Objective: To investigate the antitumor effect of the combination of metformin with alpha-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 x 10(5)) 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.