GW583340 and GW2974, human EGFR and HER-2 inhibitors, reverse ABCG2- and ABCB1-mediated drug resistance

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• 作者：Kamlesh Sodani ; Amit K. Tiwari ; Satyakam Singh ; Atish Patel ; Zhi-Jie Xiao ; Jun-Jiang Chen ; Yue-Li Sun ; Tanaji T. Talele ; Zhe-Sheng Chen ; ^{Chenz@stjohns.edu}
• 关键词：MDR ; multidrug resistance ; ABC ; ATP-binding cassette ; ABCB1 (P-gp) ; P-glycoprotein ; ABCG2 ; also called BCRP (breast cancer resistance protein)/MXR (mitoxantrone resistance protein) ; ABCC1 (MRP1) ; multidrug resistance protein 1 ; EGFR ; epidermal growth fact
• 刊名：Biochemical Pharmacology
• 出版年：2012
• 期刊代码：2_00062952
• 类别：pha
• 出版时间：15 June, 2012
• 卷：83
• 期：12
• 页码：1613-1622
• 文件大小：1028 K

摘要

The overexpression of ATP binding cassette (ABC) transporters often leads to the development of multidrug resistance (MDR) and results in a suboptimal response to chemotherapy. Previously, we reported that lapatinib (GW572016), a human epidermal growth factor receptor (EGFR) and HER-2 tyrosine kinase inhibitor (TKI), significantly reverses MDR in cancer cells by blocking the efflux function of ABC subfamily B member 1 (ABCB1) and ABC subfamily G member 2 (ABCG2). In the present study, we conducted in vitro experiments to evaluate if GW583340 and GW2974, structural analogues of lapatinib, could reverse ABCB1- and ABCG2-mediated MDR. Our results showed that GW583340 and GW2974 significantly sensitized ABCB1 and ABCG2 overexpressing MDR cells to their anticancer substrates. GW583340 and GW2974 significantly increased the intracellular accumulation of [³H]-paclitaxel in ABCB1 overexpressing cells and [³H]-mitoxantrone in ABCG2 overexpressing cells respectively. In addition, GW583340 and GW2974 significantly inhibited ABCG2-mediated transport of methotrexate in ABCG2 overexpressing membrane vesicles. There was no significant change in the expression levels of ABCB1 and ABCG2 in the cell lines exposed to 5 渭M of either GW583340 or GW2974 for 3 days. In addition, a docking model predicted the binding conformation of GW583340 and GW2974 to be within the transmembrane region of homology modeled human ABCB1 and ABCG2. We conclude that GW583340 and GW2974, at clinically achievable plasma concentrations, reverse ABCB1- and ABCG2-mediated MDR by blocking the drug efflux function of these transporters. These findings may be useful in developing combination therapy for cancer treatment with EGFR TKIs.