Peripheral benzodiazepine receptor ligands reverse apoptosis resistance of cancer cells in vitro and in vivo.
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.
Decaudin
Didier
D
Department of Hematology, and UMR 147 CNRS, Section de Recherche, Institut Curie, 75005 Paris, France. didier.decaudin@curie.net
Castedo
Maria
M
Nemati
Fariba
F
Beurdeley-Thomas
Arnaud
A
De Pinieux
Gonzague
G
Caron
Antoine
A
Pouillart
Pierre
P
Wijdenes
John
J
Rouillard
Dany
D
Kroemer
Guido
G
Poupon
Marie-France
MF
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
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