Mechanisms of mitochondrial apoptosis induced by peripheral benzodiazepine receptor ligands in human colorectal cancer cells.
Specific ligands of the peripheral benzodiazepine receptor (PBR) have been shown to induce apoptosis in gastrointestinal cancers. The aim of this study was to characterize the signaling pathways of PBR ligand-induced apoptosis. FGIN-1-27 but not PK 11195-induced apoptosis was associated with a decrease of mitochondrial membrane potential and an increase of mitochondrial volume in HT29 colorectal cancer cells. However, PK 11195-elicited apoptosis was associated with a downregulation of Bcl-2, translocation of Bax to the mitochondria including subsequent oligomerization, and activation of caspase-9, indicating the involvement of mitochondria in PK 11195-induced apoptosis. Moreover, PK 11195-induced apoptosis was associated with the generation of reactive oxygen species. This study demonstrates a novel mechanism of PK 11195-induced mitochondrial apoptosis without alteration of the mitochondrial membrane potential. The characterization of signaling pathways associated with PBR ligand-induced apoptosis will build the base for a future use of these ligands in anti-neoplastic therapeutic approaches.
Maaser
Kerstin
K
Medical Clinic I, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, 12200 Berlin, Germany.
Sutter
Andreas P
AP
Scherübl
Hans
H
D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007210:Indoleacetic Acids / Q000378:metabolism / Q000494:pharmacology; D007546:Isoquinolines / Q000378:metabolism / Q000494:pharmacology; D008024:Ligands; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051028:bcl-2-Associated X Protein
D000970:Antineoplastic Agents; C494826:BAX protein, human; D007210:Indoleacetic Acids; D007546:Isoquinolines; D008024:Ligands; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D011963:Receptors, GABA-A; D051028:bcl-2-Associated X Protein; C081306:N,N-di-n-hexyl-2-(4-fluorophenyl)indole-3-acetamide; C506433:CASP9 protein, human; D053453:Caspase 9; D020169:Caspases; C037850:PK 11195