Flavonoids are inhibitors of breast cancer resistance protein (ABCG2)-mediated transport.

Shuzhong Zhang, Xinning Yang, Marilyn E Morris

Department of Pharmaceutical Sciences, 517 Hochstetter Hall, University at Buffalo, State University of New York, Amherst 14260-1200, USA.

Molecular pharmacology 2004 May

filter terms:

Breast cancer resistance protein (BCRP) is a newly identified ATP-binding cassette transporter, shown to confer multidrug resistance (MDR) to a number of important anticancer agents and play an important function in governing drug disposition. Flavonoids are a class of polyphenolic compounds widely present in foods and herbal products. The interactions of flavonoids with P-glycoprotein and multidrug resistance-associated protein 1 have been reported; however, their interaction with BCRP is unknown. Our objective was to evaluate the effects of 20 naturally occurring flavonoids on the cellular accumulation and cytotoxicity of mitoxantrone in both BCRP-overexpressing and BCRP-negative human cell lines. BCRP-overexpressing and BCRP-negative human breast cancer cell s (MCF-7) and large cell lung carcinoma cells (NCI-H460) were used in these studies. Many of the tested flavonoids (50 microM) increased mitoxantrone accumulation in BCRP-overexpressing cells, completely reversing mitoxantrone resistance, with no effect on the corresponding BCRP-negative cells, indicating that these flavonoids are BCRP inhibitors. The effects of these flavonoids on the cellular accumulation and cytotoxicity of mitoxantrone were flavonoid concentration dependent, and significant changes were produced at concentrations lower than 10 microM for most of the flavonoids. Chrysin and biochanin A were the most potent BCRP inhibitors, producing significant increases in mitoxantrone accumulation at concentrations of 0.5 or 1.0 microM and in mitoxantrone cytotoxicity at a concentration of 2.5 microM. Flavonoid glycosides had no effects on the BCRP-mediated transport of mitoxantrone. The results obtained in this study could be clinically relevant in terms of both MDR reversal in cancer treatment and drug-flavonoid pharmacokinetic interactions.

Citation

Shuzhong Zhang, Xinning Yang, Marilyn E Morris. Flavonoids are inhibitors of breast cancer resistance protein (ABCG2)-mediated transport. Molecular pharmacology. 2004 May;65(5):1208-16