Dietary polyacetylenes of the falcarinol type are inhibitors of breast cancer resistance protein (BCRP/ABCG2)

• Published in: European journal of pharmacology Vol. 723; pp. 346 - 352
• Main Authors: Tan, Kee W., Killeen, Daniel P., Li, Yan, Paxton, James W., Birch, Nigel P., Scheepens, Arjan
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15.01.2014
• Subjects: ABC transporter; Adenosine Triphosphatases - metabolism; ATP Binding Cassette Transporter, Sub-Family G, Member 2; ATP-Binding Cassette Transporters - antagonists & inhibitors; ATP-Binding Cassette Transporters - metabolism; BCRP; Biological Transport; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Falcarindiol; Falcarindiol 3,8-diacetate; Falcarindiol 3-acetate; Falcarinol; HEK293 Cells; Humans; Mitoxantrone - pharmacology; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - metabolism; Phytochemicals - pharmacology; Polyacetylenes - pharmacology; BCRP; Falcarindiol 3-acetate; Falcarindiol; Falcarindiol 3,8-diacetate; ABC transporter; Falcarinol
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2013.11.005

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.