Study on the Anti-Lewis Lung Carcinoma Effect of Metformin Combined with MCT1 Inhibitor CHC

Abstract

To investigate the antitumor effect of the combination of metformin with α-cyano-4-hydroxycinnamic acid (CHC, a MCT1 inhibitor) in the treatment of Lewis lung cancer. Methods In vitro, the utilization of lactate acid was measured by lactate assay in cultured medium and the inhibition of LL/2 cell proliferation of four groups[control group, metformin group (1 mmol/L and 5 mmol/L), CHC group (5 mmol/L) and the combination group (metformin 5 mmol/L and CHC 5 mmol/L)] was detected in 24 h, 48 h, and their apoptosis in 24 h was also detected. In vivo, twenty eight C57BL/6 mice bearing LL/2 (5×105) subcutaneous Lewis lung cancer on the right flank was established and then randomly assigned into four groups:control, metformin (200 mg/kg body mass in 0.1 mL i.g. with NS 0.1 mL i.p.), CHC (100 mg/kg body mass in 0.1 mL i.p. with NS 0.1 mL i.g.) and the combination (metformin 200 mg/kg body mass in 0.1 mL i.g. with CHC 100 mg/kg body mass in 0.1 mL i.p.). Tumor volume was measured. The pathologic observation and apoptotic analysis of tumors was assessed by TUNEL assay. Results Compared to the contorl, metformin or CHC alone, combination of two drugs leaded to a significant lactate acid production in cultured medium and the inhibition of LL/2 cell viability (P<0.05). In vivo, the systemic administration of two drugs leaded to obvious retarded tumor growth compared with used alone in early stage (P<0.05). The TUNEL assay showed the significantly increased number of apoptosis cells in tumor tissues from the combination group. Conclusion Combination of metformin and CHC transformed the lactic acid metabolism in LL/2 cells and induced cell apoptosis and showed the antitumor effect.

Keywords: Metabolic symbiosis, Monocarboxylate transp orter 1, Metformin, Lactic acid