title: Collateral sensitivity of resistant MRP1-overexpressing cells to flavonoids and derivatives through GSH efflux.
abstract: The multidrug resistance protein 1 (MRP1) is involved in multidrug resistance of cancer cells by mediating drug efflux out of cells, often in co-transport with glutathione (GSH). GSH efflux mediated by MRP1 can be stimulated by verapamil. In cells overexpressing MRP1, we have previously shown that verapamil induced a huge intracellular GSH depletion which triggered apoptosis of the cells. That phenomenon takes place in the more global anticancer strategy called "collateral sensitivity" and could be exploited to eradicate some chemoresistant cancer cells. Seeking alternative compounds to verapamil, we screened a library of natural flavonoids and synthetic derivatives. A large number of these compounds stimulate MRP1-mediated GSH efflux and the most active ones have been evaluated for their cytotoxic effect on MRP1-overexpressing cells versus parental cells. Interestingly, some are highly and selectively cytotoxic for MRP1-cells, leading them to apoptosis. However, some others do not exhibit any cytotoxicity while promoting a strong GSH efflux, indicating that GSH efflux is necessary but not sufficient for MRP1-cells apoptosis. In support to this hypothesis, structure activity relationships show that the absence of a hydroxyl group at position 3 of the flavonoid C ring is an absolute requirement for induction of MRP1-cells death, but is not for GSH efflux stimulation. Chrysin (compound 8) and its derivatives, compounds 11 and 22, exhibit a high selectivity toward MRP1-cells with a IC₅₀ value of 4.1 μM for compound 11 and 4.9 μM for chrysin and compound 22, making them among the best described selective killer compounds of multidrug ABC transporter-overexpressing cells.
authors.affiliation: Equipe Labellisée Ligue 2012, Université Lyon 1, Univ Lyon, Lyon, France; CNRS, UMR 5086, Bases Moléculaires et Structurales des Systèmes Infectieux, IBCP, 7 passage du Vercors, F-69367 Lyon, France. Electronic address: doriane.lorendeau@ibcp.fr.
authors.forename: Doriane
authors.initials: D
authors.lastname: Lorendeau
authors.affiliation: Equipe Labellisée Ligue 2012, Université Lyon 1, Univ Lyon, Lyon, France; CNRS, UMR 5086, Bases Moléculaires et Structurales des Systèmes Infectieux, IBCP, 7 passage du Vercors, F-69367 Lyon, France. Electronic address: lauriane.dury@ibcp.fr.
authors.forename: Lauriane
authors.initials: L
authors.lastname: Dury
authors.affiliation: Département de Pharmacochimie Moléculaire Université Grenoble-Alpes, CNRS UMR 5063, Grenoble, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Genoux-Bastide
authors.affiliation: Département de Pharmacochimie Moléculaire Université Grenoble-Alpes, CNRS UMR 5063, Grenoble, France. Electronic address: florine.lecerfschmidt@gmail.com.
authors.forename: Florine
authors.initials: F
authors.lastname: Lecerf-Schmidt
authors.affiliation: Pharmacochimie, Section des Sciences Pharmaceutiques, Université de Genève/Lausanne, Genève, Suisse; Pharmacochimie, Section des Sciences Pharmaceutiques, Université de Genève/Lausanne, Genève, Suisse. Electronic address: claudia.avello@unige.ch.
authors.forename: Claudia
authors.initials: C
authors.lastname: Simões-Pires
authors.affiliation: Pharmacochimie, Section des Sciences Pharmaceutiques, Université de Genève/Lausanne, Genève, Suisse; Pharmacochimie, Section des Sciences Pharmaceutiques, Université de Genève/Lausanne, Genève, Suisse. Electronic address: pierre-alain.carrupt@unige.ch.
authors.forename: Pierre-Alain
authors.initials: PA
authors.lastname: Carrupt
authors.affiliation: CNRS, UMR 5086, Bases Moléculaires et Structurales des Systèmes Infectieux, IBCP, 7 passage du Vercors, F-69367 Lyon, France; Equipe "Bioinformatique: structures et interactions", Université Lyon 1, Univ Lyon, Lyon, France. Electronic address: r.terreux@ibcp.fr.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Terreux
authors.affiliation: Equipe Labellisée Ligue 2012, Université Lyon 1, Univ Lyon, Lyon, France; CNRS, UMR 5086, Bases Moléculaires et Structurales des Systèmes Infectieux, IBCP, 7 passage du Vercors, F-69367 Lyon, France. Electronic address: s.magnard@ibcp.fr.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Magnard
authors.affiliation: Equipe Labellisée Ligue 2012, Université Lyon 1, Univ Lyon, Lyon, France; CNRS, UMR 5086, Bases Moléculaires et Structurales des Systèmes Infectieux, IBCP, 7 passage du Vercors, F-69367 Lyon, France. Electronic address: a.dipietro@ibcp.fr.
authors.forename: Attilio
authors.initials: A
authors.lastname: Di Pietro
authors.affiliation: Département de Pharmacochimie Moléculaire Université Grenoble-Alpes, CNRS UMR 5063, Grenoble, France. Electronic address: ahcene.boumendjel@ujf-grenoble.fr.
authors.forename: Ahcène
authors.initials: A
authors.lastname: Boumendjel
authors.affiliation: Equipe Labellisée Ligue 2012, Université Lyon 1, Univ Lyon, Lyon, France; CNRS, UMR 5086, Bases Moléculaires et Structurales des Systèmes Infectieux, IBCP, 7 passage du Vercors, F-69367 Lyon, France. Electronic address: hcortay@ibcp.fr.
authors.forename: Hélène
authors.initials: H
authors.lastname: Baubichon-Cortay
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D055808:Drug Discovery; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D054852:Small Molecule Libraries; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000975:Antioxidants; D005419:Flavonoids; D005978:Glutathione; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; D054852:Small Molecule Libraries; C421109:multidrug resistance-associated protein 1
keywords: Chrysin (PubChem CID: 5281607); Collateral sensitivity; Flavonoids; Galangin (PubChem CID: 5281616); Glutathione; Kaempferol (PubChem CID: 5280863); Multidrug resistance; Multidrug resistance protein 1