Effect of metformin in combination with cisplatin on the proliferation of glioma cells and its mechanisms

Abstract

Objective To observe the effect of metformin on U251 cell proliferation, apoptosis, and the growth of glioma in nude mice. Methods Metformin in combination with cisplatin were used to treated the U251 cells, and the cell viability was assayed by MTT methods. Cell cycle, apoptosis rate were assayed by flow cytometry. The expression of apoptotic related proteins (Bcl-2, Bcl-xl, Bax, PARP, et al) were detected by western-blotting. Nude mice were transplanted with U251 cells, and tumor growth inhibition rate by metformin combined with or without cisplatin were detected. Results Compared with the control group, metformin combined with or without cisplatin could inhibit the proliferation of U251 cells in a dose- and time-dependent manner. After U251 cells were treated with 10 mM metformin for 48 h, the growth cycle was arrested in S phase, the apoptosis rate was (20.57±3.16)%. The expression of anti-apoptotic protein Bcl-2, Bcl-xl were down-regulated after metformin treatment, while the pro-apoptotic protein Bax was significantly increased. In vivo studies, the inhibition rates in the metformin-treated group, cisplatin-treated group, and cisplatin combined with metformin-treated group were 39.22%, 52.97%, and 71.55%, respectively. The inhibition rates in the above three groups were all higher than that in the control group. The difference between the two groups was statistically significant (metformin-treated group vs. control group, cisplatin combined with metformin-treated group vs. cisplatin-treated group, P<0.01). However, metformin could not inhibit the glioma metastasis in vivo. Conclusion Metformin inhibits the proliferation of U251 cells, enhances the sensitivity of glioma U251 cells to cisplatin, and induces apoptosis via the mitochondria mediated apoptotic signaling pathway in vitro. Key words: Neuroglioma; Metformin; Cell apoptosis; Mitochondrial-mediated