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

Abstract

Gold(III)-dithiocarbamato complexes have recently gained increasing attention as potential anticancer agents because of their strong tumor cell growth-inhibitory effects, generally achieved by exploiting non-cisplatin-like mechanisms of action. The rationale of our research work is to combine the antitumor properties of the gold(III) metal center with the potential chemoprotective function of coordinated dithiocarbamates in order to reduce toxic side effects (in particular nephrotoxicity) induced by clinically established platinum-based drugs. In this context, [Au III Br 2 (ESDT)] (AUL12) was proved to exert promising and outstanding antitumor activity in vitro and to overcome both acquired and intrinsic resistance showed by some types of tumors toward cisplatin. As a subsequent extension of our previous work, we here report on detailed in vivo studies in rodents, including antitumor activity toward three transplantable murine tumor models, toxicity, nephrotoxicity and histopathological investigations. Remarkably, the gold(III) complex AUL12 stands out for higher anticancer activity than cisplatin toward all the murine tumor models examined, inducing up to 80% inhibition of tumor growth. In addition, it shows low acute toxicity levels (lethal dose, LD 50 5 30 mg kg 21 ) and reduced nephrotoxicity. Altogether, these results confirm the reliability of our drug design strategy and support the validation of this gold(III)-dithiocarbamato derivative as a suitable candidate for clinical trials.The accidental discovery of the anticancer properties of cisplatin (cis-dichlorodiammineplatinum(II), cis-[Pt II Cl 2 (NH 3 ) 2 ]; Fig. 1) in the mid-1960s 1 has triggered the development of both platinum 2 -and other metal-based 3,4 alternative compounds. Although well-established in current cancer chemotherapy, the use of platinum compounds for the treatment of tumor diseases is massively hampered by severe side effects such as nausea, alopecia, ototoxicity, neurotoxicity, myelosuppression, nephrotoxicity and tumor resistance, either intrinsic or acquired during cycles of therapy. 5 Consequently, the development of novel metallodrugs showing a different pharmacological profile is a major goal of modern medicinal chemistry and drug design.Among the non-platinum antitumor agents, gold complexes have recently gained increasing attention because of their strong inhibitory effects on tumor cell growth, generally achieved by exploiting non-cisplatin-like pharmacodynamic and pharmacokinetic properties and mechanisms of action. 6,7 Owing to their traditional use in medicine for the treatment of rheumatoid arthritis, gold derivatives are suitable candidates as potential alternatives to platinum drugs. In fact, the antiarthritic activity arises from their known immunosuppressive and anti-inflammatory actions, thus establishing, at least in principle, a connection between the two therapies. Moreover, gold(III) complexes show chemical features that are very close to those of clinically established platinum(II) derivatives, such as the pre...

Dithiocarbamates strongly inhibit the β-class carbonic anhydrases fromMycobacterium tuberculosis

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“…Furthermore, many such derivatives have applications in agriculture as antifungals for the protection of crops, as well as in medicine 26,27 . Although known for at least six decades, it is amazing that they have been scarcely investigated as metalloenzyme inhibitors.…”

2D-DIGE analysis of ovarian cancer cell responses to cytotoxic gold compounds

“…The volume of 3 protein spots (1, 2, 3) was significantly up-regulated in the Au 2 Phen-treated cells with a p-value ranging between 0.05 and 0.005 when compared with the control group. Among the identified protein spots we found 1 spot down-expressed in both treatments (11) and 7 proteins up-regulated (9,10,12,13,14,15,16).…”

“…In addition, it shows low acute toxicity levels and reduced nephrotoxicity. 10 The application of wide approaches, such as proteomics, might lead to further progress in understanding the mechanisms of action of gold compounds. Proteomic approaches were recently exploited to investigate the mode of action of anticancer metallodrugs.…”

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