Redox-dependent modulation of metformin contributes to enhanced sensitivity of esophageal squamous cell carcinoma to cisplatin
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Pin Dong Li1,*, Zhao Liu1,*, Tian Tian Cheng3, Wen Guang Luo4, Jing Yao1, Jing Chen1, Zhen Wei Zou1, Li Li Chen2, Charlie Ma2 and Xiao Fang Dai1
1Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
2Department of Radiation Oncology, Fox Chase Cancer Center, American Oncologic Hospital, Philadelphia, PA 19111, USA
3Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou 510095, China
4Department of Radiation Oncology, Anhui Provincial Hospital, Hefei 230001, China
*These authors have contributed equally to this work
Xiao Fang Dai, email: [email protected]
Keywords: esophageal squamous cell carcinoma, metformin, cisplatin, chemoresistance, redox
Received: September 24, 2016 Accepted: May 21, 2017 Published: July 01, 2017
Glutathione is the major intracellular anti-oxidant against reactive oxygen species and serves as a detoxification essential. The anti-diabetic drug metformin has been showed to exert anti-tumor activity via modulation of redox homeostasis. In this study, we provided evidence that metformin inhibits proliferation and induces apoptosis of esophageal squamous cancer cells. Importantly, we found that metformin acts as pro-oxidant via depletion of intracellular glutathione. Co-treatment with metformin reversed the elevated intracellular glutathione induced by cisplatin and therefore enhanced the sensitivity to cisplatin in vitro and in vivo. Taken together, our data indicate that combination of metformin with cisplatin may represent a novel therapeutic strategy for esophageal squamous cell carcinoma treatment.
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