Abstract P3-01-07: Metformin has an additive effect to cisplatin in triple negative breast cancer cells with high lactate dehydrogenase B (LDHB) expression

Abstract

Abstract Background; Glycolysis is one of the major metabolic pathways in cancer cells. The conversion of glucose to lactate in the presence of oxygen is a critical aerobic pathway that allows cancer cells to proliferate rapidly and the amount of lactate produced is correlated with tumor aggressiveness. Moreover, the increase in glycolysis is partially mediated by hypoxia-inducible transcription factor (HIF-1) and a metabolic enzyme, lactate dehydrogenase B (LDHB). However, the mechanism behind this metabolic shift is not well understood. Metformin reduces the overall risk of cancer incidence by 31%, improves cancer-related mortality and enhances response to chemotherapy in diabetic patients pre-operatively. This study aimed to evaluate metabolism in triple negative breast cancer. Methods; Breast cancer cell lines (estrogen receptor positive MCF7 and triple negative MDA-MB 231 and MDA-MB468) were analysed for protein expression by western blotting and mRNA expression by qRT-PCR with or without cisplatin and metformin. To study the biological mechanism, we evaluated cell growth using proliferation assay in the presence of metformin and cisplatin. The contribution of LDHB to glycolysis was evaluated using MDA-MB-231 and MDA-MB468 cell lines. Results; We first examined the basal expression levels of LDHB and HIF1a in these cancer cell lines. LDHB expression was high in MDA-MB 231, and HIF1α was high in MDA-MB468. Both metformin and cisplatin treatment resulted in the down-regulation of LDHB and HIF1α in MDA-MB231, metformin led to downregulation of LDHB in MDA-MB 468, while MCF7 demonstrated no significant changes. Inhibition of cell proliferation was dose-dependent and significant at low concentrations of cisplatin and metformin in only MDA-MB468 but not in MCF7 and MDA-MB231. The combination of cisplatin in with metformin had an added inhibitory effect on cell proliferation in these MD-MB231 cells. Conclusion; These studies suggest that combination treatment of metformin and cisplatin have potent anticancer activity in LDHB highly expressed triple negative breast cancer cells. Identification of a new targeted therapeutic approach could contribute to the new therapy to the breast cancer patients. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-01-07.