Antitumor activity of gold(III)‐dithiocarbamato derivatives on prostate cancer cells and xenografts

Abstract

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 cisplatinresistant 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.Prostate cancer is a major cause of cancer morbidity and mortality in men.1 Most prostate tumors initially respond to androgen depletion therapy, but ultimately progress to androgen-independent disease with few therapeutic options, 2 so the development of new treatment strategies are currently under investigation.Cisplatin was one of the first chemotherapeutic agents to exhibit a broad activity toward solid tumors, and still remains among the most widely used anticancer agents. Anyway, all drugs have drawbacks, and cisplatin is no exception. Thus, much effort in designing alternative both platinum and nonplatinum anticancer agents was aimed at making metal-based therapy safer to patients, in particular by lessening or removing unpredictable and severe side-effects, providing oral bioavailability, and overcoming both intrinsic and acquired resistance.3 In this regard, the idea of combining the well-known antitumor properties of some metal ions with the promising chemoprotective function of dithiocarbamates was proved to be a somewhat winning strategy. [4][5][6][7][8] Dithiocarbamates are bidentate chelating ligands and, upon coordination to a metal ion, the resulting complexes are expected to be quite stable due to the so-called ''chelate effect,'' and possible...

In vitro antibacterial and time-kill evaluation of phosphanegold(I) dithiocarbamates, R3PAu[S2CN(iPr)CH2CH2OH] for R = Ph, Cy and Et, against a broad range of Gram-positive and Gram-negative bacteria

“…phosphanegold(I) dithiocarbamates, several studies focussing on cytotoxicity profiles and mechanisms of cell death have appeared [17][18][19]. Even more studies of gold(III) dithiocarbamates are available as these potent compounds exhibit in vivo potential, have limited nephrotoxicity and a different mechanism of action to the widely used anti-cancer drug cisplatin, (NH 3 ) 2 PtCl 2 [20][21][22][23][24]. Herein, we redress this shortcoming in the gold/antimicrobial literature by reporting the exciting antibacterial activity of 2-4, as outlined above.…”

A DFT/ECP-Small Basis Set Modelling of Cisplatin: Molecular Structure and Vibrational Spectrum

“…It is a prototype of several thousands platinum [5][6][7][8][9][10][11][12] and other metal [6,8,9,[13][14][15][16] coordination compounds synthesized and tested so far in the search for novel cytostatic agents with improved therapeutic characteristics with respect to the parent compound. Among them, only five more Pt(II) complexescarboplatin, oxaliplatin, nedaplatin, lobaplatin and heptaplatin-have gained international or local marketing approval [8,17].…”

Gold(III)‐dithiocarbamato anticancer agents: Activity, toxicology and histopathological studies in rodents

“…In this regard, proteasome has been recognized as a major in vitro and in vivo target, 14,15 as well as the selenoenzyme thioredoxin reductase, both cytosolic and mitochondrial. 16,17 The choice of the ligands was not accidental. As previously reminded, nephrotoxicity (i.e., renal toxicity) is a major drawback in platinum-based chemotherapy.…”