In vitro and in vivo antitumoral action of metformin on hepatocellular carcinoma
Article first published online: 23 APR 2012
© 2012 The Japan Society of Hepatology
Volume 42, Issue 9, pages 922–933, September 2012
How to Cite
Qu, Z., Zhang, Y., Liao, M., Chen, Y., Zhao, J. and Pan, Y. (2012), In vitro and in vivo antitumoral action of metformin on hepatocellular carcinoma. Hepatology Research, 42: 922–933. doi: 10.1111/j.1872-034X.2012.01007.x
- Issue published online: 9 AUG 2012
- Article first published online: 23 APR 2012
- Accepted manuscript online: 26 MAR 2012 07:50PM EST
- Received 17 December 2011; revision 12 February 2012; accepted 14 March 2012.
- 5′-adenosine monophosphate-activated protein kinase;
- hepatocellular carcinoma;
- mammalian target of rapamycin;
Aims: Metformin is a biguanide that has been widely used to treat type 2 diabetes. Several studies have shown that metformin is also effective in treating cancer, including hepatocellular carcinoma (HCC). The objective of this study was to evaluate the antitumor effects of metformin in HCC, and to investigate the potential molecular target(s) of metformin-mediated antitumor activity.
Methods: The antiproliferative effects of metformin were assessed in human HCC cell lines and normal human liver cells at various concentrations. Orthotopic xenograft tumors were established in athymic nude mice, and tumor growth was monitored after metformin treatment. Western blot analysis and cell cycle regulation were performed to determine the involvement of various mediators of apoptosis.
Results: Metformin specifically inhibited the growth of HCC cells without affecting the growth of normal liver cells both in vitro and in vivo. Metformin caused cell cycle arrest in HCC cells, which resulted in caspase-3 activation. Livin levels decreased in a dose-dependent manner upon metformin treatment. Metformin activated 5′-adenosine monophosphate-activated protein kinase, inhibited the mammalian target of rapamycin pathway and downregulated Livin protein expression.
Conclusion: Our findings indicate that metformin is effective at initiating apoptosis and inhibiting key survival signaling pathways in HCC cells. These data provide a foundation for further studies to evaluate metformin in the clinic either as a single agent or in combination with other first-line agents as a treatment option for HCC.