title: Flavonoid dimers are highly potent killers of multidrug resistant cancer cells overexpressing MRP1.
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.
authors.affiliation: Université de Lyon, UMR 5086 CNRS/Université Lyon 1, IBCP, 69367 Lyon, France. Electronic address: lauriane.dury@gmail.com.
authors.forename: Lauriane
authors.initials: L
authors.lastname: Dury
authors.affiliation: Université de Lyon, UMR 5086 CNRS/Université Lyon 1, IBCP, 69367 Lyon, France. Electronic address: rachad.nasr@ibcp.fr.
authors.forename: Rachad
authors.initials: R
authors.lastname: Nasr
authors.affiliation: Université de Lyon, UMR 5086 CNRS/Université Lyon 1, IBCP, 69367 Lyon, France. Electronic address: doriane.lorendeau@gmail.com.
authors.forename: Doriane
authors.initials: D
authors.lastname: Lorendeau
authors.affiliation: Université de Lyon, UMR 5086 CNRS/Université Lyon 1, IBCP, 69367 Lyon, France. Electronic address: elisabetacomsa@yahoo.com.
authors.forename: Elisabeta
authors.initials: E
authors.lastname: Comsa
authors.affiliation: Department of Applied Biology and Chemical Technology, and State Key Laboratory of Chirosciences, The Hong Kong Polytechnic University, Hung Hom, Hong Kong Special Administrative Region. Electronic address: iris.l.k.wong@polyu.edu.hk.
authors.forename: Iris
authors.initials: I
authors.lastname: Wong
authors.affiliation: Department of Applied Biology and Chemical Technology, and State Key Laboratory of Chirosciences, The Hong Kong Polytechnic University, Hung Hom, Hong Kong Special Administrative Region. Electronic address: duomiantixiaozhen@gmail.com.
authors.forename: Xuezhen
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Applied Biology and Chemical Technology, and State Key Laboratory of Chirosciences, The Hong Kong Polytechnic University, Hung Hom, Hong Kong Special Administrative Region. Electronic address: kfchan@polyu.edu.hk.
authors.forename: Kin-Fai
authors.initials: KF
authors.lastname: Chan
authors.affiliation: Department of Applied Biology and Chemical Technology, and State Key Laboratory of Chirosciences, The Hong Kong Polytechnic University, Hung Hom, Hong Kong Special Administrative Region. Electronic address: tak-hang.chan@polyul.edu.hk.
authors.forename: Tak-Hang
authors.initials: TH
authors.lastname: Chan
authors.affiliation: Department of Applied Biology and Chemical Technology, and State Key Laboratory of Chirosciences, The Hong Kong Polytechnic University, Hung Hom, Hong Kong Special Administrative Region. Electronic address: bclchow@polyu.edu.hk.
authors.forename: Larry
authors.initials: L
authors.lastname: Chow
authors.affiliation: Université de Lyon, UMR 5086 CNRS/Université Lyon 1, IBCP, 69367 Lyon, France. Electronic address: pierre.falson@ibcp.fr.
authors.forename: Pierre
authors.initials: P
authors.lastname: Falson
authors.affiliation: Université de Lyon, UMR 5086 CNRS/Université Lyon 1, IBCP, 69367 Lyon, France. Electronic address: ac.dipietro2@gmail.com.
authors.forename: Attilio
authors.initials: A
authors.lastname: Di Pietro
authors.affiliation: Université de Lyon, UMR 5086 CNRS/Université Lyon 1, IBCP, 69367 Lyon, France. Electronic address: helene.cortay@ibcp.fr.
authors.forename: Hélène
authors.initials: H
authors.lastname: Baubichon-Cortay
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D019281:Dimerization; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005419:Flavonoids / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D005419:Flavonoids; D005978:Glutathione; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C421109:multidrug resistance-associated protein 1
keywords: Collateral sensitivity; Flavonoid dimers; Glutathione; Multidrug resistance protein 1