Icotinib antagonizes ABCG2-mediated multidrug resistance, but not the pemetrexed resistance mediated by thymidylate synthase and ABCG2
作者： De-Shen Wang , Atish Patel , Suneet Shukla , Yun-Kai Zhang , Yi-Jun Wang
关键词:
摘要: ABCG2 is a potential biomarker causing multidrug resistance (MDR) in Non-Small Cell Lung Cancer (NSCLC). We conducted this study to investigate whether Icotinib, small-molecule inhibitor of EGFR tyrosine kinase, could interact with transporter NSCLC. Our results showed that Icotinib reversed ABCG2-mediated MDR by antagonizing the drug efflux function ABCG2. stimulated ATPase activity concentration-dependent manner and inhibited photolabeling [125I]-Iodoarylazidoprazosin, demonstrating it interacts at drug-binding pocket. Homology modeling predicted binding conformation Asn629 centroid-based grid However, reversal concentration did not affect expression levels AKT Furthermore, combination topotecan exhibited significant synergistic anticancer against NCI-H460/MX20 tumor xenografts. inhibition transport was insufficient overcome pemetrexed cells, which due co-upregulated thymidylate synthase (TS) expression. This first report show up-regulation TS ABCG2-overexpressing cell line may play role pemetrexate. findings suggested different possible strategies overcoming NSCLC patients.
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