Get access
Journal of Cellular Biochemistry

Inhibition of tumor proteasome activity by gold–dithiocarbamato complexes via both redox-dependent and -independent processes

Authors

  • Xia Zhang,

    1. The Prevention Program, Department of Pathology, Barbara Ann Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, Michigan
    2. 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
    Search for more papers by this author
  • Michael Frezza,

    1. The Prevention Program, Department of Pathology, Barbara Ann Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, Michigan
    Search for more papers by this author
  • Vesna Milacic,

    1. The Prevention Program, Department of Pathology, Barbara Ann Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, Michigan
    Search for more papers by this author
  • Luca Ronconi,

    1. Department of Chemical Sciences, University of Padova, Via Marzolo 1, 35131 Padova, Italy
    Search for more papers by this author
  • Yuhua Fan,

    1. 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
    Search for more papers by this author
  • Caifeng Bi,

    1. 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
    Search for more papers by this author
  • Dolores Fregona,

    1. Department of Chemical Sciences, University of Padova, Via Marzolo 1, 35131 Padova, Italy
    Search for more papers by this author
  • Q. Ping Dou

    Corresponding author
    1. The Prevention Program, Department of Pathology, Barbara Ann Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, Michigan
    • The Prevention Program, Department of Pathology, Barbara Ann Karmanos Cancer Institute, School of Medicine, Wayne State University, 540.1 HWCRC, 4100 John R Road, Detroit, MI 48201.
    Search for more papers by this author

  • Xia Zhang and Michael Frezza contributed equally to this study.

  • The authors disclose no conflicts of interest.

Abstract

We have previously reported on a gold(III) complex, namely [AuBr2(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 [AuBr2(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.

Get access to the full text of this article

Ancillary