Redox-dependent modulation of metformin contributes to enhanced sensitivity of esophageal squamous cell carcinoma to cisplatin

// Pin Dong Li 1, * , Zhao Liu 1, * , Tian Tian Cheng 3 , Wen Guang Luo 4 , Jing Yao 1 , Jing Chen 1 , Zhen Wei Zou 1 , Li Li Chen 2 , Charlie Ma 2 and Xiao Fang Dai 1 1 Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China 2 Department of Radiation Oncology, Fox Chase Cancer Center, American Oncologic Hospital, Philadelphia, PA 19111, USA 3 Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou 510095, China 4 Department of Radiation Oncology, Anhui Provincial Hospital, Hefei 230001, China * These authors have contributed equally to this work Correspondence to: Xiao Fang Dai, email: daixf2016@163.com Keywords: esophageal squamous cell carcinoma, metformin, cisplatin, chemoresistance, redox Received: September 24, 2016      Accepted: May 21, 2017      Published: July 01, 2017 ABSTRACT 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.