Trametinib modulates cancer multidrug resistance by targeting ABCB1 transporter
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Jian-Ge Qiu1, Yao-Jun Zhang2, Yong Li3, Jin-Ming Zhao4, Wen-Ji Zhang1, Qi-Wei Jiang1, Xiao-Long Mei1, You-Qiu Xue1, Wu-Ming Qin1, Yang Yang1, Di-Wei Zheng1, Yao Chen1, Meng-Ning Wei1 and Zhi Shi1
1 Department of Cell Biology and Institute of Biomedicine, College of Life Science and Technology, Jinan University, National Engineering Research Center of Genetic Medicine, Guangdong Provincial Key Laboratory of Bioengineering Medicine, Guangzhou, Guangdong, China
2 Department of Hepatobiliary Surgery, Cancer Center, Sun Yat-Sen University, Guangzhou, Guangdong, China
3 Department of Gastrointertinal Surgery and General Surgery, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
4 Department of Thoracic Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
Zhi Shi, email:
Keywords: trametinib, multidrug resistance, ABCB1, chemotherapy
Received: February 09, 2015 Accepted: March 10, 2015 Published: April 14, 2015
Overexpression of adenine triphosphate (ATP)-binding cassette (ABC) transporters is one of the main reasons of multidrug resistance (MDR) in cancer cells. Trametinib, a novel specific small-molecule mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor, is currently used for the treatment of melanoma in clinic. In this study, we investigated the effect of trametinib on MDR mediated by ABC transporters. Trametinib significantly potentiated the effects of two ABCB1 substrates vincristine and doxorubicin on inhibition of growth, arrest of cell cycle and induction of apoptosis in cancer cells overexpressed ABCB1, but not ABCC1 and ABCG2. Furthermore, trametinib did not alter the sensitivity of non-ABCB1 substrate cisplatin. Mechanistically, trametinib potently blocked the drug-efflux activity of ABCB1 to increase the intracellular accumulation of rhodamine 123 and doxorubicin and stimulates the ATPase of ABCB1 without alteration of the expression of ABCB1. Importantly, trametinib remarkably enhanced the effect of vincristine against the xenografts of ABCB1-overexpressing cancer cells in nude mice. The predicted binding mode showed the hydrophobic interactions of trametinib within the large drug binding cavity of ABCB1. Consequently, our findings may have important implications for use of trametinib in combination therapy for cancer treatment.
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