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Effects of Single and Multiple Flavonoids on BCRP-Mediated Accumulation, Cytotoxicity and Transport of Mitoxantrone In Vitro

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ABSTRACT

Purpose

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 µM of these flavonoids, was also significantly decreased.

Conclusion

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.

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Abbreviations

ABC:

ATP binding cassette

BCRP:

breast cancer resistance protein

FTC:

fumitremogin C

MDCK:

Madin-Darby canine kidney

MDR:

multidrug resistance

SRB:

sulforhodamine B

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ACKNOWLEDGEMENT

This study was supported in part by a grant from the Susan G. Komen Breast Cancer Foundation (BCTR0601385).

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Authors and Affiliations

  1. 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

    Guohua An & Marilyn E. Morris

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  1. Guohua An
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  2. Marilyn E. Morris
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Corresponding author

Correspondence to Marilyn E. Morris.

Additional information

A detailed description of the mitoxantrone assay has been published (An G and Morris ME. HPLC analysis of mitoxantrone in mouse plasma and tissues: Application in a pharmacokinetic study. J Pharm Biomed Anal 51 (2010) 750–753).

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An, G., Morris, M.E. Effects of Single and Multiple Flavonoids on BCRP-Mediated Accumulation, Cytotoxicity and Transport of Mitoxantrone In Vitro . Pharm Res 27, 1296–1308 (2010). https://doi.org/10.1007/s11095-010-0108-8

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  • DOI: https://doi.org/10.1007/s11095-010-0108-8

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