曲美替尼
多重耐药
癌症研究
MEK抑制剂
药理学
ABCC1公司
ATP结合盒运输机
癌细胞
化学
MAPK/ERK通路
癌症
生物
抗药性
医学
激酶
细胞生物学
运输机
生物化学
内科学
基因
微生物学
作者
Jian-Ge Qiu,Yaojun Zhang,Yong Li,Jinming Zhao,Wenji Zhang,Qiwei Jiang,Xiao-Long Mei,Youqiu Xue,Wu-Ming Qin,Yang� Yang,Da Zheng,Yao Chen,Meng-Ning Wei,Zhi Shi
出处
期刊:Oncotarget
[Impact Journals, LLC]
日期:2015-04-14
卷期号:6 (17): 15494-15509
被引量:58
标识
DOI:10.18632/oncotarget.3820
摘要
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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