Basic Study
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Aug 18, 2016; 8(23): 985-993
Published online Aug 18, 2016. doi: 10.4254/wjh.v8.i23.985
Reversal of multidrug resistance of hepatocellular carcinoma cells by metformin through inhibiting NF-κB gene transcription
Wei Wu, Jun-Ling Yang, Yi-Lang Wang, Han Wang, Min Yao, Li Wang, Juan-Juan Gu, Yin Cai, Yun Shi, Deng-Fu Yao
Wei Wu, Jun-Ling Yang, Deng-Fu Yao, Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
Yi-Lang Wang, Department of Oncology, the 2nd Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
Han Wang, Department of Liver Surgery, Zhongshan Hospital of Fudan University, Shanghai 200032, China
Min Yao, Departments of Immunology, Medical College of Nantong University, Nantong 226001, Jiangsu Province, China
Li Wang, Department of Medical Informatics, Medical College of Nantong University, Nantong 226001, Jiangsu Province, China
Juan-Juan Gu, Yin Cai, Yu Shi, Department of Oncology, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
Author contributions: Wu W, Yang JL, Wang YL and Wang H contributed equally to this work; Wu W, Yao M, Shi Y and Wang L designed and performed the research; Yang JL, Gu JJ and Cai Y contributed new reagents/analytic tools; Yao M and Wang L analyzed the data; Wu W, Shi Y and Yao DF wrote the paper; Yao DF is the guarantor; all authors have read and approved the final version to be published.
Supported by Projects of Jiangsu Elitist Peak in Six Fields, Nos. 2013-WSN-078, 2013-WSW-011, and 2014-YY-028; the QingLan Program of Jiangsu Higher Education, the Youth Science Foundation of Nantong Health Department, No. WQ2014005; and the International Science and Technology Cooperation Program, No. 2013DFA32150.
Institutional review board statement: The study was reviewed and approved by the Affiliated Hospital of Nantong University.
Conflict-of-interest statement: The authors declare no potential conflict of interest.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Deng-Fu Yao, MD, PhD, Professor, Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, No. 20 West Temple Road, Nantong 226001, Jiangsu Province, China. yaodf@ahnmc.com
Telephone: +86-513-85052297 Fax: +86-513-85052523
Received: April 7, 2016
Peer-review started: April 8, 2016
First decision: May 23, 2016
Revised: May 25, 2016
Accepted: June 14, 2016
Article in press: June 16, 2016
Published online: August 18, 2016
Core Tip

Core tip: Metformin might target AMP-activated protein kinase mammalian target of rapamycin pathway, suppress hypoxiainducible factor-1α and transcriptionally down-regulate P-glycoprotein (P-gp) and multidrug resistance (MDR)-associated protein 1, suggesting that metformin may reverse MDR by targeting the AMP-activated protein kinase/mammalian target of rapamycin/hypoxia-inducible factor-1α/P-gp and MDR-associated protein 1 pathways. In the present study, HepG2/ADM cells pretreated with metformin were sensitized to doxorubicin and P-gp was decreased through the nuclear factor-κB (NF-κB) signaling pathway. The synergistic effects were found in the cells with regard to proliferation inhibition, cell cycle arrest and inducing apoptosis, and inhibiting P-gp expression via the NF-κB signaling pathway effectively reversed MDR by down-regulating MDR1/P-gp expression.