Abstract:
Metformin is a biguanide anti-diabetic drug with various pharmacological activities including anti-carcinogenic action. This study was to determine the effects of metformin on function and expression of MRP2 in human breast cancer MCF-7 cells. The activity of MRP2 was assessed by measuring intracellular accumulation of CDCF fluorochrome. The results showed that metformin had no direct effect on CDCF accumulation after 30-min treatment. Prolong treatment of MCF-7 cells with metformin (1-5 mM) for 24-48 hr resulted in significant reduction of MRP2 mRNA levels, as measured by RT-PCR assay. Metformin down-regulated expression of MRP2 mRNA in concentration-dependent manners. Moreover, the cells treated with metformin (5 mM) had lower levels of phosphorylated ERK (p-ERK) and p38 (p-p38) than those of the control groups. These results suggested that metformin could inhibit basal activities of ERK and p38 in the MAPK pathway. The presence of an AMPK inhibitor compound C (10 µM) could prevent down-regulation of MRP2 mRNA as well as reduction of basal MAPK activities caused by metformin. These findings suggested that metformin might decrease MRP2 mRNA expression in the MCF-7 cells via inhibition of MAPK signaling pathway. The metformin-mediated alteration of MAPK signaling might relate to activation of AMPK pathway. Further determination of MRP2 protein level in the metformin-treated cells should be pursued.
