title: Flavonoid structure-activity studies identify 6-prenylchrysin and tectochrysin as potent and specific inhibitors of breast cancer resistance protein ABCG2.
abstract: Overexpression of breast cancer resistance protein ABCG2 confers multidrug resistance in cancer cells. The GF120918-sensitive drug efflux activity of human wild-type (R482) ABCG2-transfected cells was used for rational screening of inhibitory flavonoids and establishment of structure-activity relationships. Flavones were found more efficient than flavonols, isoflavones, and flavanones. Differentially substituted flavone derivatives indicated positive OH effects at position 5, in contrast to positions 3 and 7. A methoxy at position 7 was slightly positive in tectochrysin, whereas a strong positive effect was produced by prenylation at position 6. The potency of 6-prenylchrysin was comparable with that of GF120918 (IC50 = 0.3 micromol/L). Both 6-prenylchrysin and tectochrysin seemed specific for ABCG2 because no interaction was detected with either P-glycoprotein or MRP1. The ABCG2 resistance profile in vitro is altered by mutation at amino acid 482. The R482T mutation limited the effect of prenylation on ABCG2 inhibition. Whereas GF120918 strongly inhibited the ATPase activity of wild-type ABCG2, neither 6-prenylchrysin nor tectochrysin altered the activity. In contrast, all three inhibitors stimulated the ATPase activity of mutant ABCG2. 6-Prenylchrysin at 0.5 micromol/L efficiently sensitized the growth of wild-type ABCG2-transfected cells to mitoxantrone, whereas higher concentrations were required for the mutant ones. In contrast, 1 micromol/L tectochrysin was sufficient to fully sensitize mutant ABCG2-transfected cells, whereas higher concentrations were required for the wild-type ones. Both flavones exhibited a lower intrinsic cytotoxicity than GF120918 and were apparently not transported by ABCG2. 6-Prenylchrysin and tectochrysin therefore constitute new and promising inhibitors for the reversal of ABCG2-mediated drug transport.
authors.affiliation: Institut de Biologie et Chimie des Protéines, Centre National de la Recherche Scientifique-Université Claude Bernard de Lyon, BioSciences Lyon-Gerland, Lyon, France.
authors.forename: Abdelhakim
authors.initials: A
authors.lastname: Ahmed-Belkacem
authors.forename: Alexandre
authors.initials: A
authors.lastname: Pozza
authors.forename: Francisco
authors.initials: F
authors.lastname: Muñoz-Martínez
authors.forename: Susan E
authors.initials: SE
authors.lastname: Bates
authors.forename: Santiago
authors.initials: S
authors.lastname: Castanys
authors.forename: Francisco
authors.initials: F
authors.lastname: Gamarro
authors.forename: Attilio
authors.initials: A
authors.lastname: Di Pietro
authors.forename: José M
authors.initials: JM
authors.lastname: Pérez-Victoria
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics; D000166:Acridines / Q000494:pharmacology; D000251:Adenosine Triphosphatases / Q000378:metabolism; D001562:Benzimidazoles / Q000493:pharmacokinetics; D002460:Cell Line; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008942:Mitoxantrone / Q000493:pharmacokinetics / Q000494:pharmacology; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D012235:Rhodamines / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000494:pharmacology; D014162:Transfection
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000166:Acridines; D000251:Adenosine Triphosphatases; D001562:Benzimidazoles; D005419:Flavonoids; D008942:Mitoxantrone; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D012235:Rhodamines; D044005:Tetrahydroisoquinolines; C502336:6-prenylchrysin; C116614:ABCG2 protein, human; C026188:rhodamine 6G; C402729:tectochrysin; C083501:Elacridar; C017807:bisbenzimide ethoxide trihydrochloride; C421109:multidrug resistance-associated protein 1