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

Attilio Di Pietro (1, 2) , Lauriane Dury (1, 2) , Rachad Nasr (1, 2) , Doriane Lorendeau (1, 2) , Elisabeta Comsa (1, 2) , Iris Wong , Xuezhen Zhu , Kin-Fai Chan , Tak-Hang Chan , Larry Chow , Pierre Falson (1, 2) , Hélène Baubichon-Cortay (1, 2)

1 MMSB - Microbiologie moléculaire et biochimie structurale / Molecular Microbiology and Structural Biochemistry
2 IBCP - Institut de biologie et chimie des protéines [Lyon]

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 EC 50 value of 0.1 lM, 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 erad-ication of MRP1-overexpressing chemoresistant cancer cells in tumors.

Domaines: Chimie thérapeutique; Biochimie [q-bio.BM]; Cancer

Attilio Di Pietro, Lauriane Dury, Rachad Nasr, Doriane Lorendeau, Elisabeta Comsa, et al.. Flavonoid dimers are highly potent killers of multidrug resistant cancer cells overexpressing MRP1. Biochemical Pharmacology, 2017, 124, pp.10-18. ⟨10.1016/j.bcp.2016.10.013⟩. ⟨hal-02329628⟩