Organopalladium compound 7b targets mitochondrial thiols and induces caspase-dependent apoptosis in human myeloid leukemia cells

Organopalladium compound 7b targets mitochondrial thiols and induces caspase-dependent apoptosis in human myeloid leukemia cells

Author Moraes, V. W. R. Google Scholar
Caires, A. C. F. Google Scholar
Paredes-Gamero, Edgar Julian Autor UNIFESP Google Scholar
Rodrigues, T. Google Scholar
Institution Universidade Federal do ABC (UFABC)
Univ Mogi das Cruzes
Universidade Federal de São Paulo (UNIFESP)
Abstract The advances in the treatment of chronic myeloid leukemia (CML) during the last years were also accompanied by the development of evading strategies by tumor cells, resulting in chemotherapy resistance in some patients. Patented organopalladium compounds derived from the reaction of N, N-dimethyl-1-phenethylamine (dmpa) with [1,2-ethanebis(diphenylphosphine)] (dppe) exhibited a potent antitumor activity in vivo and in vitro in melanoma cells. We showed here that the cyclopalladated derivative [Pd-2(R(+))C-2, N-dmpa)(2)(mu-dppe) Cl-2], named compound 7b, was highly effective to promote cell death in the K562 human leukemia cells and its mechanisms of action were investigated. It was shown that compound 7b was able to promote exclusively apoptotic cell death in K562 cells associated to cytochrome c release and caspase 3 activation. This cytotoxic effect was not observed in normal peripheral mononuclear blood cells. the compound 7b-induced intrinsic apoptotic pathway was triggered by the protein thiol oxidation that resulted in the dissipation of the mitochondrial transmembrane potential. the preventive effect of the dithiothreitol on the compound 7b-induced cell death and all downstream events associated to apoptosis confirmed that death signal was elicited by the thiol oxidation. These findings contribute to the elucidation of the palladacycle 7b-induced cell death mechanism and present this compound as a promising drug in the CML antitumor chemotherapy.
Keywords antitumor chemotherapy
apoptosis
K562 cells
leukemia
mitochondrial permeabilization
palladacycle
Language English
Sponsor Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Grant number FAPESP: 2012/12247-8
CNPq: 476824/2010-9
Date 2013-06-01
Published in Cell Death & Disease. London: Nature Publishing Group, v. 4, 8 p., 2013.
ISSN 2041-4889 (Sherpa/Romeo, impact factor)
Publisher Nature Publishing Group
Extent 8
Origin http://dx.doi.org/10.1038/cddis.2013.190
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000321111700009
URI http://repositorio.unifesp.br/handle/11600/36361

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