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.
Methoxy stilbenes as potent, specific, untransported, and noncytotoxic inhibitors of breast cancer resistance protein
TRINGALI, Corrado;
2012-01-01
Abstract
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.File | Dimensione | Formato | |
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