1.The epigallocatechin gallate derivative Y reverses drug resistance mediated by the ABCB1 transporter both and .
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
Acta Pharmaceutica Sinica B 2019;9(2):316-323
Previously, we reported that Y, 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 in reversing drug resistance both and by determining its effect on the adenosine triphosphate-binding cassette protein B1 transporter (ABCB1 or P-glycoprotein, P-gp). Our results showed that Y significantly sensitized cells overexpressing the ABCB1 transporter to anticancer drugs that are ABCB1 substrates. Y significantly stimulated the adenosine triphosphatase activity of ABCB1. Furthermore, Y 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 (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 significantly reversed ABCB1-mediated multidrug resistance and its mechanisms of action may result from its competitive inhibition of the ABCB1 drug efflux function.
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