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

Lara Cattaruzza, Dolores Fregona, Maurizio Mongiat, Luca Ronconi, Ambrogio Fassina, Alfonso Colombatti, Donatella Aldinucci

Research output: Contribution to journalArticle

97 Citations (Scopus)

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 [AuCl2(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-[PtCl2(NH3)2]). In particular, [AuCl2(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 [AuCl2(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.

Original languageEnglish
Pages (from-to)206-215
Number of pages10
JournalInternational Journal of Cancer
Volume128
Issue number1
DOIs
Publication statusPublished - Jan 1 2011

Fingerprint

Methoxychlor
Heterografts
Gold
Cisplatin
Prostatic Neoplasms
Mitochondrial Membranes
Caspases
Platinum
Drug Resistance
Nude Mice
Pharmaceutical Preparations
Antineoplastic Agents
Androgens
Cell Movement
Prostate
Neoplasms
Cell Cycle
Up-Regulation
Down-Regulation
Cell Proliferation

Keywords

  • Anticancer drugs
  • Dithiocarbamates
  • Gold(III)
  • Prostate cancer
  • Thioredoxin reductase

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Antitumor activity of gold(III)-dithiocarbamato derivatives on prostate cancer cells and xenografts. / Cattaruzza, Lara; Fregona, Dolores; Mongiat, Maurizio; Ronconi, Luca; Fassina, Ambrogio; Colombatti, Alfonso; Aldinucci, Donatella.

In: International Journal of Cancer, Vol. 128, No. 1, 01.01.2011, p. 206-215.

Research output: Contribution to journalArticle

Cattaruzza, Lara ; Fregona, Dolores ; Mongiat, Maurizio ; Ronconi, Luca ; Fassina, Ambrogio ; Colombatti, Alfonso ; Aldinucci, Donatella. / Antitumor activity of gold(III)-dithiocarbamato derivatives on prostate cancer cells and xenografts. In: International Journal of Cancer. 2011 ; Vol. 128, No. 1. pp. 206-215.
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