| R(+)-methanandamide elicits a cyclooxygenase-2-dependent mitochondrial apoptosis signaling pathway in human neuroglioma cells. | |
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MedLine Citation:
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PMID: 16267630 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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PURPOSE: Cannabinoids have been associated with tumor regression and apoptosis of cancer cells. Recently, we have shown that R(+)-methanandamide (R(+)-MA) induces apoptosis of H4 human neuroglioma cells via a mechanism involving de novo expression of the cyclooxygenase-2 (COX-2) enzyme. The present study investigated a possible involvement of a mitochondrial-driven pathway in this process. METHODS: Cell death was determined by the WST-1 cell viability test, and changes in apoptotic parameters [i.e., release of mitochondrial cytochrome c, activation of caspases, cleavage of poly(ADP-ribose) polymerase (PARP)] were detected by Western blotting. RESULTS: H4 cells treated with R(+)-MA showed typical signs of mitochondrial apoptosis, i.e., release of mitochondrial cytochrome c into the cytosol and activation of initiator caspase-9. Moreover, activation of the executor caspase-3 was observed following cannabinoid treatment. Cells were fully protected from apoptotic cell death by the caspase-3 inhibitor Ac-DEVD-CHO, indicating a crucial role for caspase-3 activation in R(+)-MA-elicited apoptosis. Furthermore, cleavage of the caspase-3 target protein PARP was registered. All of the aforementioned effects were substantially reduced by the selective COX-2 inhibitor celecoxib (1 muM) at a pharmacologically relevant, nonapoptotic concentration. CONCLUSION: R(+)-MA-induced apoptosis is mediated via a mitochondrial-dependent pathway that becomes activated, at least in part, through up-regulation of the COX-2 enzyme. |
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Authors:
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Karin Eichele; Ulrike Weinzierl; Robert Ramer; Kay Brune; Burkhard Hinz |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2006-11-08 |
Journal Detail:
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Title: Pharmaceutical research Volume: 23 ISSN: 0724-8741 ISO Abbreviation: Pharm. Res. Publication Date: 2006 Jan |
Date Detail:
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Created Date: 2006-02-09 Completed Date: 2006-04-24 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 8406521 Medline TA: Pharm Res Country: United States |
Other Details:
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Languages: eng Pagination: 90-4 Citation Subset: IM |
Affiliation:
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Department of Experimental and Clinical Pharmacology and Toxicology, Friedrich Alexander University Erlangen-Nürnberg, Fahrstrasse 17, D-91054, Erlangen, Germany. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis / drug effects* Arachidonic Acids / pharmacology* Blotting, Western Brain Neoplasms / pathology* CHO Cells Caspase 3 Caspase 9 Caspases / metabolism Cell Survival / drug effects Cricetinae Cyclooxygenase 2 / metabolism* Cyclooxygenase 2 Inhibitors / pharmacology Cytochromes c / metabolism Glioma / pathology* Humans Mitochondria / drug effects* Poly(ADP-ribose) Polymerases / metabolism Pyrazoles / pharmacology Signal Transduction / drug effects* Sulfonamides / pharmacology |
| Chemical | |
Reg. No./Substance:
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0/Arachidonic Acids; 0/Cyclooxygenase 2 Inhibitors; 0/Pyrazoles; 0/Sulfonamides; 150314-39-9/methanandamide; 169590-42-5/celecoxib; 9007-43-6/Cytochromes c; EC 1.14.99.1/Cyclooxygenase 2; EC 2.4.2.30/Poly(ADP-ribose) Polymerases; EC 3.4.22.-/CASP3 protein, human; EC 3.4.22.-/CASP9 protein, human; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspase 9; EC 3.4.22.-/Caspases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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