title: Peripheral benzodiazepine receptor ligands reverse apoptosis resistance of cancer cells in vitro and in vivo.
abstract: The mitochondrial peripheral benzodiazepine receptor (mPBR) is involved in a functional structure designated as the permeability transition pore, which controls apoptosis. Binding of Fas/APO-1/CD95 triggers a prototypic apoptosis-inducing pathway. Using four different human tumor cell lines (T-cell Jurkat, neuroblastoma SHEP, osteosarcoma 143N2, and glioblastoma SNB79 cell lines), all of which express CD95 and mPBR, we investigated the potential role of mPBR ligands in CD95-induced apoptosis. We show that, in vitro, the three mPBR ligands tested (RO5-4864, PK11195, and diazepam) enhanced apoptosis induced by anti-CD95 antibody in Jurkat cells, as demonstrated by mitochondrial transmembrane potential drop and DNA fragmentation. In contrast, RO5-4864, but not PK11195 or diazepam, enhanced anti-CD95 apoptosis in all other cell lines. These effects were obtained in Bcl-2-overexpressing SHEP cell lines, but not in Bcl-X(L) SHEP cell lines. Enhancement of anti-CD95 antibody-induced apoptosis by RO5-4864 was characterized by an increased mitochondrial release of cytochrome c and Smac/DIABLO proteins and an enhanced activation of caspases 9 and 3, suggesting a mitochondrion-dependent mechanism. Preincubation of cells with the different mPBR ligands or anti-CD95 did not affect the levels of expression of either mPBR or CD95. In vivo, we found that the RO5-4864 mPBR ligand significantly increased the growth inhibition induced by two chemotherapeutic agents, etoposide and ifosfamide, using two human small cell lung cancers xenografted into nude mice. Peripheral benzodiazepine receptor ligands may therefore act as chemosensitizing agents for the treatment of human neoplasms.
authors.affiliation: Department of Hematology, and UMR 147 CNRS, Section de Recherche, Institut Curie, 75005 Paris, France. didier.decaudin@curie.net
authors.forename: Didier
authors.initials: D
authors.lastname: Decaudin
authors.forename: Maria
authors.initials: M
authors.lastname: Castedo
authors.forename: Fariba
authors.initials: F
authors.lastname: Nemati
authors.forename: Arnaud
authors.initials: A
authors.lastname: Beurdeley-Thomas
authors.forename: Gonzague
authors.initials: G
authors.lastname: De Pinieux
authors.forename: Antoine
authors.initials: A
authors.lastname: Caron
authors.forename: Pierre
authors.initials: P
authors.lastname: Pouillart
authors.forename: John
authors.initials: J
authors.lastname: Wijdenes
authors.forename: Dany
authors.initials: D
authors.lastname: Rouillard
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Poupon
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001426:Bacterial Proteins; D001570:Benzodiazepinones / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D019169:Jurkat Cells; D008024:Ligands; D008928:Mitochondria / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D011963:Receptors, GABA-A / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology; D019014:fas Receptor / Q000032:analysis / Q000502:physiology
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D001426:Bacterial Proteins; D001570:Benzodiazepinones; C414536:FasR protein, Rhodococcus fascians; D007546:Isoquinolines; D008024:Ligands; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D014157:Transcription Factors; D019014:fas Receptor; C028513:4'-chlorodiazepam; C037850:PK 11195