Mechanisms of Cytotoxicity of Selected Organogold(III) Compounds

Coronnello, Marcella; Mini, Enrico; Caciagli, Barbara; Cinellu, Maria Agostina; Bindoli, Alberto; Gabbiani, Chiara; Messori, Luigi

doi:10.1021/jm050493o

Cited by 122 publications

(73 citation statements)

References 20 publications

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“…Numerous cancer drugs or drug candidates affect Txnrd1 activity, either as a primary target or, as in the case of cisplatin and other platinum-containing compounds (Sasada et al, 1999;Witte et al, 2005), as a collateral target. Some of these include arsenic trioxide (Lu et al, 2007), various organo-gold compounds Casini et al, 2009;Coronnello et al, 2005;Gandin et al, 2009;Marzano et al, 2007;Rigobello et al, 2009), some mercury-containing compounds (Carvalho et al, 2008), and certain quinols , flavinoids (Du et al, 2009;Lu et al, 2006) and polyphenols (Du et al, 2009;Fang et al, 2005). Many other drugs will interact with the Txnrd1 pathway and, if used in combination therapies, might have their pharmacokinetics affected by compounds that inhibit Txnrd1.…”

Section: Implications For Txnrd-and Txn-targeted Pharmaceuticalsmentioning

confidence: 99%

Hepatocytes lacking thioredoxin reductase 1 have normal replicative potential during development and regeneration

Rollins

Heide

Weisend

et al. 2010

Journal of Cell Science

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SummaryCells require ribonucleotide reductase (RNR) activity for DNA replication. In bacteria, electrons can flow from NADPH to RNR by either a thioredoxin-reductase-or a glutathione-reductase-dependent route. Yeast and plants artificially lacking thioredoxin reductases exhibit a slow-growth phenotype, suggesting glutathione-reductase-dependent routes are poor at supporting DNA replication in these organisms. We have studied proliferation of thioredoxin-reductase-1 (Txnrd1)-deficient hepatocytes in mice. During development and regeneration, normal mice and mice having Txnrd1-deficient hepatocytes exhibited similar liver growth rates. Proportions of hepatocytes that immunostained for PCNA, phosphohistone H3 or incorporated BrdU were also similar, indicating livers of either genotype had similar levels of proliferative, S and M phase hepatocytes, respectively. Replication was blocked by hydroxyurea, confirming that RNR activity was required by Txnrd1-deficient hepatocytes. Regenerative thymidine incorporation was similar in normal and Txnrd1-deficient livers, further indicating that DNA synthesis was unaffected. Using genetic chimeras in which a fluorescently marked subset of hepatocytes was Txnrd1-deficient while others were not, we found that the multigenerational contributions of both hepatocyte types to development and to liver regeneration were indistinguishable. We conclude that, in mouse hepatocytes, a Txnrd1-independent route for the supply of electrons to RNR can fully support DNA replication and normal proliferative growth.

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Section: Implications For Txnrd-and Txn-targeted Pharmaceuticalsmentioning

confidence: 99%

Hepatocytes lacking thioredoxin reductase 1 have normal replicative potential during development and regeneration

Rollins

Heide

Weisend

et al. 2010

Journal of Cell Science

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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: 97%

“…Hence, over the last two decades, several promising families of Au-based drug candidates, with the gold center in the oxidation state +3 or +1, featuring diverse structural motifs, were prepared, characterized and their biological and pharmacological profiles initially assessed [7,8]. Relevant examples are offered by a few classical mononuclear gold(III) complexes [9] such as gold(III) dithiocarbamates [10] and gold(III) porphyries [11]; by some organogold(III) compounds [12,13]; a few binuclear gold(III) complexes [14]; various neutral, two-coordinate gold(I) complexes [15], inspired to auranofin; a number of lyophilise cationic gold(I) complexes such as [Au(dope)2]+, and others.…”

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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“…Previous studies showed that cytotoxic gold(III) compounds are able to induce cell death through apoptosis [10,11]. 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.…”

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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Mechanisms of Cytotoxicity of Selected Organogold(III) Compounds

Cited by 122 publications

References 20 publications

Hepatocytes lacking thioredoxin reductase 1 have normal replicative potential during development and regeneration

Hepatocytes lacking thioredoxin reductase 1 have normal replicative potential during development and regeneration

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

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

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