Metformin improves the sensitivity of ovarian cancer cells to chemotherapeutic agents

Ovarian cancer is a common tumor of the reproductive system, and primarily responds to cytoreductive surgery and cisplatin (DDP)-based chemotherapy. However, chemoresistance results in high ovarian cancer mortality. Therefore, the aim of the present study was to investigate the effects of metformin on the apoptosis and autophagy of ovarian cancer drug-resistant SKOV3/DDP cells. To do so, MTT assay, flow cytometry, electron microscopy and western blotting were used in the present study. Metformin could inhibit the growth of SKOV3 and SKOV3/DDP cells in a concentration- and time-dependent manner (P<0.05). The half-inhibitory concentration (IC(50)) values of DDP and methotrexate (MTX) were 14.35 and 4.21 µg/ml for SKOV3 cells, and 70.26 and 15.27 µg/ml for SKOV3/DDP cells, respectively. In addition, the resistance index of SKOV3/DDP for DDP and MTX was 4.89 and 3.62, respectively. After combining metformin with DDP and MTX, the IC(50) values for SKOV3 cells were 11.20 and 2.80 µg/ml, and 6.21 and 2.74 µg/ml for SKOV3/DDP cells, respectively. Metformin decreased the IC(50) of DDP and MTX in drug-resistant cancer cells SKOV3/DDP by 11.31- and 6.18-fold. This indicated that cell proliferation was inhibited when treated with the combination of metformin and chemotherapeutic agents, compared with chemotherapeutic agents alone. In addition, autophagy was not observed in SKOV3 and SKOV3/DDP cells; however, it was observed in SKOV3/DDP cells following incubation with 10 mmol/l metformin for 48 h. Furthermore, the expression levels of microtubule-associated protein 1 light chain 3-II protein in SKOV3/DDP cells were upregulated compared with in SKOV3 cells (P<0.05). These results demonstrated that metformin can sensitize drug-resistant ovarian cancer cells to chemotherapeutic agents, and that it may be associated with the induction of autophagy.