Dichloroacetate and metformin synergistically suppress the growth of ovarian cancer cells

// Bo Li 1, * , Xinzhe Li 1, * , Zhenhong Ni 1 , Yan Zhang 1 , Yijun Zeng 1 , Xiaohuan Yan 2 , Yan Huang 3 , Jintao He 4 , Xilin Lyu 1 , Yaran Wu 1 , Yuting Wang 1 , Yingru Zheng 2 , Fengtian He 1 1 Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China 2 Department of Obstetrics and Gynecology, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing 400042, China 3 Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing 400042, China 4 Battalion 17 of Students, College of Preventive Medicine, Third Military Medical University, Chongqing 400038, China * These authors have contributed equally to this work Correspondence to: Yingru Zheng, email: zyrdaping@aliyun.com Fengtian He, email: hefengtian06@aliyun.com Keywords: dichloroacetate, metformin, Mcl-1, cancer metabolism, ovarian cancer Received: January 24, 2016      Accepted: July 09, 2016      Published: July 19, 2016 ABSTRACT Both dichloroacetate (DCA) and metformin (Met) have shown promising antitumor efficacy by regulating cancer cell metabolism. However, the DCA-mediated protective autophagy and Met-induced lactate accumulation limit their tumor-killing potential respectively. So overcoming the corresponding shortages will improve their therapeutic effects. In the present study, we found that DCA and Met synergistically inhibited the growth and enhanced the apoptosis of ovarian cancer cells. Interestingly, we for the first time revealed that Met sensitized DCA via dramatically attenuating DCA-induced Mcl-1 protein and protective autophagy, while DCA sensitized Met through markedly alleviating Met-induced excessive lactate accumulation and glucose consumption. The in vivo experiments in nude mice also showed that DCA and Met synergistically suppressed the growth of xenograft ovarian tumors. These results may pave a way for developing novel strategies for the treatment of ovarian cancer based on the combined use of DCA and Met.