title: Ferrocene-embedded flavonoids targeting the Achilles heel of multidrug-resistant cancer cells through collateral sensitivity.
abstract: With the aim to develop anticancer agents acting selectively against resistant tumor cells, we investigated ferrocene embedded into chalcone, aurone and flavone skeletons. These compounds were conceived and then investigated based on the concept of collateral sensitivity, where the target is the Achilles Heel of cancer cells overexpressing the multidrug ABC transporter MRP1. The 14 synthesized compounds were evaluated for their ability to induce efflux of glutathione (GSH) from tumor cells overexpressing MRP1. When tested at 5 and 20 μM, at least one compound from each series was found to be a highly inducer of GSH efflux. The different compounds inducing a high efflux of GSH were evaluated on both sensitive and resistant cell lines, and two of them, belonging to the flavones class were found to be more cytotoxic on resistant cancer cells, with the best selectivity ratio >9.1. Our results bring chemical and biological bases for further optimization.
authors.affiliation: Département de Pharmacochimie Moléculaire, Université Grenoble-Alpes, CNRS UMR 5063, F-38041 Grenoble, France. Electronic address: basile.peres@univ-grenoble-alpes.fr.
authors.forename: Basile
authors.initials: B
authors.lastname: Pérès
authors.affiliation: Molecular Microbiology and Structural Biochemistry, UMR 5086, CNRS-University of Lyon IBCP, 7 passage du Vercors, F-69367 Lyon, France. Electronic address: rachad.nasr@ibcp.fr.
authors.forename: Rachad
authors.initials: R
authors.lastname: Nasr
authors.affiliation: Département de Pharmacochimie Moléculaire, Université Grenoble-Alpes, CNRS UMR 5063, F-38041 Grenoble, France. Electronic address: m.zarioh17@gmail.com.
authors.forename: Malik
authors.initials: M
authors.lastname: Zarioh
authors.affiliation: Département de Pharmacochimie Moléculaire, Université Grenoble-Alpes, CNRS UMR 5063, F-38041 Grenoble, France. Electronic address: florine.lecerfschmidt@gmail.com.
authors.forename: Florine
authors.initials: F
authors.lastname: Lecerf-Schmidt
authors.affiliation: Molecular Microbiology and Structural Biochemistry, UMR 5086, CNRS-University of Lyon IBCP, 7 passage du Vercors, F-69367 Lyon, France. Electronic address: ac.dipietro2@gmail.com.
authors.forename: Attilio
authors.initials: A
authors.lastname: Di Pietro
authors.affiliation: Molecular Microbiology and Structural Biochemistry, UMR 5086, CNRS-University of Lyon IBCP, 7 passage du Vercors, F-69367 Lyon, France. Electronic address: helene.cortay@ibcp.fr.
authors.forename: Hélène
authors.initials: H
authors.lastname: Baubichon-Cortay
authors.affiliation: Département de Pharmacochimie Moléculaire, Université Grenoble-Alpes, CNRS UMR 5063, F-38041 Grenoble, France. Electronic address: ahcene.boumendjel@univ-grenoble-alpes.fr.
authors.forename: Ahcène
authors.initials: A
authors.lastname: Boumendjel
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003603:Cytotoxins / Q000737:chemistry / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005296:Ferrous Compounds / Q000737:chemistry*; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D000075163:Metallocenes; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis; D012680:Sensitivity and Specificity
chemical_list: D000970:Antineoplastic Agents; D003603:Cytotoxins; D005296:Ferrous Compounds; D005419:Flavonoids; D005978:Glutathione; D000075163:Metallocenes; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C004998:ferrocene; C421109:multidrug resistance-associated protein 1