Inhibition of tumor proteasome activity by gold-dithiocarbamato complexes via both redox-dependent and -independent processes.
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.
Zhang
Xia
X
The Prevention Program, Barbara Ann Karmanos Cancer Institute, and Department of Pathology, School of Medicine, Wayne State University, Detroit, Michigan, USA.|Key Laboratory of Marine Chemistry Engineering and Technology, Ministry of Education, College of Chemistry and Chemical Engineering, Ocean University of China, Qingdao, 266100, People's Republic of China.
Frezza
Michael
M
The Prevention Program, Barbara Ann Karmanos Cancer Institute, and Department of Pathology, School of Medicine, Wayne State University, Detroit, Michigan, USA.
Milacic
Vesna
V
The Prevention Program, Barbara Ann Karmanos Cancer Institute, and Department of Pathology, School of Medicine, Wayne State University, Detroit, Michigan, USA.
Ronconi
Luca
L
Department of Chemical Sciences, University of Padova, via Marzolo 1, 35131 Padova, Italy.
Fan
Yuhua
Y
Key Laboratory of Marine Chemistry Engineering and Technology, Ministry of Education, College of Chemistry and Chemical Engineering, Ocean University of China, Qingdao, 266100, People's Republic of China.
Bi
Caifeng
C
Key Laboratory of Marine Chemistry Engineering and Technology, Ministry of Education, College of Chemistry and Chemical Engineering, Ocean University of China, Qingdao, 266100, People's Republic of China.
Fregona
Dolores
D
Department of Chemical Sciences, University of Padova, via Marzolo 1, 35131 Padova, Italy.
Dou
Q Ping
QP
The Prevention Program, Barbara Ann Karmanos Cancer Institute, and Department of Pathology, School of Medicine, Wayne State University, Detroit, Michigan, USA.
D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D004050:Ditiocarb / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D050607:Organogold Compounds / Q000494:pharmacology*; D010084:Oxidation-Reduction; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism
D000970:Antineoplastic Agents; D050607:Organogold Compounds; D017382:Reactive Oxygen Species; D004050:Ditiocarb; D046988:Proteasome Endopeptidase Complex