Effect of Y6, an epigallocatechin gallate derivative, on reversing doxorubicin drug resistance in human hepatocellular carcinoma cells
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Yan Wen1,2,*, Rui-Qiang Zhao2,3,*, Yun-Kai Zhang2, Pranav Gupta2, Li-Xiang Fu4, An-Zhou Tang5, Bu-Ming Liu6, Zhe-Sheng Chen2, Dong-Hua Yang2, Gang Liang4
1Department of Pharmacy, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, P.R. China
22Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY 11439, USA
3Department of Biochemistry and Molecular Biology, School of Preclinical Medicine, Guangxi Medical University, Nanning 530021, P.R. China
4College of Pharmacy, Guangxi Medical University, Nanning 530021, P.R. China
5Department of Otolaryngology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, P.R. China
6Guangxi Key Laboratory of Traditional Chinese Medicine Quality Standards, Guangxi Institute of Chinese Medicine and Pharmaceutical Sciences, Nanning 530022, P.R. China
*These authors contributed equally to this work
Gang Liang, email: firstname.lastname@example.org
Dong-Hua Yang, email: email@example.com
Keywords: Y6, epigallocatechin-3-gallate (EGCG), multidrug resistance, resistance reversal agent, doxorubicin
Received: January 16, 2017 Accepted: February 12, 2017 Published: March 07, 2017
Cancer cells can acquire resistance to a wide variety of diverse and unrelated drugs, this phenomenon is termed multidrug resistance (MDR). Multidrug resistance has been an obstacle to the success of cancer chemotherapy. The present study investigated the reversal effect of Y6, a new compound obtained by chemically modifying the structure of epigallocatechin-3-gallate (EGCG) extracted from green tea. Y6 was proven to be effective in inhibiting cell proliferation and reversing drug resistance in doxorubicin (DOX) resistant human hepatocellular carcinoma cells (BEL-7404/DOX). BEL-7404/DOX cells were treated with either doxorubicin combination regimen (doxorubicin plus Y6 or epigallocatechin-3-gallate or verapamil separately) or doxorubicin alone. The results showed that cell proliferation was inhibited and late cell apoptosis increased in the combination treatment group, especially in the group treated with doxorubicin plus Y6. Further analysis revealed that the expressions of hypoxia-inducible factor-1α and multidrug resistance 1/P-glycoprotein decreased at both messenger RNA and protein levels by treatments with combined drugs compared to doxorubicin alone. Our results indicated that Y6, as a drug resistance reversal agent, increased the sensitivity of drug resistant cells to doxorubicin. The mechanisms of actions of Y6 in reversal effect were associated with the decreased expression of hypoxia-inducible factor-1α and multidrug resistance 1/P-glycoprotein.
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