title: Methoxy stilbenes as potent, specific, untransported, and noncytotoxic inhibitors of breast cancer resistance protein.
abstract: 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',4'-tetramethoxy trans-stilbene) had an IC(50) of 0.16 μM 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.
authors: Equipe Labellisée Ligue, Institut de Biologie et Chimie des Protéines FR, Université Lyon, Lyon, France.
authors: Glaucio
authors: G
authors: Valdameri
authors: Luciana
authors: L
authors: Pereira Rangel
authors: Carmela
authors: C
authors: Spatafora
authors: Jérôme
authors: J
authors: Guitton
authors: Charlotte
authors: C
authors: Gauthier
authors: Ophélie
authors: O
authors: Arnaud
authors: Antonio
authors: A
authors: Ferreira-Pereira
authors: Pierre
authors: P
authors: Falson
authors: Sheila M B
authors: SM
authors: Winnischofer
authors: Maria E M
authors: ME
authors: Rocha
authors: Corrado
authors: C
authors: Tringali
authors: Attilio
authors: A
authors: Di Pietro
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy*; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008942:Mitoxantrone / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077185:Resveratrol; D013267:Stilbenes / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D013267:Stilbenes; D008942:Mitoxantrone; D000077185:Resveratrol