期刊
JOURNAL OF CELLULAR BIOCHEMISTRY
卷 115, 期 8, 页码 1381-1391出版社
WILEY
DOI: 10.1002/jcb.24787
关键词
ARRY-334543; ABCG2; MULTIDRUG RESISTANCE; TYROSINE KINASE INHIBITOR; LUNG CANCER
资金
- National Institutes of Health [1R15CA143701]
- St. John's University [579-1110-7002]
- National Institutes of Health, National Cancer Institute, Center for Cancer Research
- Ministry of Education [84000-3191003]
- International Program of 985 Project, Sun Yat-sen University for overseas study at St. John's University
ARRY-334543 is a small molecule inhibitor of ErbB1 and ErbB2 tyrosine kinases. We conducted this study to determine whether ARRY-334543 can enhance the efficacy of conventional anticancer drugs through interaction with ABC transporters. Lung cancer cell line NCI-H460 and its ABCG2-overexpressing NCI-H460/MX20, as well as the ABCG2-, ABCB1-, and ABCC10-overexpressing transfected cell lines were used for the reversal study. Our results demonstrated that ARRY-334543 (1.0 mu M) significantly reversed ABCG2-mediated multidrug resistance (MDR) by directly inhibiting the drug efflux function of ABCG2, resulting in the elevated intracellular accumulation of chemotherapeutic drugs in the ABCG2-overexpressing cell lines. In addition, in isolated membranes, ARRY-334543 stimulated ATPase activity and inhibited photolabeling of ABCG2 with [I-125]-iodoarylazidoprazosin in a concentration-dependent manner indicating that this drug directly interacts at the drug-binding pocket of this transporter. ARRY-334543 (1.0 mu M) only slightly reversed ABCB1- and partially reversed ABCC10-mediated MDR suggesting that it exhibits high affinity toward ABCG2. Moreover, homology modeling predicted the binding conformation of ARRY-334543 at Arg482 centroid-based grid of ABCG2. However, ARRY-334543 at reversal concentrations did not affect the expression level of ABCG2, AKT and ERK1/2 and regulate the re-localization of ABCG2. We conclude that ARRY-334543 significantly reverses drug resistance mediated by ABCG2. (C) 2014 Wiley Periodicals, Inc.
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