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Synergistic effect of metformin on sorafenib in in vitro study using hepatocellular carcinoma cell lines
Ann Hepatobiliary Pancreat Surg 2018 Aug;22(3):179-84
Published online August 31, 2018
Copyright © 2018 Ann Hepatobiliary Pancreat Surg.

Yong-Gyu Chung1,*, Eunyoung Tak2,*, Shin Hwang1, Joo-Young Lee2, Ji-Ye Kim2, Ye-Young Kim2, Gi-Won Song1, Kyoung-Jin Lee2, Nayoung Kim2

1Department of Surgery and 2Asan Institute of Life Sciences, Asan Medical Center, 
University of Ulsan College of Medicine, Seoul, Korea
Received June 6, 2018; Revised June 11, 2018; Accepted June 14, 2018.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Backgrounds/Aims: Hepatocellular carcinoma (HCC) recurrence remains a great concern following hepatic resection and liver transplantation. We investigated the metformin-induced cytotoxic effects on sorafenib in an in vitro study using HCC cell lines. 
Methods: This research was conducted through an in vitro study using one HepG2.2.15 liver tumor and two patient-derived graft HCC cell lines. 
Results: An in vitro study revealed noticeable cytotoxic effects of metformin as well as noticeable synergistic cytotoxic effects of metformin and sorafenib on cell viability. Assays for the mechanisms of action of antitumor effects revealed that alpha-fetoprotein expression was suppressed by both metformin and sorafenib, but no synergistic effect was observed. LC3-I and LC3-II assays revealed the synergistic upregulation of autophagy and assays for IL-1β, IL-6, p53, and TNF-α revealed the synergistic upregulation of cell damage and apoptosis. In contrast, metformin did not affect HBx expression, thus no noticeable synergistic effect was considered to be present. 
Conclusions: Our in vitro study demonstrated cytotoxic effects of metformin and synergistic antitumor effects of sorafenib. These results should be verified in further clinical studies with patients of advanced HCC.
Keywords : Diabetic mellitus; Metformin; Cytotoxicity; Synergistic effect


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