title: MRP1-dependent Collateral Sensitivity of Multidrug-resistant Cancer Cells: Identifying Selective Modulators Inducing Cellular Glutathione Depletion.
abstract: Cancer cells are permanently being selected for survival and proliferation. During this process, tumor cells often co-opt basic physiological mechanisms to protect themselves from toxic chemotherapy. One of these mechanisms is the overexpression of ATP-binding cassette (ABC) drug efflux pumps leading to multidrug resistance (MDR) of cancer cells through an increase of drug efflux. In the past 20 years, many efforts were done to circumvent MDR through the inhibition of ABC transporters. A number of inhibitors of these transporters were found but are rarely specific or rationally developed. Beside this approach, a new therapeutic strategy towards eradicating drug resistant tumor cells has recently emerged from the observation that cancer cells expressing a high level of these pumps show an unexpected hypersensitivity, called collateral sensitivity (CS) to a selected subset of chemical compounds. In this review, we target the multidrug resistance protein 1 (MRP1) and after a non-exhaustively highlighting of some of the most exemplary inhibitors of MRP1 and modulators of its expression, we focus on CS agents specifically targeting MRP1 which becomes, when overexpressed, the so called &quot;Achilles&#039; heel&quot; of multidrug resistant cancer cells. We discuss the link between the prominent role of glutathione translocation and related redox balance of the cell and the CS induced by certain types of compounds. The latter are discussed according to their chemical class, and perspectives in their development for successful eradication of resistant cancer are proposed.
authors.affiliation: Drug Resistance and Membrane Proteins, UMR 5086 CNRS/Université Lyon 1, Molecular Microbiology and Structural Biochemistry, IBCP, 7 passage du Vercors, 69367 Lyon. France.
authors.forename: Doriane
authors.initials: D
authors.lastname: Lorendeau
authors.affiliation: Drug Resistance and Membrane Proteins, UMR 5086 CNRS/Université Lyon 1, Molecular Microbiology and Structural Biochemistry, IBCP, 7 passage du Vercors, 69367 Lyon. France.
authors.forename: Lauriane
authors.initials: L
authors.lastname: Dury
authors.affiliation: Drug Resistance and Membrane Proteins, UMR 5086 CNRS/Université Lyon 1, Molecular Microbiology and Structural Biochemistry, IBCP, 7 passage du Vercors, 69367 Lyon. France.
authors.forename: Rachad
authors.initials: R
authors.lastname: Nasr
authors.affiliation: Université Joseph Fourier, Département de Pharmacochimie Moléculaire, UMR-CNRS 5063, ICMG FR-2607, BP 53, 38041, Grenoble Cedex 9. French Guiana.
authors.forename: Ahcene
authors.initials: A
authors.lastname: Boumendjel
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child's Health, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Via Ugo Schiff 6, 50019 Sesto Fiorentino. Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Teodori
authors.affiliation: Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn. Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Gutschow
authors.affiliation: Drug Resistance and Membrane Proteins, UMR 5086 CNRS/Université Lyon 1, Molecular Microbiology and Structural Biochemistry, IBCP, 7 passage du Vercors, 69367 Lyon. France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Falson
authors.affiliation: Drug Resistance and Membrane Proteins, UMR 5086 CNRS/Université Lyon 1, Molecular Microbiology and Structural Biochemistry, IBCP, 7 passage du Vercors, 69367 Lyon. France.
authors.forename: Attilio
authors.initials: A
authors.lastname: Di Pietro
authors.affiliation: Drug Resistance and Membrane Proteins, UMR 5086 CNRS/Université Lyon 1, Molecular Microbiology and Structural Biochemistry, IBCP, 7 passage du Vercors, 69367 Lyon. France.
authors.forename: Helene
authors.initials: H
authors.lastname: Baubichon-Cortay
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005978:Glutathione / Q000172:deficiency* / Q000378:metabolism*; D006801:Humans; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D005978:Glutathione
keywords: ABCC1/MRP1; Quantitative Structure-Activity Relationships; collateral sensitivity; drug design; flavonoids; glutathione; molecular models; multidrug resistance; multidrug resistance protein 1