Targeting the mitochondrial cell death pathway with gold compounds

Barnard, Peter J.; Berners‐Price, Susan J.

doi:10.1016/j.ccr.2007.04.006

Cited by 388 publications

(323 citation statements)

References 117 publications

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“…However, in contrast to general expectations, a number of subsequent studies suggested that gold(III) compounds exert their cytotoxicity and antiproliferative effects mainly through DNA independent mechanisms [16]. Notably, it has been shown that these gold(III) compounds are able to trigger apoptosis by a direct mitochondrial damage [1,12,17,18]. Also, there are suggestions that a few peculiar proteins such as thioredoxin reductase, the proteasome or the nuclear factor kb (NF-kb) system may constitute major targets for these gold compounds [1,[18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Proteomic analysis of A2780/S ovarian cancer cell response to the cytotoxic organogold(III) compound Aubipyc

Gamberi

Massai

Magherini

et al. 2014

Journal of Proteomics

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Aubipy c is an organogold(III) compound endowed with encouraging anti-proliferative properties in vitro that is being evaluated pre-clinically as a prospective anticancer agent. A classical proteomic approach is exploited here to elucidate the mechanisms of its biological actions in A2780 human ovarian cancer cells. Based on 2-D gel electrophoresis separation and subsequent mass spectrometry identification, a considerable number of differentially expressed proteins were highlighted in A2780 cancer cells treated with Aubipy c . Bioinformatic analysis of the groups of up-regulated and down-regulated proteins pointed out that Aubipy c primarily perturbs mitochondrial processes and the glycolytic pathway. Notably, some major alterations in the glycolytic pathway were validated through Western blot and metabolic investigations. Biological significanceThis is the first proteomic analysis regarding Aubipy c cytotoxicity in A2780/S ovarian cancer cell line. Aubipy c is a promising gold(III) compound which manifests an appreciable cytotoxicity toward the cell line A2780, being able to overcome resistance to platinum. The proteomic study revealed for Aubipy c different cellular alterations with respect to cisplatin as well as to other gold compound such as auranofin. Remarkably, the bioinformatic analysis of proteomic data pointed out that Aubipy c treatment affected, directly or indirectly, several glycolytic enzymes. These data suggest a new mechanism of action for this gold drug and might have an impact on the use of gold-based drug in cancer treatment.

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Section: Introductionmentioning

confidence: 99%

Proteomic analysis of A2780/S ovarian cancer cell response to the cytotoxic organogold(III) compound Aubipyc

Gamberi

Massai

Magherini

et al. 2014

Journal of Proteomics

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“…4). 12 The wingtip groups have been modified in order to adjust the lipophilic character of the complexes, a critical factor for targeting malignant cells. The assays carried 140 out on these gold compounds have demonstrated that ionic [Au(NHC) 2 ] + complexes selectively induce apoptosis in cancer cells but not in normal cell lines.…”

Section: Antitumor Agentsmentioning

confidence: 99%

Beyond catalysis: N-heterocyclic carbene complexes as components for medicinal, luminescent, and functional materials applications

2010

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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

102

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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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Targeting the mitochondrial cell death pathway with gold compounds

Cited by 388 publications

References 117 publications

Proteomic analysis of A2780/S ovarian cancer cell response to the cytotoxic organogold(III) compound Aubipyc

Proteomic analysis of A2780/S ovarian cancer cell response to the cytotoxic organogold(III) compound Aubipyc

Beyond catalysis: N-heterocyclic carbene complexes as components for medicinal, luminescent, and functional materials applications

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

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