Specific ligands of the peripheral benzodiazepine receptor induce apoptosis and cell cycle arrest in human esophageal cancer cells.
Esophageal cancer is the most markedly increasing tumor entity in Western countries. Due to very poor 5-year-survival, new therapeutic approaches are mandatory. Peripheral benzodiazepine receptors (PBR) have been implicated in growth control of various tumor models, but they have not been studied yet in esophageal cancer. We used esophageal cancer cell lines and primary cell cultures of human esophageal cancers and evaluated (i) expression and localization of PBR; (ii) PBR-ligand-induced inhibition of cell growth; (iii) induction of apoptosis; and (iv) alterations in cell cycle. Expression of PBR was detected both in cell lines and in primary cell cultures of human esophageal cancers. PBR was localized in the mitochondria. The PBR-specific ligands FGIN-1-27 and PK 11195, but not the centrally acting benzodiazepine clonazepam or the indolacetamide FGIN-1-52, neither of which displaying any affinity to the PBR, inhibited cell proliferation. FGIN-1-27 and PK 11195, but not clonazepam, potently induced apoptosis. FGIN-1-27 was shown to sequentially decrease the mitochondrial membrane potential, then to activate caspase-3 and finally to cause DNA fragmentation. In addition, PBR-specific ligands induced cell cycle arrest in the G1/G0 phase. Our data qualify PBR-specific ligands as innovative proapoptotic and antiproliferative substances. They might prove suitable for the treatment of esophageal cancer.
Sutter
Andreas P
AP
Medical Clinic I, Benjamin Franklin University Hospital, Free University of Berlin, Berlin, Germany.
Maaser
Kerstin
K
Höpfner
Michael
M
Barthel
Bettina
B
Grabowski
Patricia
P
Faiss
Siegbert
S
Carayon
Pierre
P
Zeitz
Martin
M
Scherübl
Hans
H
D000368:Aged; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002998:Clonazepam / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000473:pathology*; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007210:Indoleacetic Acids / Q000378:metabolism / Q000494:pharmacology; D007546:Isoquinolines / Q000378:metabolism / Q000494:pharmacology; D008024:Ligands; D008297:Male; D008875:Middle Aged; D011963:Receptors, GABA-A / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D007210:Indoleacetic Acids; D007546:Isoquinolines; D008024:Ligands; D011963:Receptors, GABA-A; C081306:N,N-di-n-hexyl-2-(4-fluorophenyl)indole-3-acetamide; D002998:Clonazepam; D020169:Caspases; C037850:PK 11195