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: Kee W Tan, Daniel P Killeen, Yan Li, James W Paxton, Nigel P Birch, Arjan Scheepens
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 723 Pg. 346-52 (Jan 15 2014) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 24269959 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 Elsevier B.V. All rights reserved.

Chemical References

• ABCG2 protein, human
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters
• Neoplasm Proteins
• Phytochemicals
• Polyynes
• Mitoxantrone
• Adenosine Triphosphatases

Topics

• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters (antagonists & inhibitors, metabolism)
• Adenosine Triphosphatases (metabolism)
• Biological Transport
• Drug Resistance, Multiple
• Drug Resistance, Neoplasm
• HEK293 Cells
• Humans
• Mitoxantrone (pharmacology)
• Neoplasm Proteins (antagonists & inhibitors, metabolism)
• Phytochemicals (pharmacology)
• Polyynes (pharmacology)