Document Detail


Biphosphinic palladacycle complex mediates lysosomal-membrane permeabilization and cell death in K562 leukaemia cells.
MedLine Citation:
PMID:  16831419     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-06-10
Journal Detail:
Title:  European journal of pharmacology     Volume:  542     ISSN:  0014-2999     ISO Abbreviation:  Eur. J. Pharmacol.     Publication Date:  2006 Aug 
Date Detail:
Created Date:  2006-07-24     Completed Date:  2006-12-14     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  1254354     Medline TA:  Eur J Pharmacol     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  37-47     Citation Subset:  IM    
Affiliation:
Centro Interdisciplinar de Investigação Bioquímica, Universidade de Mogi das Cruzes, Mogi das Cruzes, SP, Brazil.
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MeSH Terms
Descriptor/Qualifier:
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:
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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