Methoxy stilbenes as potent, specific, untransported, and noncytotoxic inhibitors of breast cancer resistance protein

The ABCG2 multidrug transporter is knownto confer cancer cell multidrug resistance by causing the effluxof anticancer drugs; therefore, selective inhibitors have thepotential to improve chemotherapeutic treatments. Here,various methoxy derivatives of resveratrol are shown to bepotent inhibitors of mitoxantrone efflux by ABCG2: among aseries of 11 derivatives, compound 9 (3,5,3′,4′-tetramethoxytrans-stilbene) had an IC50 of 0.16 μM and showed a maximalinhibition of 75%, as measured by flow cytometry. It was nottransported, as shown by HPLC fractionation and mass spectrometry titration and the lack of any cross-resistance in cell survivalexperiments. 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 effectswere observed with ABCB1 and ABCC1. The action mechanism of compound 9 was different from that of GF120918, whichproduced 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 eitherbound to distinct sites or induced different conformational changes. Mitoxantrone efflux was fully inhibited by combining lowconcentrations of compound 9 with either GF120918 or a transport substrate such as prazosin or nilotinib. We conclude thatmethoxy derivatives of stilbene are good candidates for investigating future in vivo modulation of ABCG2 drug-efflux activity.