Flavonoid dimers are highly potent killers of multidrug resistant cancer cells overexpressing MRP1

Lauriane Dury, Rachad Nasr, Doriane Lorendeau, Elisabeta Comsa, Pierre Falson, Attilio Di Pietro, Hélène Baubichon-Cortay, Iris Wong, Xuezhen Zhu, Kin Fai Chan, Tak Hang Chan, Ming Cheung Chow

Research output: Journal article publicationJournal articleAcademic researchpeer-review

20 Citations (Scopus)

Abstract

MRP1 overexpression in multidrug-resistant cancer cells has been shown to be responsible for collateral sensitivity to some flavonoids that stimulate a huge MRP1-mediated GSH efflux. This massive GSH depletion triggers the death of these cancer cells. We describe here that bivalent flavonoid dimers strikingly stimulate such MRP1-mediated GSH efflux and trigger a 50–100 fold more potent cell death than their corresponding monomers. This selective and massive cell death of MRP1-overexpressing cells (both transfected and drug-selected cell lines) is no longer observed either upon catalytic inactivation of MRP1 or its knockdown by siRNA. The best flavonoid dimer, 4e, kills MRP1-overexpressing cells with a selective ratio higher than 1000 compared to control cells and an EC50value of 0.1 μM, so far unequaled as a collateral sensitivity agent targeting ABC transporters. This result portends the flavonoid dimer 4e as a very promising compound to appraise in vivo the therapeutic potential of collateral sensitivity for eradication of MRP1-overexpressing chemoresistant cancer cells in tumors.
Original languageEnglish
Pages (from-to)10-18
Number of pages9
JournalBiochemical Pharmacology
Volume124
DOIs
Publication statusPublished - 15 Jan 2017

Keywords

  • Collateral sensitivity
  • Flavonoid dimers
  • Glutathione
  • Multidrug resistance protein 1

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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