title: The acridone derivative MBLI-87 sensitizes breast cancer resistance protein-expressing xenografts to irinotecan.
abstract: The breast cancer resistance protein ABCG2 confers cellular resistance to irinotecan (CPT-11) and its active metabolite SN-38. We utilised ABCG2-expressing xenografts as a model to evaluate the ability of a non-toxic ABCG2 inhibitor to increase intracellular drug accumulation. We assessed the activity of irinotecan in vivo in SCID mice: irinotecan completely inhibited the development of control pcDNA3.1 xenografts, whilst only delaying the growth of ABCG2-expressing xenografts. Addition of MBLI-87, an acridone derivative inhibitor, significantly increased the irinotecan effect against the growth of ABCG2-expressing xenografts. In vitro, MBLI-87 was as potent as GF120918 against ABCG2-mediated irinotecan efflux, and additionally was specific for ABCG2. A significant sensitisation to irinotecan was achieved despite the fact that doses remained well below the maximum tolerated dose (due to the rather limited solubility of MBLI-87). This suggested that MBLI-87 is an excellent candidate to prevent drug efflux by ABCG2, without altering plasma concentrations of irinotecan and SN-38 after IP (intra-peritoneal) injections. This could constitute a useful strategy to improve drug pharmacology, to facilitate drug penetration into normal tissue compartments protected by ABCG2, and potentially to reverse drug resistance in cancer cells.
authors.affiliation: Equipe labellisée Ligue 2009, Institut de Biologie et Chimie des Protéines, UMR 5086 CNRS/Université Lyon 1, IFR 128 BioSciences Gerland-Lyon Sud, Lyon Cedex 07, France.
authors.forename: O
authors.initials: O
authors.lastname: Arnaud
authors.forename: A
authors.initials: A
authors.lastname: Boumendjel
authors.forename: A
authors.initials: A
authors.lastname: Gèze
authors.forename: M
authors.initials: M
authors.lastname: Honorat
authors.forename: E L
authors.initials: EL
authors.lastname: Matera
authors.forename: J
authors.initials: J
authors.lastname: Guitton
authors.forename: W D
authors.initials: WD
authors.lastname: Stein
authors.forename: S E
authors.initials: SE
authors.lastname: Bates
authors.forename: P
authors.initials: P
authors.lastname: Falson
authors.forename: C
authors.initials: C
authors.lastname: Dumontet
authors.forename: A
authors.initials: A
authors.lastname: Di Pietro
authors.forename: L
authors.initials: L
authors.lastname: Payen
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000166:Acridines / Q000494:pharmacology*; D054831:Acridones / Q000494:pharmacology; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009368:Neoplasm Transplantation; D014183:Transplantation, Heterologous
chemical_list: C559426:9-oxo-9,10-dihydroacridine-4-carboxylic acid 3,4-dimethoxyphenethyl amide; C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000166:Acridines; D054831:Acridones; D000972:Antineoplastic Agents, Phytogenic; D009363:Neoplasm Proteins; C041300:acridone; D000077146:Irinotecan; D002166:Camptothecin