| Sanguinarine-induced apoptosis is associated with an early and severe cellular glutathione depletion. | |
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MedLine Citation:
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PMID: 12700925 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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PURPOSE: The quaternary benzophenanthridine alkaloid sanguinarine exhibits a broad range of activity, including cytotoxicity against various human tumour and normal cell lines. Here, we examined its potency as an anticancer drug. METHODS: The differential cytotoxicity against cancer versus normal cells was assessed in vitro by two fluorimetric assays (RRT and Hoechst 33342 dye DNA assays, respectively) in a panel of human solid cancer cell lines and a human fibroblast primary culture. The ability to induce apoptosis was demonstrated in PC3 human prostatic adenocarcinoma cells by analysis of morphological changes, internucleosomal DNA fragmentation, cellular poly(ADP-ribose) polymerase cleavage and caspase 3/7 activation. Production of reactive oxygen species was evaluated by the 2',7'-dichlorofluorescin diacetate assay. Depletion of cellular glutathione content was assessed with the monochlorobimane assay. RESULTS: Sanguinarine markedly inhibited the growth of all tested cells (IC(50) 0.9-3.3 microM) without differential cytotoxicity against normal versus cancer cells. In PC3 cells, continuous treatment with 5 microM sanguinarine induced an early (within 10 min) cellular reduced glutathione depletion insensitive to dithiothreitol or N-acetylcysteine treatment, followed by a caspase 3/7-dependent apoptotic response within 2 h. Complementary assays suggested that the glutathione depletion was initiated by direct reactivity of sanguinarine with reduced glutathione. CONCLUSIONS: Taken together, these results show that (1) sanguinarine exhibits no specificity for cancer cells, and (2) its strong cytotoxicity is probably due to a rapid apoptotic response induced by an early and severe glutathione-depleting effect. They also suggest that the clinical usefulness of this alkaloid as an anticancer drug is limited. |
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Authors:
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Eric Debiton; Jean-Claude Madelmont; Jean Legault; Chantal Barthomeuf |
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Publication Detail:
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Type: Journal Article Date: 2003-04-17 |
Journal Detail:
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Title: Cancer chemotherapy and pharmacology Volume: 51 ISSN: 0344-5704 ISO Abbreviation: Cancer Chemother. Pharmacol. Publication Date: 2003 Jun |
Date Detail:
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Created Date: 2003-06-12 Completed Date: 2003-07-29 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 7806519 Medline TA: Cancer Chemother Pharmacol Country: Germany |
Other Details:
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Languages: eng Pagination: 474-82 Citation Subset: IM |
Affiliation:
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UMR-INSERM U-484, Rue Montalembert, BP 184, 63005, Clermont-Ferrand, France. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Alkaloids
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pharmacology* Antineoplastic Agents, Phytogenic / pharmacology* Apoptosis / drug effects* Benzimidazoles Benzophenanthridines Caspase 3 Caspase 7 Caspases / metabolism Cell Division / drug effects Cell Survival / drug effects Cells, Cultured DNA Fragmentation Electrophoresis, Agar Gel Glutathione / physiology* Humans Indicators and Reagents Isoquinolines Neoplasms / pathology Oxazines / chemistry Reactive Oxygen Species / metabolism Tumor Cells, Cultured Xanthenes* |
| Chemical | |
Reg. No./Substance:
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0/Alkaloids; 0/Antineoplastic Agents, Phytogenic; 0/Benzimidazoles; 0/Benzophenanthridines; 0/Indicators and Reagents; 0/Isoquinolines; 0/Oxazines; 0/Reactive Oxygen Species; 0/Xanthenes; 23491-52-3/HOE 33342; 2447-54-3/sanguinarine; 550-82-3/resazurin; 70-18-8/Glutathione; EC 3.4.22.-/CASP3 protein, human; EC 3.4.22.-/CASP7 protein, human; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspase 7; EC 3.4.22.-/Caspases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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