Cancer cell death induced by phosphine gold(I) compounds targeting thioredoxin reductase

Gandin, Valentina; Fernandes, Aristi P.; Dani, Barbara; Sorrentino, Francesca; Tisato, Francesco; Björnstedt, Mikael; Bindoli, Alberto; Sturaro, A.; Rella, R.; Marzano, Cristina

doi:10.1016/j.bcp.2009.07.023

Cited by 222 publications

(199 citation statements)

References 54 publications

(43 reference statements)

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“…Organic gold compounds such as auranofin (2,3,4,6-tetra-Oacetyl-1-thio-β-D-glucopyranosato-S-(triethylphosphine) gold) exert cytotoxic effects by causing direct mitochondrial damage through selective modification of the selenol active site in TrxR (Rigobello et al 2004) and induces mitochondrial permeability, which results in the release of cytochrome c from mitochondria into cytoplasm with consequent apoptotic cell death (Cox et al 2008). AF-like gold complexes synthetized by Gandin et al are super inhibitors of TrxR1 and TrxR2 with IC 50 values with low to sub-nanomolar range and also inhibits cancer cell growth (Gandin et al 2010). AF is probably the most effective inhibitor of mammalian TrxR found to date and might be utilized as an anticancer agent to induce apoptotic cell death.…”

Section: Auranofin (Af)mentioning

confidence: 99%

Thioredoxin system – a novel therapeutic target

Koháryová¹,

Kollárová²

2015

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Abstract. Nowadays there are numerous pathogens that have created a resistance to commonly used antibiotics and drugs. Therefore research is focused on finding new therapeutic targets and on determination of their 3D structures that could help in designing new effective substances and inhibitors. Thioredoxin system not only plays a crucial role as thiol/disulfide redox controller, it is also essential for certain organisms as the only system ensuring the redox homeostasis. It is the redox-regulating function, which makes thioredoxin and thioredoxin reductase attractive for scientific research, especially in many studies of diseases caused by redox instability. Thanks to these facts, the proteins of thioredoxin system are suitable candidates for new therapeutic purposes. In this review we summarized the basic features of the thioredoxin system, we justified why the proteins of thioredoxin system are appropriate therapeutical targets and we provided overview of the possibilities of their inhibition by several types of inhibitors.

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Section: Auranofin (Af)mentioning

confidence: 99%

Thioredoxin system – a novel therapeutic target

Koháryová¹,

Kollárová²

2015

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“…Prominent amongst these are gold dithiocarbamates, including phosphane gold(I) dithiocarbamates. The exploration of the potential anti-cancer activity of phosphane gold(I) dithiocarbamates dates back over a decade [12] and studies on related compounds continue [13][14][15]. Recently, phosphanegold(I) dithiocarbamates, functionalised with ethylhydroxy groups, proved to be very effective against breast cancer MCF-7R cell lines and to induce cell death (apoptosis or necrosis) via both extrinsic and intrinsic pathways [16].…”

Section: Introductionmentioning

confidence: 99%

Bis(phosphane)copper(I) and silver(I) dithiocarbamates: crystallography and anti-microbial assay

Jamaludin

Halim

Khoo

et al. 2016

Zeitschrift Für Kristallographie - Crystalline Materials

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Keywords: Copper(I) / silver(I) / dithiocarbamate / crystal structure analysis / X-ray diffraction Abstract.The crystal and molecular structures of (Ph3P)2M[S2CN(Me)CH2CH2OH], M = Cu, isolated as a 1:1 dichloromethane solvate (1.CH2Cl2), and M = Ag (4) show the central metal atom to be coordinated by a symmetrically (1.CH2Cl2) and asymmetrically chelating (4) dithiocarbamate ligand. The distorted tetrahedral geometries are completed by two PPh3 ligands. The presence of hydroxyl-O-H … S(dithiocarbamate) hydrogen bonds leads to centrosymmetric dimeric aggregates in each crystal structure. In the molecular packing of 1.CH2Cl2, channels comprising 1 are formed via aryl-C-H … O interactions with the solvent molecules associated with the walls of the channels via methylene-C-H … S, π(aryl) interactions. For 4, the dimeric aggregates are connected via a network of aryl-C-H … π(aryl) interactions. Preliminary screening for antimicrobial activity was conducted. The compounds were only potent against Gram-positive bacteria. Some further selectivity in activity was noted. Most notably, all compounds were active against methicillin resistant Staphylococcus aureus.

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“…In recent years research has increasingly focused on gold(III) compounds as anticancer drug candidates because gold(III) complexes typically display the same electronic configuration (d 8 ) and similar structural and reactivity features of platinum(II) complexes (in particular a strong preference for square-planar geometry and a rather favorable kinetic profile) [3]. Accordingly, our laboratories have developed a variety of structurally diverse gold(III) compounds as potential chemotherapeutic leads [4].…”

Section: Introductionmentioning

confidence: 99%

“…The behavior of Auoxo6 is compared with that of auranofin, a gold(I) antiarthritic drug, endowed with significant cytotoxic properties in vitro (but not in vivo) [7]. Auranofin was chosen as a control compound since it is a typical gold(I) drug in clinical use and a lot is known about its biochemical effects at the cellular level [8,9]. The chemical structures of Auoxo6 and auranofin are shown in Fig.…”

Section: Introductionmentioning

confidence: 99%

Exploring the biochemical mechanisms of cytotoxic gold compounds: a proteomic study

et al. 2010

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We have recently shown that a group of structurally diverse gold compounds are highly cytotoxic toward a panel of 36 human tumor cell lines through a variety of biochemical mechanisms. A classic proteomic approach is exploited here to gain deeper insight into those mechanisms. This investigation is focused on Auoxo6, a novel binuclear gold(III) complex, and auranofin, a clinically established gold(I) antiarthritic drug. First, the 72-h cytotoxicity profiles of Auoxo6 and auranofin were determined against A2780 human ovarian carcinoma cells. Subsequently, protein extraction from gold-treated A2780 cells sensitive to cisplatin and 2D gel electrophoresis separation were carried out according to established procedures. Notably, both metallodrugs caused relatively modest changes in protein expression in comparison with controls as only 11 out of approximately 1,300 monitored spots showed appreciable quantitative changes. Very remarkably, six altered proteins were in common between the two treatments. Eight altered proteins were identified by mass spectrometry; among them was ezrin, a protein associated with the cytoskeleton and involved in apoptosis. Interestingly, two altered proteins, i.e., peroxiredoxins 1 and 6, are known to play crucial roles in the cell redox metabolism. Increased cleavage of heterogeneous ribonucleoprotein H was also evidenced, consistent with caspase 3 activation. Overall, the results of the present proteomic study point out that the mode of action of Auoxo6 is strictly related to that of auranofin, that the induced changes in protein expression are limited and selective, that both gold compounds trigger caspase 3 activation and apoptosis, and that a few affected proteins are primarily involved in cell redox homeostasis.

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Cancer cell death induced by phosphine gold(I) compounds targeting thioredoxin reductase

Cited by 222 publications

References 54 publications

Thioredoxin system – a novel therapeutic target

Thioredoxin system – a novel therapeutic target

Bis(phosphane)copper(I) and silver(I) dithiocarbamates: crystallography and anti-microbial assay

Exploring the biochemical mechanisms of cytotoxic gold compounds: a proteomic study

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