title: MBL-II-141, a chromone derivative, enhances irinotecan (CPT-11) anticancer efficiency in ABCG2-positive xenografts.
abstract: ABCG2 is responsible for the multidrug resistance (MDR) phenotype, and strongly modulates cancer outcomes. Its high expression at a number of physiological barriers, including blood-brain and intestinal barriers, impacts on drug pharmacokinetics parameters. We characterized MBL-II-141, a specific and potent ABCG2 inhibitor. Combination of 10 mg/kg MBL-II-141 with the anticancer agent CPT-11 completely blocked the growth of 90% freshly implanted ABCG2-positive tumors. Moreover, the same combination slowed the growth of already established tumors. As required for preclinical development, we defined the main pharmacokinetics parameters of MBL-II-141 and its influence on the kinetics of CPT-11 and its active metabolite SN-38 in mice. MBL-II-141 distribution into the brain occurred at a low, but detectable, level. Interestingly, preliminary data suggested that MBL-II-141 is well tolerated (at 50 mg/kg) and absorbed upon force-feeding. MBL-II-141 induced a potent sensitization of ABCG2-positive xenografts to CPT-11 through in vivo ABCG2 inhibition. MBL-II-141 strongly increased CPT-11 levels in the brain, and therefore would be a valuable agent to improve drug distribution into the brain to efficiently treat aggressive gliomas. Safety and other pharmacological data strongly support the reglementary preclinical development of MBL-II-141.
authors.affiliation: Institut des Sciences Pharmaceutiques et Biologiques (ISPB), Université Lyon 1, Lyon 69373, France. INSERM UMR-S1052, CNRS UMR 5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon (CRCL), LabEx DEVweCAN, Centre Léon Bérard, Lyon 69373, France. Hospices Civils of Lyon, Laboratoire de Biochimie de Lyon Sud (CBS), Lyon, France.
authors.forename: Léa
authors.initials: L
authors.lastname: Payen
authors.affiliation: Institut des Sciences Pharmaceutiques et Biologiques (ISPB), Université Lyon 1, Lyon 69373, France. INSERM UMR-S1052, CNRS UMR 5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon (CRCL), LabEx DEVweCAN, Centre Léon Bérard, Lyon 69373, France. Equipe labellisée Ligue 2014, BMSSI UMR 5086 CNRS-Université Lyon 1, IBCP, Lyon 69373, France.
authors.forename: Mylène
authors.initials: M
authors.lastname: Honorat
authors.affiliation: Institut des Sciences Pharmaceutiques et Biologiques (ISPB), Université Lyon 1, Lyon 69373, France. EA 3738, Laboratoire de Ciblage Thérapeutique en Cancérologie, Centre Hospitalier Lyon-Sud, Pierre Bénite, France. Hospices Civils of Lyon, Laboratoire de Biochimie de Lyon Sud (CBS), Lyon, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Guitton
authors.affiliation: Equipe labellisée Ligue 2014, BMSSI UMR 5086 CNRS-Université Lyon 1, IBCP, Lyon 69373, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Gauthier
authors.affiliation: INSERM UMR-S1052, CNRS UMR 5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon (CRCL), LabEx DEVweCAN, Centre Léon Bérard, Lyon 69373, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Bouard
authors.affiliation: Univ. Grenoble Alpes/CNRS, DPM UMR 5063, F-38041 Grenoble, France.
authors.forename: Florine
authors.initials: F
authors.lastname: Lecerf-Schmidt
authors.affiliation: Univ. Grenoble Alpes/CNRS, DPM UMR 5063, F-38041 Grenoble, France.
authors.forename: Basile
authors.initials: B
authors.lastname: Peres
authors.affiliation: Institut des Sciences Pharmaceutiques et Biologiques (ISPB), Université Lyon 1, Lyon 69373, France. Equipe labellisée Ligue 2014, BMSSI UMR 5086 CNRS-Université Lyon 1, IBCP, Lyon 69373, France.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Terreux
authors.affiliation: INSERM UMR-S1052, CNRS UMR 5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon (CRCL), LabEx DEVweCAN, Centre Léon Bérard, Lyon 69373, France.
authors.forename: Héloïse
authors.initials: H
authors.lastname: Gervot
authors.affiliation: Hospices Civils of Lyon, Laboratoire de Biochimie de Lyon Sud (CBS), Lyon, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Rioufol
authors.affiliation: Univ. Grenoble Alpes/CNRS, DPM UMR 5063, F-38041 Grenoble, France.
authors.forename: Ahcène
authors.initials: A
authors.lastname: Boumendjel
authors.affiliation: INSERM UMR-S1052, CNRS UMR 5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon (CRCL), LabEx DEVweCAN, Centre Léon Bérard, Lyon 69373, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Puisieux
authors.affiliation: Equipe labellisée Ligue 2014, BMSSI UMR 5086 CNRS-Université Lyon 1, IBCP, Lyon 69373, France.
authors.forename: Attilio
authors.initials: A
authors.lastname: Di Pietro
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D002867:Chromones / Q000493:pharmacokinetics / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D000077146:Irinotecan; D013058:Mass Spectrometry; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: C571193:5-(4-bromobenzyloxy)-2-(2-(5-methoxyindolyl)ethyl-1-carbonyl)-4H-chromen-4-one; C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D002867:Chromones; D007211:Indoles; D009363:Neoplasm Proteins; D000077146:Irinotecan; D002166:Camptothecin