title: Ligands of the mitochondrial 18 kDa translocator protein attenuate apoptosis of human glioblastoma cells exposed to erucylphosphohomocholine.
abstract: BACKGROUND
  We have previously shown that the anti-neoplastic agent erucylphosphohomocholine (ErPC3) requires the mitochondrial 18 kDa Translocator protein (TSPO), formerly known as the peripheral-type benzodiazepine receptor (PBR), to induce cell death via the mitochondrial apoptosis pathway.
  
  
  METHODS
  With the aid of the dye JC-1 and cyclosporin A, applied to glioblastoma cells, we now investigated the significance of opening of the mitochondrial permeability transition pore (MPTP) for ErPC3-induced apoptosis in interaction with the TSPO ligands, PK 11195 and Ro5 4864. Furthermore, we measured cytochrome c release, and caspase-9 and -3 activation in this paradigm.
  
  
  RESULTS
  The human glioblastoma cell lines, U87MG, A172 and U118MG express the MPTP-associated TSPO, voltage-dependent anion channel and adenine nucleotide transporter. Indeed, ErPC3-induced apoptosis was inhibited by the MPTP blocker cyclosporin A and by PK 11195 and Ro5 4864 in a concentration-dependent manner. Furthermore, PK 11195 and Ro5 4864 inhibited collapse of the mitochondrial membrane potential, cytochrome c release, and caspase-9 and -3 activation caused by ErPC3 treatment.
  
  
  CONCLUSIONS
  This study shows that PK 11195 and Ro5 4864 inhibit the pro-apoptotic function of ErPC3 by blocking its capacity to cause a collapse of the mitochondrial membrane potential. Thus, the TSPO may serve to open the MPTP in response to anti-cancer drugs such as ErPC3.
authors.affiliation: Abteilung Pädiatrie I, Zentrum Kinderheilkunde und Jugendmedizin, Universitätsklinikum Göttingen, D-37075 Göttingen, Germany.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Kugler
authors.forename: Leo
authors.initials: L
authors.lastname: Veenman
authors.forename: Yulia
authors.initials: Y
authors.lastname: Shandalov
authors.forename: Svetlana
authors.initials: S
authors.lastname: Leschiner
authors.forename: Ilana
authors.initials: I
authors.lastname: Spanier
authors.forename: Max
authors.initials: M
authors.lastname: Lakomek
authors.forename: Moshe
authors.initials: M
authors.lastname: Gavish
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001570:Benzodiazepinones / Q000494:pharmacology; D015153:Blotting, Western; D020169:Caspases / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D045304:Cytochromes c / Q000187:drug effects; D004883:Erucic Acids / Q000494:pharmacology*; D005909:Glioblastoma / Q000378:metabolism*; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D008024:Ligands; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology; D018079:Receptors, GABA / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D001570:Benzodiazepinones; D004883:Erucic Acids; D007546:Isoquinolines; D008024:Ligands; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D018079:Receptors, GABA; C499229:TSPO protein, human; C518520:erucylphosphohomocholine ErPC3; D010767:Phosphorylcholine; C028513:4'-chlorodiazepam; D045304:Cytochromes c; D020169:Caspases; C037850:PK 11195