Biphosphinic palladacycle complex mediates lysosomal-membrane permeabilization and cell death in K562 leukaemia cells

Biphosphinic palladacycle complex mediates lysosomal-membrane permeabilization and cell death in K562 leukaemia cells

Author Barbosa, Christiano M. V. Google Scholar
Oliveira, Carlos R. Google Scholar
Nascimento, Fabio D. Google Scholar
Smith, Mickaela C. M. Google Scholar
Fausto, Damela M. Google Scholar
Soufen, Marco Antonio Google Scholar
Sena, Eliana Google Scholar
Araujo, Ronaldo C. Google Scholar
Tersariol, Ivarne L. S. Google Scholar
Bincoletto, Claudia Google Scholar
Caires, Antonio C. F. Google Scholar
Institution UMC
Universidade de São Paulo (USP)
Universidade Federal de São Paulo (UNIFESP)
Universidade Estadual de Campinas (UNICAMP)
Abstract 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 mu M 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 intralysossomal accumulation by proton-trapping, since its pK(a) 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-transpropylcarbamoyl-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. (c) 2006 Elsevier B.V. All rights reserved.
Keywords palladacycle
K562
Bcl-2/Bax
apoptosis
lysosomes
acridine orange
Language English
Date 2006-08-07
Published in European Journal of Pharmacology. Amsterdam: Elsevier B.V., v. 542, n. 1-3, p. 37-47, 2006.
ISSN 0014-2999 (Sherpa/Romeo, impact factor)
Publisher Elsevier B.V.
Extent 37-47
Origin http://dx.doi.org/10.1016/j.ejphar.2006.06.004
Access rights Closed access
Type Article
Web of Science ID WOS:000239467800006
URI http://repositorio.unifesp.br/handle/11600/29087

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