title: Modulation of breast cancer resistance protein (BCRP/ABCG2) by non-basic chalcone analogues.
abstract: Chalcones are biosynthetic precursors of flavonoids found to possess cytotoxic and chemopreventive activities. In this study, 17 non-basic chalcone analogues were synthesized and evaluated for their ability to modulate the function of either the human wild-type (482R) or mutant (482T) breast cancer resistance protein (BCRP/ABCG2) stably expressed in breast cancer MDA-MB-231 cells. At 5microM, chalcones with 2,4-dimethoxy groups or 2,4-dihydroxyl groups on ring A were found to increase mitoxantrone accumulation to a greater extent than an established BCRP inhibitor, fumitremorgin C. At the same time, these chalcones had negligible effect on calcein accumulation in P-glycoprotein overexpressing MDCKII cells, indicating their potential as selective BCRP inhibitors. Functionally, these compounds were able to increase the sensitivity of BCRP-overexpressing cancer cells to mitoxantrone by 2-5-fold. The effect of chalcone compounds on both wild-type and mutant BCRP ATPase activity was also examined and variable effects were observed. A stimulatory effect was mostly observed with chalcones with 2,4-dimethoxy substitution on ring A which were earmarked as good BCRP inhibitors in the MX accumulation and cytotoxicity assays. These findings underscore the potential of methoxylated and hydroxylated chalcones as selective and potent inhibitors of BCRP whose mode of action may not involve the inhibition of ATPase activity.
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore 117543, Singapore.
authors.forename: Yi
authors.initials: Y
authors.lastname: Han
authors.forename: Meliana
authors.initials: M
authors.lastname: Riwanto
authors.forename: Mei-Lin
authors.initials: ML
authors.lastname: Go
authors.forename: Pui Lai
authors.initials: PL
authors.lastname: Ee
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000187:drug effects* / Q000235:genetics; D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000633:toxicity; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D047188:Chalcones / Q000494:pharmacology*; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D005434:Flow Cytometry; D005452:Fluoresceins; D005456:Fluorescent Dyes; D006801:Humans; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008942:Mitoxantrone / Q000633:toxicity; D009363:Neoplasm Proteins / Q000187:drug effects* / Q000235:genetics
chemical_list: C116614:ABCG2 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D047188:Chalcones; D018076:DNA, Complementary; D004273:DNA, Neoplasm; D005452:Fluoresceins; D005456:Fluorescent Dyes; D007202:Indicators and Reagents; D009363:Neoplasm Proteins; C085925:calcein AM; D008942:Mitoxantrone; D000251:Adenosine Triphosphatases