Methoxy Stilbenes as Potent, Specific, Untransported, and Noncytotoxic Inhibitors of Breast Cancer Resistance Protein

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• 作者：Glaucio Valdameri ; Luciana Pereira Rangel ; Carmela Spatafora ; J茅r么me Guitton ; Charlotte Gauthier ; Oph茅lie Arnaud ; Antonio Ferreira-Pereira ; Pierre Falson ; Sheila M. B. Winnischofer ; Maria E. M. Rocha ; Corrado Tringali ; Attilio Di Pietro
• 刊名：ACS Chemical Biology
• 出版年：2012
• 出版时间：February 17, 2012
• 年：2012
• 卷：7
• 期：2
• 页码：322-330
• 全文大小：319K
• 年卷期：v.7,no.2(February 17, 2012)
• ISSN：1554-8937

文摘

The ABCG2 multidrug transporter is known to confer cancer cell multidrug resistance by causing the efflux of anticancer drugs; therefore, selective inhibitors have the potential to improve chemotherapeutic treatments. Here, various methoxy derivatives of resveratrol are shown to be potent inhibitors of mitoxantrone efflux by ABCG2: among a series of 11 derivatives, compound 9 (3,5,3鈥?4鈥?tetramethoxy trans-stilbene) had an IC₅₀ of 0.16 渭M and showed a maximal inhibition of 75%, as measured by flow cytometry. It was not transported, as shown by HPLC fractionation and mass spectrometry titration and the lack of any cross-resistance in cell survival experiments. Compound 9 had a very low intrinsic cytotoxicity and was able to chemosensitize the growth of resistant ABCG2-transfected HEK293 cells at submicromolar concentrations. Drug-efflux inhibition was specific for ABCG2 since very low effects were observed with ABCB1 and ABCC1. The action mechanism of compound 9 was different from that of GF120918, which produced a complete and partly competitive but not ABCG2-specific inhibition, since ABCB1 was even more strongly inhibited. The two inhibitors also displayed different effects on the ABCG2 vanadate-sensitive ATPase activity, suggesting that they either bound to distinct sites or induced different conformational changes. Mitoxantrone efflux was fully inhibited by combining low concentrations of compound 9 with either GF120918 or a transport substrate such as prazosin or nilotinib. We conclude that methoxy derivatives of stilbene are good candidates for investigating future in vivo modulation of ABCG2 drug-efflux activity.