The epigallocatechin gallate derivative Y_6 reverses drug resistance mediated by the ABCB1 transporter both in vitro and in vivo

作     者：Yan Wen Ruiqiang Zhao Pranav Gupta Yingfang Fan Yunkai Zhang Zhenguang Huang Xiaohui Li Yuangang Su Lijuan Liao Yu-An Xie Donghua Yang Zhe-Sheng Chen Gang Liang 

作者机构：Department of Pharmaceutical Sciences College of Pharmacy and Health Sciences St.John's University Department of Pharmacy the First Affiliated Hospital of Guangxi Medical University Guangxi Colleges and Universities Key Laboratory of Biological Molecular Medicine Research Guangxi Medical University Department of Biochemistry and Molecular Biology School of Preclinical Medicine Guangxi Medical University Department of Hepatobiliary Surgery Zhujiang Hospital Southern Medical University Department of Biotechnology School of Preclinical Medicine Guangxi Medical University The Affiliated Tumor Hospital of Guangxi Medical University College of Pharmacy Guangxi Medical University 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2019年第9卷第2期

页      面：316-323页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 1004[医学-公共卫生与预防医学(可授医学、理学学位)] 100706[医学-药理学] 1001[医学-基础医学(可授医学、理学学位)] 100602[医学-中西医结合临床] 10[医学] 

基　　金：supported by the National Natural Science Foundation of China (No. 81160532) the Open Project of Guangxi Colleges and Universities Key Laboratory of Biological Molecular Medicine Research (No. GXBMR201602, China) the Young and Middle-aged Teachers Foundation Ability Enhancement Project of Guangxi Colleges and Universities (No. 2018KY0102, China) US NIH (No. 1R15CA143701) 

主　　题：Epigallocatechin gallate(EGCG) 5,3’,4’,3″,4″,5″-6-O-ethylEGCG(Y6) Drug resistance Resistance reversal ABCB1 P-gp 

摘      要：Previously, we reported that Y_6, a new epigallocatechin gallate derivative, is efficacious in reversing doxorubicin(DOX)–mediated resistance in hepatocellular carcinoma BEL-7404/DOX cells. In this study, we evaluated the efficacy of Y_6 in reversing drug resistance both in vitro and in vivo by determining its effect on the adenosine triphosphate-binding cassette protein B1 transporter(ABCB1 or P-glycoprotein, P-gp). Our results showed that Y_6 significantly sensitized cells overexpressing the ABCB1 transporter to anticancer drugs that are ABCB1 substrates. Y_6 significantly stimulated the adenosine triphosphatase activity of ABCB1. Furthermore, Y_6 exhibited a higher docking score as compared with epigallocatechin gallate inside the transmembrane domain of ABCB1. In addition, in the nude mousetumor xenograft model, Y_6(110 mg/kg, intragastric administration), in combination with doxorubicin(2 mg/kg, intraperitoneal injection), significantly inhibited the growth of BEL-7404/DOX cell xenograft tumors, compared to equivalent epigallocatechin gallate. In conclusion, Y_6 significantly reversed ABCB1-mediated multidrug resistance and its mechanisms of action may result from its competitive inhibition of the ABCB1 drug efflux function.