Effects of single and multiple flavonoids on BCRP-mediated accumulation, cytotoxicity and transport of mitoxantrone in vitro

Guohua An; Marilyn E Morris

doi:10.1007/s11095-010-0108-8

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Effects of single and multiple flavonoids on BCRP-mediated accumulation, cytotoxicity and transport of mitoxantrone in vitro

Journal article

Peer reviewed

Effects of single and multiple flavonoids on BCRP-mediated accumulation, cytotoxicity and transport of mitoxantrone in vitro

Guohua An and Marilyn E Morris

Pharmaceutical research, Vol.27(7), pp.1296-1308

07/2010

DOI: 10.1007/s11095-010-0108-8

PMID: 20369276

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Abstract

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. 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. 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. 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.

Drug Resistance, Multiple

Humans

Antineoplastic Agents - therapeutic use

Chromatography, High Pressure Liquid

Breast Neoplasms - drug therapy

Flavonoids - pharmacokinetics

Blotting, Western

Antineoplastic Agents - toxicity

Mitoxantrone - toxicity

Cell Line, Tumor

Female

Antineoplastic Agents - pharmacokinetics

Biological Transport - drug effects

Flavonoids - pharmacology

Molecular Structure

Mitoxantrone - pharmacokinetics

Mitoxantrone - therapeutic use

Details

Title: Subtitle: Effects of single and multiple flavonoids on BCRP-mediated accumulation, cytotoxicity and transport of mitoxantrone in vitro
Creators: Guohua An - 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
Marilyn E Morris
Resource Type: Journal article
Publication Details: Pharmaceutical research, Vol.27(7), pp.1296-1308
Publisher: United States
DOI: 10.1007/s11095-010-0108-8
PMID: 20369276
ISSN: 0724-8741
eISSN: 1573-904X
Language: English
Date published: 07/2010
Academic Unit: Pharmaceutical Sciences and Experimental Therapeutics
Record Identifier: 9984065689902771

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