Document Detail


Antitumor activity of gold(III)-dithiocarbamato derivatives on prostate cancer cells and xenografts.
MedLine Citation:
PMID:  20209498     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Among the nonplatinum antitumor drugs, gold(III)-dithiocarbamato derivatives have recently attracted considerable attention due to their strong in vitro and in vivo antiproliferative activity and reduced renal toxicity. Some of them, namely [AuCl(2) (DMDT)] (compound 1) and [AuBr(2) (ESDT)] (compound 2), have shown to be highly active against the androgen-resistant prostate cancer cell lines PC3 and DU145, both inhibiting cell proliferation in a dose-dependent way, and are more active than the reference drug cisplatin (cis-[PtCl(2) (NH(3) )(2) ]). In particular, [AuCl(2) (DMDT)] was proved cytotoxic against cisplatin-resistant R-PC3 cells, with activity levels comparable to those induced on the parent cisplatin-sensitive PC3 cells, ruling out the occurrence of cross-resistance phenomena. Moreover, it causes early cell damage, slightly affecting the cell cycle, thus suggesting a different mechanism of action from clinically established platinum-based drugs. In fact, the investigated gold(III) complex alters mitochondrial functions, promoting mitochondrial membrane permeabilization and Cyt-c release, stimulating ROS generation, and strongly inhibiting the activity of the selenoenzyme TrxR, which is overexpressed in prostate cancer and associated with the onset of drug resistance. In addition, it induces apoptosis, caspase activation, Bcl-2 downregulation and Bax upregulation, reduces the expression of the phosphorylated form of the EGFR, and it inhibits PC3 cell migration. Finally, the treatment of PC3 prostate tumor-bearing nude mice with [AuCl(2) (DMDT)] significantly inhibited tumor growth in vivo, causing minimal systemic toxicity. Altogether, our results confirm that these gold(III)-dithiocarbamato derivatives have potential for the treatment of prostate cancer.
Authors:
Lara Cattaruzza; Dolores Fregona; Maurizio Mongiat; Luca Ronconi; Ambrogio Fassina; Alfonso Colombatti; Donatella Aldinucci
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  International journal of cancer. Journal international du cancer     Volume:  128     ISSN:  1097-0215     ISO Abbreviation:  Int. J. Cancer     Publication Date:  2011 Jan 
Date Detail:
Created Date:  2010-10-28     Completed Date:  2010-12-30     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0042124     Medline TA:  Int J Cancer     Country:  United States    
Other Details:
Languages:  eng     Pagination:  206-15     Citation Subset:  IM    
Copyright Information:
Copyright © 2010 UICC.
Affiliation:
Centro di Riferimento Oncologico, Division of Experimental Oncology 2, Aviano (PN), Italy.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antineoplastic Agents / chemistry,  pharmacology
Apoptosis / drug effects
Caspases / metabolism
Cell Cycle / drug effects
Cell Line, Tumor
Cell Movement / drug effects
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Female
Gold Compounds / chemistry,  pharmacology*
Humans
Male
Mice
Mice, Nude
Mitochondria / drug effects,  metabolism,  physiology
Molecular Structure
Phosphorylation / drug effects
Prostatic Neoplasms / metabolism,  pathology,  prevention & control*
Reactive Oxygen Species / metabolism
Receptor, Epidermal Growth Factor / metabolism
Thiocarbamates / chemistry,  pharmacology*
Thioredoxin-Disulfide Reductase / antagonists & inhibitors,  metabolism
Tumor Burden / drug effects
Xenograft Model Antitumor Assays*
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Gold Compounds; 0/Reactive Oxygen Species; 0/Thiocarbamates; EC 1.8.1.9/Thioredoxin-Disulfide Reductase; EC 2.7.10.1/Receptor, Epidermal Growth Factor; EC 3.4.22.-/Caspases

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