Journal
ACTA PHARMACEUTICA SINICA B
Volume 9, Issue 2, Pages 316-323Publisher
INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
DOI: 10.1016/j.apsb.2018.10.001
Keywords
Epigallocatechin gallate (EGCG); 5,3 ',4 ',3 '',4 '',5 ''-6-O-ethyl-EGCG (Y-6); Drug resistance; Resistance reversal; ABCB1; P-gP
Categories
Funding
- National Natural Science Foundation of China [81160532]
- Open Project of Guangxi Colleges and Universities Key Laboratory of Biological Molecular Medicine Research (China) [GXBMR201602]
- Young and Middle-aged Teachers Foundation Ability Enhancement Project of Guangxi Colleges and Universities (China) [2018KY0102]
- US NIH [1R15CA143701]
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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 mouse tumor 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. (C) 2019 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
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