title: PK11195 potently sensitizes to apoptosis induction independently from the peripheral benzodiazepin receptor.
abstract: 1-(2-Chlorophenyl-N-methylpropyl)-3-isoquinolinecarboxamide (PK11195) is a prototypic ligand of the peripheral benzodiazepine receptor (PBR), a mitochondrial outer membrane protein. PK11195 can be used to chemosensitize tumor cells to a variety of chemotherapeutic agents, both in vitro and in vivo. PK11195 has been suggested to exert this effect via inhibition of the multiple drug resistance (MDR) pump and by direct mitochondrial effects which could be mediated by the PBR. Here, we established a model system in which PK11195 and another PBR ligand, 7-chloro-5-(4-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (Ro5-4864), sensitize to nutrient depletion-induced cell death. In this MDR-independent model, PK11195 and Ro5-4864 are fully active even when the PBR is knocked down by small interfering RNA. Cells that lack PBR possess low-affinity binding sites for PK11195 and Ro5-4864. The starvation-sensitizing effects of PK11195 are not due to a modulation of the adaptive response of starved cells, namely autophagy and NF-kappaB activation. Rather, it appears that the combination of PK11195 with autophagy or NF-kappaB inhibitors has a potent synergistic death-inducing effect. Starved cells treated with PK11195 exhibit characteristics of apoptosis, including loss of the mitochondrial transmembrane potential, mitochondrial cytochrome c release, caspase activation and chromatin condensation. Accordingly, stabilization of mitochondria by overexpression of Bcl-2 or expression of the viral mitochondrial inhibitor (vMIA) from cytomegalovirus inhibits cell death induced by PK11195 plus starvation. Thus, PK11195 potently sensitizes to apoptosis via a pathway that involves mitochondria, yet does not involve the PBR.
authors.affiliation: 1Centre National de la Recherche Scientifique, UMR8125, Institut Gustave Roussy, Pavillon de Recherche 1, 39 rue Camille-Desmoulins, 94805 Villejuif, France.
authors.forename: Rosa-Ana
authors.initials: RA
authors.lastname: Gonzalez-Polo
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Carvalho
authors.forename: Thorsten
authors.initials: T
authors.lastname: Braun
authors.forename: Didier
authors.initials: D
authors.lastname: Decaudin
authors.forename: Claire
authors.initials: C
authors.lastname: Fabre
authors.forename: Nathanael
authors.initials: N
authors.lastname: Larochette
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Perfettini
authors.forename: Mojgan
authors.initials: M
authors.lastname: Djavaheri-Mergny
authors.forename: Ibtissam
authors.initials: I
authors.lastname: Youlyouz-Marfak
authors.forename: Patrice
authors.initials: P
authors.lastname: Codogno
authors.forename: Martine
authors.initials: M
authors.lastname: Raphael
authors.forename: Jean
authors.initials: J
authors.lastname: Feuillard
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001570:Benzodiazepinones / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology*; D008024:Ligands; D008564:Membrane Potentials; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D034741:RNA, Small Interfering; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000502:physiology
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D001570:Benzodiazepinones; D002843:Chromatin; D000960:Hypolipidemic Agents; D007546:Isoquinolines; D008024:Ligands; D016328:NF-kappa B; D034741:RNA, Small Interfering; D011963:Receptors, GABA-A; C028513:4'-chlorodiazepam; D045304:Cytochromes c; D020169:Caspases; C037850:PK 11195