Effects of single and multiple flavonoids on BCRP-mediated accumulation, cytotoxicity and transport of mitoxantrone in vitro.
OBJECTIVE
The objective of our study was to investigate the effect of single and multiple flavonoids on the accumulation and cytotoxicity of mitoxantrone in BCRP-overexpressing breast cancer cells and on the transport of mitoxantrone in BCRP-expressing normal cells.


METHODS
The effect of flavonoids on mitoxantrone accumulation and cytotoxicity was studied in the human breast cancer MCF-7 MX100 cell line. Mitoxantrone transport in the presence of flavonoids was studied in human and murine BCRP-transfected MDCK cell lines, and mitoxantrone concentrations were determined by HPLC.


RESULTS
Our results demonstrated that multiple flavonoid combinations act additively and exhibit strong BCRP inhibition for increasing mitoxantrone accumulation in breast cancer cells. Kaempferide, biochanin A, 5,7-dimethoxyflavone, and 8-methylflavone greatly increased the cytotoxicity of mitoxantrone in BCRP-overexpressing breast cancer cells. Additionally, the basolateral-to-apical membrane-directed transport of mitoxantrone in murine Bcrp1- and human BCRP-expressing MDCK cells, in the presence of 2.5 microM of these flavonoids, was also significantly decreased.


CONCLUSIONS
The results indicate that flavonoids are potent BCRP inhibitors and that they exert additive effects when used in combination. Flavonoids demonstrate MDR-reversing effects, but also may influence the disposition of mitoxantrone and cause pharmacokinetic interactions.
An
Guohua
G
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, 517 Hochstetter Hall, Amherst, New York 14260-1200, USA.
Morris
Marilyn E
ME
D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000633:toxicity; D001692:Biological Transport / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D018432:Drug Resistance, Multiple; D005260:Female; D005419:Flavonoids / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D008942:Mitoxantrone / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000633:toxicity; D015394:Molecular Structure
D000970:Antineoplastic Agents; D005419:Flavonoids; D008942:Mitoxantrone