| Apoptotic cell death induction by F 11782 a novel dual catalytic inhibitor of topoisomerases I and II. | |
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MedLine Citation:
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PMID: 12628489 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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F 11782 (2",3"-bis-pentafluorophenoxyacetyl-4",6"ethylidene-beta-D-glucoside of 4'-phosphate-4'-dimethylepipodophyllotoxin-2N-methyl glucamine salt), is a novel dual catalytic inhibitor of topoisomerases I and II characterised by marked in vivo antitumour activity, which also proved cytotoxic and exhibited DNA damaging properties in vitro. Mechanisms associated with this cell killing by F 11782 have been examined in P388 leukaemia cells. Treatment with F 11782 resulted in a dose-dependent DNA fragmentation coupled with the characteristic morphological features of apoptosis. Apoptosis-inducing concentrations of F 11782 induced caspases-3/7 activation accompanied by proteolytic cleavage of poly(ADP-ribose)-polymerase, which could be inhibited by the caspase inhibitor acetyl-Asp-Glu-Val-Asp-aldehyde. In addition, F 11782-induced apoptosis in P388 cells was associated with an increased expression of the pro-apototic Bax protein, without significant changes in the level of the anti-apoptotic Bcl-2 protein, and with modification at the mitochondrial membrane function. These results indicate that F 11782 leads to apoptosis through a caspase-3/7 dependent mechanism and suggest that the so-called "mitochondrial pathway" is implicated in F 11782-induced apoptosis in P388 cells. |
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Authors:
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Chantal Etiévant; Anna Kruczynski; Jean-Marc Barret; Dominique Perrin; Bridget T Hill |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Biochemical pharmacology Volume: 65 ISSN: 0006-2952 ISO Abbreviation: Biochem. Pharmacol. Publication Date: 2003 Mar |
Date Detail:
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Created Date: 2003-03-11 Completed Date: 2003-03-18 Revised Date: 2005-11-17 |
Medline Journal Info:
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Nlm Unique ID: 0101032 Medline TA: Biochem Pharmacol Country: England |
Other Details:
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Languages: eng Pagination: 755-63 Citation Subset: IM |
Affiliation:
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Division de Cancérologie Expérimentale I, Centre de Recherche Pierre Fabre, 17 Avenue Jean Moulin, F-81106 Castres Cedex 06, France. chantal.etievant@pierre-fabre.com |
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis* Caspases / metabolism Catalytic Domain Cell Cycle / drug effects Cell Division / drug effects Cell Size / drug effects DNA Fragmentation / drug effects DNA Topoisomerases, Type I / antagonists & inhibitors* DNA Topoisomerases, Type II / antagonists & inhibitors* Gene Expression / drug effects Leukemia P388 / pathology Membrane Potentials / drug effects Mice Mitochondria / drug effects, physiology Naphthalenes / pharmacology* Poly(ADP-ribose) Polymerases / metabolism Proto-Oncogene Proteins / biosynthesis Proto-Oncogene Proteins c-bcl-2 / biosynthesis Pyrans / pharmacology* Tumor Cells, Cultured bcl-2-Associated X Protein |
| Chemical | |
Reg. No./Substance:
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0/Bax protein, mouse; 0/F 11782; 0/Naphthalenes; 0/Proto-Oncogene Proteins; 0/Proto-Oncogene Proteins c-bcl-2; 0/Pyrans; 0/bcl-2-Associated X Protein; EC 2.4.2.30/Poly(ADP-ribose) Polymerases; EC 3.4.22.-/Caspases; EC 5.99.1.2/DNA Topoisomerases, Type I; EC 5.99.1.3/DNA Topoisomerases, Type II |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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