoadjuvant therapy. One of the cellular targets of metformin is the inhibition of Complex I in the mitochondrial electron transport chain. This leads to an accumulation superoxide species that can cause oxidative damage to cells and eventually lead to cell death. Based on this, we hypothesized that drugs which promote mitochondrial metabolism will synergize with metformin to increase superoxide production and promote cell death of cancer cells. Cancer cells using aerobic glycolysis display a high level of glucose uptake that is processed through glycolysis to pyruvate, which is then converted to lactate and secreted from the cells. Diverting pyruvate to mitochondrial metabolism rather than its conversion to lactate was expected to enhance metformin cytotoxicity. Dichloroacetate (DCA) is well established drug that has been tested in humans for the treatment of certain metabolic diseases. DCA works through inhibition of pyruvate dehydrogenase kinase (PDK), thus reducing entry of pyruvate into mitochondrial oxidative phosphorylation pathways. Consequently DCA is expected to promote mitochondrial metabolism and reduce lactate secretion by cancer cells. We demonstrate that DCA and metformin synergistically kill cultured breast cancer cells although the drug combination has no effect on non-transformed MCF10A breast epithelial cells. The enhanced cell death of the breast cancer cells displayed is through apoptosis, as shown by caspase-dependent increases in cleaved PARP. DCA treatment was associated with reduced lactate secretion by the cells and increased pH of the growth medium which suggested it promoted oxidative phosphorylation. The combination of two drugs also promoted increased mitochondrial superoxide production compared to metformin alone which was associated with increased oxidative damage. These findings indicate that, as expected, DCA promotes metformin-mediated cell death by enhancing mitochondrial metabolism of pyruvate. Therefore, it is possible that the combination of metformin with DCA, or similar compounds, could enhance cancer therapy. Citation Format: Allison B. Haugrud, Yongxian Zhuang, Wilson K. Miskimins. DCA and metformin synergistically induce apoptosis in breast cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1869. doi:10.1158/1538-7445.AM2013-1869