Superior anti-tumor efficacy of diisopropylamine dichloroacetate compared with dichloroacetate in a subcutaneous transplantation breast tumor model

// Lei Su 1, * , Hailin Zhang 2, * , Chen Yan 1 , Aiping Chen 2 , Gang Meng 2 , Jiwu Wei 2 , Decai Yu 1 , Yitao Ding 1 1 Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, P.R. of China 2 Jiangsu Key Laboratory of Molecular Medicine, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210008, P.R. of China * These authors have contributed equally to this work Correspondence to: Yitao Ding, email: yitao__ding@sina.com Decai Yu, email: dryudecai@qq.com Keywords: diisopropylamine dichloroacetate, dichloroacetate, subcutaneous transplantation breast tumor model, MDA-MB-231 cell line Received: May 18, 2016     Accepted: August 13, 2016     Published: August 25, 2016 ABSTRACT Dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase, has anti-tumor properties in various carcinoma models. Diisopropylamine dichloroacetate (DADA), an over-the-counter drug for chronic liver disease, is a derivative of DCA. To date, few studies have evaluated the anticancer potential of DADA in breast cancer. In this study, MDA-MB-231 cells, a breast adenocarcinoma cell line, were used in in vitro and in vivo experiments to evaluate the anti-tumor efficacy of DADA and DCA. The half maximal inhibitory concentration (IC 50 ) of DADA (7.1 ± 1.1 mmol/L) against MDA-MB-231 cells was significantly lower than that of DCA (15.6 ± 2.0 mmol/L); 100 mg/kg (0.0004 mol/kg) DADA was better than 100 mg/kg (0.0008 mol/kg) DCA at suppressing the growth of subcutaneous transplantation breast tumor at the same dose after 24 days intervention. Histological examination showed that both DCA and DADA interventions led to necrosis, inflammation, and fibrosis of tumor tissue in a mouse subcutaneous transplantation breast tumor model. DADA treatment inhibited Ki67 expression in tumor tissue. In vitro experiments showed that DADA could inhibit lactic acid production and glucose uptake in MDA-MB-231 cells at 10 mmol/L and these effects were stronger than DCA. DADA administration also induced complete autophagy during early treatment stages and incomplete autophagy and cell death at later treatment stages. In conclusion, DADA showed better anti-tumor efficacy than DCA in a breast cancer model.