title: Dietary polyacetylenes of the falcarinol type are inhibitors of breast cancer resistance protein (BCRP/ABCG2).
abstract: Polyacetylenes of the falcarinol type are present in vegetables such as carrots and parsley. They display interesting bioactivities and hold potential as health-promoting and therapeutic agents. In this study, falcarinol, falcarindiol, falcarindiol 3-acetate and falcarindiol 3,8-diacetate were examined for their modulation on breast cancer resistance protein (BCRP/ABCG2), an efflux transporter important for xenobiotic absorption and disposition, and multidrug resistance in cancer. Falcarinol, falcarindiol, and falcarindiol 3-acetate were extracted from carrots and falcarindiol 3,8-diacetate prepared from falcarindiol. Their modulatory effects on ABCG2 were studied using three methods-mitoxantrone accumulation, vesicular transport, and ATPase assay. The polyacetylenes inhibited mitoxantrone (an ABCG2 substrate) efflux in ABCG2-overexpressing HEK293 cells. The inhibitory effect was confirmed in the vesicular transport assay, in which concentration-dependent inhibition of methotrexate (an ABCG2 substrate) uptake into ABCG2-overexpressing Sf9 membrane vesicles was observed (IC50=19.7-41.7µM). The polyacetylenes also inhibited baseline and sulfasalazine-stimulated vanadate-sensitive ATPase activities in ABCG2-overexpressing Sf9 membrane vesicles (IC50=19.3-79.3µM). This is the first report of an inhibitory effect of polyacetylenes on ABCG2. These results indicate a prospective use of polyacetylenes as multidrug resistance reversal agents, a possible role of ABCG2 in the absorption and disposition of polyacetylenes, and potential food-drug interactions between polyacetylene-rich foods and ABCG2 substrate drugs.
authors.affiliation: Food Innovation, The New Zealand Institute for Plant & Food Research Limited, Private Bag 92169, Auckland, New Zealand; School of Biological Sciences, Faculty of Science, The University of Auckland, Auckland, New Zealand; Department of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand. Electronic address: kee.tan@plantandfood.co.nz.
authors.forename: Kee W
authors.initials: KW
authors.lastname: Tan
authors.affiliation: Department of Chemistry, University of Otago, Dunedin, New Zealand.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Killeen
authors.affiliation: School of Interprofessional Health Studies, Faculty of Health and Environmental Sciences, Auckland University of Technology, Auckland, New Zealand.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.
authors.forename: James W
authors.initials: JW
authors.lastname: Paxton
authors.affiliation: School of Biological Sciences, Faculty of Science, The University of Auckland, Auckland, New Zealand; Centre for Brain Research, The University of Auckland, Auckland, New Zealand.
authors.forename: Nigel P
authors.initials: NP
authors.lastname: Birch
authors.affiliation: Food Innovation, The New Zealand Institute for Plant & Food Research Limited, Private Bag 92169, Auckland, New Zealand.
authors.forename: Arjan
authors.initials: A
authors.lastname: Scheepens
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000378:metabolism; D001692:Biological Transport; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D057809:HEK293 Cells; D006801:Humans; D008942:Mitoxantrone / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D064209:Phytochemicals / Q000494:pharmacology*; D053279:Polyynes / Q000494:pharmacology*
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins; D064209:Phytochemicals; D053279:Polyynes; D008942:Mitoxantrone; D000251:Adenosine Triphosphatases
keywords: ABC transporter; BCRP; Falcarindiol; Falcarindiol 3,8-diacetate; Falcarindiol 3-acetate; Falcarinol