title: Peripheral benzodiazepine receptor (PBR) ligand cytotoxicity unrelated to PBR expression.
abstract: Some synthetic ligands of the peripheral-type benzodiazepine receptor (PBR), an 18 kDa protein of the outer mitochondrial membrane, are cytotoxic for several tumor cell lines and arise as promising chemotherapeutic candidates. However, conflicting results were reported regarding the actual effect of these drugs on cellular survival ranging from protection to toxicity. Moreover, the concentrations needed to observe such a toxicity were usually high, far above the affinity range for their receptor, hence questioning its specificity. In the present study, we have shown that micromolar concentrations of FGIN-1-27 and Ro 5-4864, two chemically unrelated PBR ligands are toxic for both PBR-expressing SK-N-BE neuroblastoma cells and PBR-deficient Jurkat lymphoma cells. We have thereby demonstrated that the cytotoxicity of these drugs is unrelated to their PBR-binding activity. Moreover, Ro 5-4864-induced cell death differed strikingly between both cell types, being apoptotic in Jurkat cells while necrotic in SK-N-BE cells. Again, this did not seem to be related to PBR expression since Ro 5-4864-induced death of PBR-transfected Jurkat cells remained apoptotic. Taken together, our results show that PBR is unlikely to mediate all the effects of these PBR ligands. They however confirm that some of these ligands are very effective cytotoxic drugs towards various cancer cells, even for reputed chemoresistant tumors such as neuroblastoma, and, surprisingly, also for PBR-lacking tumor cells.
authors.affiliation: Centre of Cellular and Molecular Neurobiology, Université de Liège, 17 Place Delcour, 4020 Liège 2, Belgium. G.hans@teledisnet.be
authors.forename: Gregory
authors.initials: G
authors.lastname: Hans
authors.forename: Sabine
authors.initials: S
authors.lastname: Wislet-Gendebien
authors.forename: François
authors.initials: F
authors.lastname: Lallemend
authors.forename: Pierre
authors.initials: P
authors.lastname: Robe
authors.forename: Bernard
authors.initials: B
authors.lastname: Rogister
authors.forename: Shibeshih
authors.initials: S
authors.lastname: Belachew
authors.forename: Laurent
authors.initials: L
authors.lastname: Nguyen
authors.forename: Brigitte
authors.initials: B
authors.lastname: Malgrange
authors.forename: Gustave
authors.initials: G
authors.lastname: Moonen
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Rigo
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001570:Benzodiazepinones / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D007210:Indoleacetic Acids / Q000494:pharmacology*; D019169:Jurkat Cells; D008024:Ligands; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D009336:Necrosis; D009447:Neuroblastoma / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000502:physiology*
chemical_list: D001570:Benzodiazepinones; D007210:Indoleacetic Acids; D008024:Ligands; D009842:Oligopeptides; D011963:Receptors, GABA-A; C403754:benzyloxycarbonyl-leucyl-glutamyl-histidyl-aspartic acid fluoromethyl ketone; C081306:N,N-di-n-hexyl-2-(4-fluorophenyl)indole-3-acetamide; C028513:4'-chlorodiazepam