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

Pharm Res. 2010 Jul;27(7):1296-308. doi: 10.1007/s11095-010-0108-8. Epub 2010 Apr 6.

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 microM 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacokinetics*
  • Antineoplastic Agents / therapeutic use
  • Antineoplastic Agents / toxicity
  • Biological Transport / drug effects
  • Blotting, Western
  • Breast Neoplasms / drug therapy
  • Cell Line, Tumor
  • Chromatography, High Pressure Liquid
  • Drug Resistance, Multiple
  • Female
  • Flavonoids / pharmacokinetics*
  • Flavonoids / pharmacology
  • Humans
  • Mitoxantrone / pharmacokinetics*
  • Mitoxantrone / therapeutic use
  • Mitoxantrone / toxicity
  • Molecular Structure

Substances

  • Antineoplastic Agents
  • Flavonoids
  • Mitoxantrone