Potent interaction of flavopiridol with MRP1

J. H. Hooijberg, H. J. Broxterman, G. L. Scheffer, C. Vrasdonk, M. Heijn, M. C. De Jong, R. J. Scheper, J. Lankelma, H. M. Pinedo

Research output: Contribution to journalArticle

Abstract

The multidrug resistance protein 1 (MRP1) is an ATP-dependent transport protein for organic anions, as well as neutral or positively charged anticancer agents. In this study we show that flavopiridol, a synthetic flavonoid currently studied in phase 1 trials for its anti-prolifetative characteristics, interacts with MRP1 in a potent way. Flavopiridol, as well as other (iso)flavonoids stimulate the ATPase activity of MRP1 in a dose-dependent way at low micromolar concentrations. A new specific monoclonal antibody against MRP1 (MIB6) inhibits the (iso)flavonoid-induced ATPase activity of plasma membrane vesicles prepared from the MRP1 overexpressing cell line GLC4/ADR. The accumulation of daunorubicin in GLC4/ADR cells is increased by flavopiridol and by other non-glycosylated (iso)flavonoids that interact with MRP1 ATPase activity. However, flavopiridol is the only tested compound that affects the daunorubicin accumulation when present at concentrations below 1 μm. Glycosylated (iso)flavonoids do not affect MRP1-mediated transport or ATPase activity. Finally, MRP1 overexpressing and transfected cells are resistant to flavopiridol, but not to other (iso)flavonoids tested. These findings may be of relevance for the development of anticancer therapies with flavopiridol.

Original languageEnglish (US)
Pages (from-to)269-276
Number of pages8
JournalBritish Journal of Cancer
Volume81
Issue number2
DOIs
StatePublished - 1999
Externally publishedYes

Keywords

  • (Iso)flavonoids
  • ATPase
  • Flavopiridol
  • MRP1
  • Multidrug resistance

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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  • Cite this

    Hooijberg, J. H., Broxterman, H. J., Scheffer, G. L., Vrasdonk, C., Heijn, M., De Jong, M. C., Scheper, R. J., Lankelma, J., & Pinedo, H. M. (1999). Potent interaction of flavopiridol with MRP1. British Journal of Cancer, 81(2), 269-276. https://doi.org/10.1038/sj.bjc.6690687