Gold(III)-Dithiocarbamato Complexes Induce Cancer Cell Death Triggered by Thioredoxin Redox System Inhibition and Activation of ERK Pathway

Saggioro, Daniela; Rigobello, Maria Pia; Paloschi, Lucia; Folda, Alessandra; Moggach, Stephen A.; Parsons, Simon; Ronconi, Luca; Fregona, Dolores; Bindoli, Alberto

doi:10.1016/j.chembiol.2007.08.016

Cited by 126 publications

(116 citation statements)

References 52 publications

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“…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.…”

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confidence: 99%

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

Marzano

Ronconi

Chiara

et al. 2010

Intl Journal of Cancer

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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...

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confidence: 99%

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

Marzano

Ronconi

Chiara

et al. 2010

Intl Journal of Cancer

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“…The antiproliferative activities of gold-2a in MDA-MB-231 cells were comparable with other HDACi, such as SAHA (43) and TSA (44). Previous studies have suggested that cisplatin and gold (III) porphyrin complexes elicit their anticancer effects through distinct mechanisms at the DNA level and the protein level, respectively (45)(46)(47)(48). Among the five types of human breast cancer cells, MDA-MB-231 possesses the most active autocrine canonical Wnt signaling, followed by SKBR3, T47D, MCF-7, and BT474 (16,49), indicating that gold-2a may favor on targeting cancers that are more addicted to Wnt/β-catenin signaling.…”

Section: Discussionmentioning

confidence: 99%

A Gold(III) Porphyrin Complex with Antitumor Properties Targets the Wnt/β-catenin Pathway

et al. 2010

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Gold(III) complexes have shown promise as antitumor agents, but their clinical usefulness has been limited by their poor stability under physiological conditions. A novel gold(III) porphyrin complex [5-hydroxyphenyl-10,15,20-triphenylporphyrinato gold(III) chloride (gold-2a)] with improved aqueous stability showed 100-fold to 3,000-fold higher cytotoxicity than platinum-based cisplatin and IC 50 values in the nanomolar range in a panel of human breast cancer cell lines. Intraductal injections of gold-2a significantly suppressed mammary tumor growth in nude mice. These effects are attributed, in part, to attenuation of Wnt/β-catenin signaling through inhibition of class I histone deacetylase (HDAC) activity. These data, in combination with computer modeling, suggest that gold-2a may represent a promising class of anticancer HDAC inhibitor preferentially targeting tumor cells with aberrant Wnt/β-catenin signaling.

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“…As a result gold(III) compounds have been thought to have therapeutic effects similar to cisplatin. Research on gold(III) compounds as potential anticancer agents has been reported (Saqqioro et al 2007;Keter et al 2008;Angela et al 2008). There are a few examples of gold(III) compounds that have been reported to show activity against HIV.…”

Section: Gold(iii) Compoundsmentioning

confidence: 99%

HIV therapeutic possibilities of gold compounds

2010

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Highly active antiretroviral therapy (HAART) has resulted in decreased mortality and morbidity from the acquired immune deficiency syndrome caused by the human immunodeficiency virus (HIV). Drug resistance and toxicity of HAART has led to the search for novel inhibitors of HIV infection. Gold-based compounds have shown promising activity against a wide range of clinical conditions and microorganism infections including HIV-1. A typical example is auranofin which resulted in an elevated CD4? T-cell count in an HIV patient being treated for psoriatic arthritis. In addition, reports exist on gold-based inhibitors of reverse transcriptase (RT), protease (PR) and viral entry of host cells. These and other characteristics of goldbased HIV drugs are reviewed here.

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Gold(III)-Dithiocarbamato Complexes Induce Cancer Cell Death Triggered by Thioredoxin Redox System Inhibition and Activation of ERK Pathway

Cited by 126 publications

References 52 publications

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

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

A Gold(III) Porphyrin Complex with Antitumor Properties Targets the Wnt/β-catenin Pathway

HIV therapeutic possibilities of gold compounds

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