Thioredoxin reductase: A target for gold compounds acting as potential anticancer drugs

Bindoli, Alberto; Rigobello, Maria Pia; Scutari, Guido; Gabbiani, Chiara; Casini, Angela; Messori, Luigi

doi:10.1016/j.ccr.2009.02.026

Cited by 518 publications

(450 citation statements)

References 185 publications

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“…In particular, it was shown that this compound is strongly cytotoxic and propapoptotic in vitro and that apoptosis is probably mediated by a direct mitochondrial mechanism. Strong inhibition of thioredoxin reductase by auranofin was demonstrated as well in a number of studies [12].…”

Section: Functional Roles Of the Identified Proteinsmentioning

confidence: 68%

“…However, for most gold compounds, apoptosis seems to be essentially triggered by direct mitochondrial damage, and is not the consequence of an initial DNA lesion, as in the case of cisplatin. Within this frame, the pivotal role of thioredoxin reductase as a probable target for cytotoxic gold compounds was highlighted [12]. In particular, it seems very likely that a strong inhibition of mitochondrial thioredoxin reductase may eventually lead to a deep alteration of the mitochondrial membrane potential, to release of cytochrome c, and to consequent triggering of apoptosis [12].…”

Section: Introductionmentioning

confidence: 99%

“…Within this frame, the pivotal role of thioredoxin reductase as a probable target for cytotoxic gold compounds was highlighted [12]. In particular, it seems very likely that a strong inhibition of mitochondrial thioredoxin reductase may eventually lead to a deep alteration of the mitochondrial membrane potential, to release of cytochrome c, and to consequent triggering of apoptosis [12]. Such a type of ''mitochondrial mechanism'' was also proposed for gold(III) porphyrins [11], on which detailed proteomic studies were recently carried out, and for auranofin and a few related gold(I) compounds [13].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Functional Roles Of the Identified Proteinsmentioning

confidence: 68%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2010

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“…11 During the last decade, several gold(I) and gold(III) compounds were reported to manifest impressive antitumor properties, making up a promising class of experimental anticancer agents. 12 Among these agents, a cytotoxic gold(III) porphyrin complex, [Au(TPP)]Cl, was found to be particularly active, as it blocked the self-renewal ability of cancer stem-like cells. 13 Most notably, [Au(TPP)]Cl was neither demetallated nor reduced during circulation in biological media.…”

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confidence: 99%

A cytotoxic and cytostatic gold(iii) corrole

et al. 2014

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“…[240] The Cterminal sequence containing the seleno-cysteine (Sec) residue has been identified as reactive towards several compounds, and such interaction was shown to inhibit the activity of the protein. Although cisplatin and gold-based (Au(I) and Au(III)) complexes have been described to inhibit TrxR using in vitro assays, [248][249][250][251][252][253][254][255][256][257][258] The results suggested that arsenic trioxide binds to both sulfur and selenium in the C-terminal motif GlyCysSecGly of the protein, and although precise identification of the coordination sites was not possible, the N-terminal sequence was also found to participate in the reaction with As. [263] However, it is worth mentioning that in this report, no evidence for the selenium isotopic pattern on the peptide fragment bound to arsenic has been provided.…”

Section: Seleno-enzymesmentioning

confidence: 94%

Mass spectrometry as a powerful tool to study therapeutic metallodrugs speciation mechanisms: Current frontiers and perspectives

Wenzel

Casini

2017

Coordination Chemistry Reviews

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Metal-based compounds form a promising class of therapeutic agents, whose mechanisms of action still need to be elucidated, and that are in general prone to undergo extensive speciation in physiological environment. Thus, determination of the fate of the metal compounds in complex biological systems, contributing to their overall pharmacological and toxicological profiles, is important to develop more rationalised and targeted metal-based drugs. To these aims, a number of spectroscopic and biophysical methods, as well as analytical techniques, are nowadays extensively applied to study the reactivity of metal complexes with different biomolecules (e.g. nucleic acids, proteins, buffer components). Among the various techniques, molecular mass spectrometry (MS) has emerged in the last decade as a major tool to characterise the interactions of metallodrugs at a molecular level. In this review, we present an overview of the information available on the reactivity of various families of therapeutic metallodrugs (mainly anticancer compounds based on Pt, Ru, Au and As) with biomolecules studied by different MS techniques, including high-resolution ESI-, MALDI-and ion mobility-MS among others. Representative examples on the potential of the MS approach to study non-covalent interactions are also discussed. The review is organized to present results obtained on samples with different degrees of complexity, from the interactions of metal compounds with small model nucleophiles (amino acids and nucleobases), model peptides/oligonucleotides, target proteins/nucleic acids, to the analysis of serum, cell extracts and tissue samples. The latter requiring combination of proteomic methods with advanced MS techniques. Correlations between molecular reactivity of metallodrugs and biological activity are hard to establish, but differences in the reactivity of metallodrugs to biomolecules and their different adducts, as revealed by MS methods, may indicate differences in their modes of action. Overall, the knowledge offered by MS methods on metallodrugs speciation is invaluable to establish new rules and define new trends in the periodic table aimed at rationalizing the behavior of metal compounds in complex living systems. Keywordsmetal-based drugs; proteins; nucleic acids; mass spectrometry; metallomics. Corresponding Author Angela Casini Corresponding Author's InstitutionCardiff University To view all the submission files, including those not included in the PDF, click on the manuscript title on your EVISE Homepage, then click 'Download zip file'. Order of Authors 1 Answers to Reviewers Reviewer 1 The authors have made some effort to answer suggestions and the manuscript is improved. Since it is a review, there is, strictly, no new information but nevertheless the compilation of data and references could be useful.Answer: no further comments. Liu et al." in place of "Lu et al." iv) Some symbols in the PDF file are not correctly displayed. Reviewer Answer:We have inserted all the minor modifications requested by this rev...

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Thioredoxin reductase: A target for gold compounds acting as potential anticancer drugs

Cited by 518 publications

References 185 publications

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

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

A cytotoxic and cytostatic gold(iii) corrole

Mass spectrometry as a powerful tool to study therapeutic metallodrugs speciation mechanisms: Current frontiers and perspectives

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