Potent interaction of flavopiridol with MRP1 View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

1999-09

AUTHORS

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

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 antiproliferative 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 microM. 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. More... »

PAGES

269

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/sj.bjc.6690687

DOI

http://dx.doi.org/10.1038/sj.bjc.6690687

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1036142362

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/10496352


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