| Biphosphinic palladacycle complex mediates lysosomal-membrane permeabilization and cell death in K562 leukaemia cells. | |
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MedLine Citation:
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PMID: 16831419 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The cell death mechanism of cytotoxicity induced by the Biphosphinic Palladacycle Complex (BPC) was studied using a K562 leukaemia cell line. The IC50 values obtained for K562 cells post-72 h of BPC were less than 5.0 microM by using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) and trypan blue assays. Using the Acridine Orange vital staining combining fluorescence microscopy it was observed that the complex triggers apoptosis in K562 cells, inducing DNA fragmentation, as analysed through electrophoresis. Lysosomal-membrane permeabilization was also observed in K562 cells post-5 h of BPC, which suggests intralysosomal accumulation by proton-trapping, since its pKa value ranged from 5.1 to 6.5. Caspase-3, and -6 activity induced by BPC in K562 cells was prevented by the cathepsin-B inhibitor [N-(L-3-trans-propylcarbamoyl-oxirane-2-carbonyl)-L-isoleucyl-L-proline] (CA074). These events occurred in the presence of endogenous bcl-2 and bax expression. Acute toxicological studies demonstrated that BPC produces no lesions for liver and kidney fourteen-days after drug administration (100 mg/kg--i.p.). White and red blood cells of BPC-treated mice presented normal morphological characteristics. Taken together, these data suggest a novel lysosomal pathway for BPC-induced apoptosis, in which lysosomes are the primary target and cathepsin B acts as death mediator. |
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Authors:
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Christiano M V Barbosa; Carlos R Oliveira; Fábio D Nascimento; Mickaela C M Smith; Daniela M Fausto; Marco Antonio Soufen; Eliana Sena; Ronaldo C Araújo; Ivarne L S Tersariol; Claudia Bincoletto; Antonio C F Caires |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2006-06-10 |
Journal Detail:
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Title: European journal of pharmacology Volume: 542 ISSN: 0014-2999 ISO Abbreviation: Eur. J. Pharmacol. Publication Date: 2006 Aug |
Date Detail:
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Created Date: 2006-07-24 Completed Date: 2006-12-14 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 1254354 Medline TA: Eur J Pharmacol Country: Netherlands |
Other Details:
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Languages: eng Pagination: 37-47 Citation Subset: IM |
Affiliation:
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Centro Interdisciplinar de Investigação Bioquímica, Universidade de Mogi das Cruzes, Mogi das Cruzes, SP, Brazil. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis / drug effects* Caspase 3 / metabolism Caspase 6 / metabolism Cell Survival / drug effects Dose-Response Relationship, Drug Enzyme Activation / drug effects Gene Expression / genetics Humans Hydrogen-Ion Concentration Intracellular Membranes / metabolism* K562 Cells Kidney / drug effects, pathology Leukemia / genetics, metabolism, pathology Liver / drug effects, pathology Lysosomes / metabolism* Mice Microscopy, Confocal Organometallic Compounds / chemistry, pharmacology*, toxicity Palladium / chemistry Permeability / drug effects Phosphonic Acids / chemistry Proto-Oncogene Proteins c-bcl-2 / genetics Spectrophotometry, Infrared bcl-2-Associated X Protein / genetics |
| Chemical | |
Reg. No./Substance:
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0/2-sulfonato-1,1-ethylidene bisphosphonic acid; 0/Organometallic Compounds; 0/Phosphonic Acids; 0/Proto-Oncogene Proteins c-bcl-2; 0/bcl-2-Associated X Protein; 7440-05-3/Palladium; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspase 6 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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