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

The Prevention Program, Department of Pathology, Barbara Ann Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, Michigan.
Journal of Cellular Biochemistry (Impact Factor: 3.06). 11/2009; 109(1):162-72. DOI: 10.1002/jcb.22394
Source: PubMed

ABSTRACT 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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Some gold(III)-dithiocarbamato derivatives of either single amino acids or oligopeptides have shown promise as potential anticancer agents, but their capability to interact with biologically relevant macromolecules is still poorly understood. We investigated the affinity of the representative complex [Au(III) Br2 (dtc-Sar-OCH3 )] (dtc: dithiocarbamate; Sar: sarcosine (N-methylglycine)) with selected model molecules for histidine-, methionine-, and cysteine-rich proteins (that is, 1-methylimidazole, dimethylsulfide, and N-acetyl-L-cysteine, respectively). In particular, detailed mono- and multinuclear NMR studies, in combination with multiple (13) C/(15) N enrichments, allowed interactions to be followed over time and indicated somewhat unexpected reaction pathways. Whereas dimethylsulfide proved to be unreactive, a sudden multistep redox reaction occurred in the presence of the other potential sulfur donor, N-acetyl-L-cysteine (confirmed if glutathione was used instead). On the other hand, 1-methylimidazole underwent an unprecedented acid-base reaction with the gold(III) complex, rather than the expected coordination to the metal center by replacing, for instance, a bromide. Our results are discussed herein and compared with the data available in the literature on related complexes; our findings confirm that the peculiar reactivity of gold(III)-dithiocarbamato complexes can lead to novel reaction pathways and, therefore, to new cytotoxic mechanisms in cancer cells.
    Chemistry 09/2013; · 5.93 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Four novel oxovanadium(IV) complexes-[VO(PAHN)(phen)] (1; PAHN is 4-pyridinecarboxylic acid, 2-[(2-hydroxy)-1-naphthalenylene] hydrazide, phen is 1,10-phenanthroline), [VO(PAHN)(bpy)] (2; bpy is 2,2'-bipyridine), [VO(PAH)(phen)] (3; PAH is 4-pyridinecarboxylic acid, 2-[(2-hydroxy)-1-phenyl]methylene hydrazide), and [VO(PAH)(bpy)] (4)-have been synthesized and characterized by elemental analysis, UV-vis spectroscopy, electrospray ionization mass spectrometry, IR spectroscopy, (1)H-NMR spectroscopy, and (13)C-NMR spectroscopy. Their interactions with calf thymus DNA were investigated. The results suggest that these complexes bind to DNA in an intercalative mode. All four complexes exhibited highly cytotoxic activity against tumor cells (SH-SY5Y, MCF-7, and SK-N-SH), with 50 % inhibitory concentrations of the same order of magnitude as for cisplatin or of lower order of magnitude. Complex 1 exhibited the highest interaction ability and was found to be the most potent antitumor agent among the four complexes. It can cause G2/M phase arrest of the cell cycle, induces significant apoptosis in SK-N-SH cells, and displays typical morphological apoptotic characteristics. In addition, their hydroxyl radical scavenging properties have been tested, and complex 1 was the best inhibitor.
    European Journal of Biochemistry 09/2013; · 3.42 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Since the serendipitous discovery of cisplatin, platinum-based drugs have become well-established antitumor agents, despite the fact that their clinical use is limited by many severe side-effects. In order to both improve the chemotherapeutic index and broaden the therapeutic spectrum of current drugs, our most recent anti-neoplastic agents, Au(III) complexes, were designed as carrier-mediated delivery systems exploiting peptide transporters, which are up-regulated in some cancers. Among all, we focused on two compounds and tested them on human MDA-MB-231 (resistant to cisplatin) breast cancer cell cultures and xenografts, discovering the proteasome as a major target both in vitro and in vivo. 53% inhibition of breast tumor growth in mice was observed after 27 days of treatment at 1.0 mg kg(-1) d(-1), compared to control. Remarkably, if only the most responsive mice are taken into account, 85% growth inhibition, with some animals showing tumor shrinkage, was observed after 13 days. These results led us to file an international patent, recognizing this class of gold(III) peptidomimetics as suitable candidates for entering phase I clinical trials.
    PLoS ONE 01/2014; 9(1):e84248. · 3.73 Impact Factor