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Cell Death Dis. 2017 Nov 2;8(11):e3159. doi: 10.1038/cddis.2017.482.

Metformin ameliorates arsenic trioxide hepatotoxicity via inhibiting mitochondrial complex I.

Ling S1,2,3,4, Shan Q1,2,3, Liu P1,2,3, Feng T1,5, Zhang X1,2,3, Xiang P1,2,3, Chen K1,2,3, Xie H2,3, Song P2,3, Zhou L2,3, Liu J6, Zheng S1,2,3, Xu X1,2,3.

Author information

1
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
2
Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, China.
3
Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang Province, China.
4
Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
5
Department of Abdominal Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, China.
6
Department of Pathology and Molecular Medicine, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.

Abstract

Arsenic trioxide (ATO) is a well-accepted chemotherapy agent in managing promyelocytic leukemia. ATO often causes severe health hazards such as hepatotoxicity, dermatosis, neurotoxicity, nephrotoxicity and cardiotoxicity. The production of reactive oxygen species, (ROS) play a significant role in ATO-induced hepatotoxicity. The oral hypoglycemic drug, metformin, is considered to be a potential novel agent for chemoprevention in the treatment of cancer. Moreover, metformin has also been shown to have hepatoprotective effects. In the present study, we demonstrated that metformin protected normal hepatocytes from ATO-induced apoptotic cell death in vitro and in vivo. Gene expression screening revealed that glucose metabolism might be related to the metformin-induced protective effect on ATO-treated AML12 cells. The metformin-promoted or induced glycolysis was not responsible for the protection of AML12 cells from ATO-induced apoptotic cell death. Instead, metformin increased the intracellular NADH/NAD+ ratio by inhibiting mitochondrial respiratory chain complex I, further decreasing the intracellular ROS induced by ATO. Treatment with low glucose or rotenone, a mitochondrial respiratory chain complex I inhibitor, also protected AML12 cells from ATO-induced apoptotic cell death. We show for the first time that metformin protects the hepatocyte from ATO by regulating the mitochondrial function. With its properties of chemoprevention, chemosensitization and the amelioration of liver damage, metformin has great prospects for clinical application other than type 2 diabetes mellitus (T2DM).

PMID:
29095437
PMCID:
PMC5775401
DOI:
10.1038/cddis.2017.482
[Indexed for MEDLINE]
Free PMC Article

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