Combination of metformin and sorafenib suppresses proliferation and induces autophagy of hepatocellular carcinoma via targeting the mTOR pathway

Sunbin Ling,Ying Liu,Yan Li,Lei Shi,Zhaoyuan Hou,Tingting Feng,Feng Zhao,Fei Xu,Mingjie Wang,Ning Fan,Xu Yang,Yu Tian,Lei Song,Yanling Li,Qihong Huang,Lu Liu

doi:10.3892/ijo.2016.3799

Abstract

The multi‑kinase inhibitor sorafenib is the only drug for which randomized control trials have shown improved patient survival in advanced hepatocellular carcinoma(HCC). However, life expectancy is extended in these cases by only a few months. The anti‑typeII diabetes agent metformin was used in this study in an effort to find a more efficient approach to HCC treatment. Sorafenib effectively reversed the activation status of mTORC2 induced by metformin and enhanced the suppression of the mTORC1 and MAPK pathway by metformin in HCC cells, which may be responsible for reduced proliferation upon combined treatment. The metformin and sorafenib combination led to increased impaired proliferation and tumor inhibition of HCC invitro and invivo compared to single agent, which was partially bridged by disrupting the mTORC1/mTORC2 feedback loop. Metformin and sorafenib cooperated to promote apoptosis and autophagy in HCC cells. Pharmacological inhibition of autophagy sensitized HCC cells to metformin and sorefenib‑induced apoptotic cell death. Therefore, the anti‑autophagy treatment should be considered in metformin and sorafenib-based treatments in HCC cells.

Highlights

Liver cancer is one of the most common cancers and the third major cause of cancer‐related mortality worldwide [1,2]
We explored the anti‐proliferative effect of metformin in intrahepatic cholangiocarcinoma (ICC) cell lines [11]
The effect of a combination treatment of metformin and sorafenib on hepatocellular carcinoma (HCC) proliferation was investigated in Bel‐7402 and HepG2 cells using CCK‐8 and clonogenic assays

Summary

Introduction

Liver cancer is one of the most common cancers and the third major cause of cancer‐related mortality worldwide [1,2]. As a major histological subtype, hepatocellular carcinoma (HCC), account for 70 to 80% of primary liver cancers [3]. Conventional chemotherapies for liver cancer are generally ineffective and the multi‐kinase inhibitor sorafenib is the only drug for which randomized control trials have shown an improved survival in advanced HCC [4]. Sorafenib inhibits tumor growth through inducing tumor cell apoptosis by suppressing the kinase activity of Raf, an enzyme of the mitogen‐activated protein kinase (MAPK) signaling pathway. Sorafenib inhibits VEGF receptor (VEGFR) and platelet‐derived growth factor receptor‐β (PDGF‐β) signaling to block tumor angiogenesis [5]. Sorafenib is proved to merely extend the life expectancy of patients with HCC by a few months [4,6] because of the heterogeneity of HCC. Sorafenib is insufficient to suppress HCC for both primary and secondary drug resistance

Methods

Results

Conclusion