Metformin in combination with cisplatin inhibits cell viability and induces apoptosis of human ovarian cancer cells by inactivating ERK 1/2.

Abstract

Metformin protects against insulin resistance by restoring insulin sensitivity and may also possess anticancer activity. The aim of the present study was to investigate the effects of metformin alone or combined with cisplatin (DDP) on the cell viability and apoptosis of HO-8910 human ovarian cancer cells, and to investigate metformin as a potential novel therapeutic for treating ovarian cancer. The viability of HO-8910 cells was assessed using a cell proliferation and cytotoxicity assay following treatment with different concentrations of metformin (0.01, 0.5, 1, 5 and 10 mM) and/or 5 µM of DDP. Flow cytometry was performed to examine cell apoptosis, and western blotting was used to measure the expression of extracellular signal-related kinase 1/2 (ERK1/2) phosphorylated (p)-ERK1/2, vascular endothelial growth factor (VEGF), VEGF receptor 2 (VEGFR2), B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X (Bax) and caspase-3. The resultsof the present study revealed that metformin reduced the viability of HO-8910 cells in a time- and concentration-dependent manner and induced cell apoptosis in a concentration-dependent manner. Metformin combined with DDP evidently inhibited cell viability and induced apoptosis. In addition, ERK1/2 and genes associated with apoptosis regulation, such as VEGF, VEGFR2, Bcl-2, Bax and caspase-3, exhibited differential expression in the HO-8910 cells. The present study demonstrated that expression of p-ERK1/2, VEGF, VEGFR2 and Bcl-2 was downregulated by treatment with increasing concentrations of metformin, whereas expression of Bax and caspase-3 was evidently upregulated. Taken together, these data demonstrate that metformin in combination with DDP reduces cell viability and induces apoptosis of human ovarian cancer cells.