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Inhibition of tumor proteasome activity by gold–dithiocarbamato complexes via both redox‐dependent and ‐independent processes
Author(s) -
Zhang Xia,
Frezza Michael,
Milacic Vesna,
Ronconi Luca,
Fan Yuhua,
Bi Caifeng,
Fregona Dolores,
Dou Q. Ping
Publication year - 2009
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.22394
Subject(s) - proteasome , dithiothreitol , gold compounds , chemistry , colloidal gold , ubiquitin , proteasome inhibitor , reactive oxygen species , in vivo , in vitro , cysteine , biochemistry , intracellular , cancer cell , microbiology and biotechnology , biology , enzyme , cancer , nanotechnology , combinatorial chemistry , materials science , genetics , nanoparticle , gene
We have previously reported on a gold(III) complex, namely [AuBr 2 (DMDT)] ( N , N ‐dimethyldithiocarbamate) showing potent in vitro and in vivo growth inhibitory activities toward human cancer cells and identifying the cellular proteasome as one of the major targets. However, the importance of the oxidation state of the gold center and the involved mechanism of action has yet to be established. Here we show that both gold(III)− and gold(I)–dithiocarbamato species, namely [AuBr 2 (ESDT)] (AUL12) and [Au(ESDT)] 2 (AUL15), could inhibit the chymotrypsin‐like activity of purified 20S proteasome and 26S proteasome in human breast cancer MDA‐MB‐231 cells, resulting in accumulation of ubiquitinated proteins and proteasome target proteins, and induction of cell death, but at significantly different levels. Gold(I)‐ and gold(III)‐compound‐mediated proteasome inhibition and cell death induction were completely reversed by the addition of a reducing agent, dithiothreitol or N ‐acetyl‐ L ‐cysteine, suggesting the involvement of redox processes. Furthermore, treatment of MDA‐MB‐231 cells with gold(III) compound (AUL12), but not the gold(I) analog (AUL15), resulted in the production of significant levels of reactive oxygen species. Our study provides strong evidence that the cellular proteasome is an important target of both gold(I) and gold(III)–dithiocarbamates, but distinct cellular mechanisms of action are responsible for their different overall effect. J. Cell. Biochem. 109: 162–172, 2010. © 2009 Wiley‐Liss, Inc.