Please use this identifier to cite or link to this item: http://hdl.handle.net/10397/65750
Title: Flavonoid dimers are highly potent killers of multidrug resistant cancer cells overexpressing MRP1
Authors: Dury, L
Nasr, R
Lorendeau, D
Comsa, E
Falson, P
Di, Pietro
Baubichon-Cortay, H
Wong, I
Zhu, X
Chan, KF 
Chan, TH
Chow, L 
Keywords: Collateral sensitivity
Flavonoid dimers
Glutathione
Multidrug resistance protein 1
Issue Date: 2017
Publisher: Elsevier
Source: Biochemical pharmacology, 2017, v. 124, p. 10-18 How to cite?
Journal: Biochemical pharmacology 
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 EC50 value 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.
URI: http://hdl.handle.net/10397/65750
EISSN: 0006-2952
DOI: 10.1016/j.bcp.2016.10.013
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