On the mechanism and rate of gold incorporation into thiol-dependent flavoreductases

Saccoccia, Fulvio; Angelucci, Francesco; Boumis, G.; Brunori, Maurizio; Miele, A.E.; Williams, David L.; Bellelli, Andrea

doi:10.1016/j.jinorgbio.2011.11.005

Cited by 49 publications

(43 citation statements)

References 36 publications

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“…The lethal effect of AF and other nucleophilic compounds has been related to its ability to inhibit the selenium-dependent thioredoxin reductase [36]. Previously, we reported that 10 M AF fully inhibits TGR in cysticerci [34], an effect also observed in T. solium cysticerci (Fig.…”

Section: Nac Inhibits and Bso Enhances The Af-mediated Lethal Effect mentioning

confidence: 80%

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Auranofin-induced oxidative stress causes redistribution of the glutathione pool in Taenia crassiceps cysticerci

Martínez-González

Guevara-Flores

Rendón

et al. 2015

Molecular and Biochemical Parasitology

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Section: Nac Inhibits and Bso Enhances The Af-mediated Lethal Effect mentioning

confidence: 80%

“…AF is an antirheumatic http://dx.doi.org/10.1016/j.molbiopara.2015.05.001 0166-6851/© 2015 Elsevier B.V. All rights reserved. gold-derivatized salt [35], which specifically inhibits selenoproteins, such as mammalian TrxR and TGR [36].…”

Section: Introductionmentioning

confidence: 99%

Auranofin-induced oxidative stress causes redistribution of the glutathione pool in Taenia crassiceps cysticerci

Martínez-González

Guevara-Flores

Rendón

et al. 2015

Molecular and Biochemical Parasitology

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“…8) Approximately 25% of the dosage is detected in the plasma and it predominantly binds to albumin. 7,63,64) The plasma concentration of auranofin reaches 60 to 90 µg/L within 1 to 2 h. [65][66][67] The terminal plasma half-life of auranofin ranges from 17 to 25 d and it is eliminated from the body after an average of 55 to 80 d. 27) A total of 85% of auranofin is excreted via the feces, and the remaining 15% via the kidneys. 7,67) Based on its pharmacokinetics, auranofin was recently evaluated in clinical studies for treating cancer (see www.clinicaltrials.gov trial numbers NCT01419691, NCT01737502, NCT01747798, and NCT03456700).…”

Section: Auranofin As An Anticancer Agentmentioning

confidence: 99%

Potential Anticancer Activity of Auranofin

2019

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Gold compounds have a long history of use in medicine. Auranofin was developed more than 30 years ago as an oral therapy for rheumatoid arthritis. Now, however, auranofin is rarely used in clinical practice despite its efficacy for treating rheumatoid arthritis because more novel antirheumatic medications are available. Although its use in clinical practice has decreased, studies on auranofin have continued and it shows promise for the treatment of several different diseases, including cancer and bacterial and parasitic infections. Several potential novel applications of auranofin for treating human disease have been proposed. Auranofin inhibits the activity of thioredoxin reductase (TrxR), an enzyme of the thioredoxin (Trx) system that is important for maintaining the intracellular redox state. Particularly in cancers, TrxR inhibition leads to an increase in cellular oxidative stress and induces apoptosis. TrxR overexpression is associated with aggressive tumor progression and poor survival in patients with breast, ovarian, and lung cancers. The Trx system may represent an attractive target for the development of new cancer treatments. Therefore, the TrxR inhibitor auranofin may be a potent anticancer agent. This review summarizes the current understanding of auranofin for cancer therapy.

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“…Auranofin contains a molecule of gold in a 3,4,5-Triacetyloxy-6-sulfanyl-oxan-2-yl methyl ethanoate scaffold and has been proposed to be a pro-drug (37) that delivers gold to dithiol groups, like those found in proteins that bear thioredoxin-containing domains (38). Although auranofin inhibits mammalian thioredoxin reductase (39), the source of its anti-inflammatory activity remains ill-defined and may reflect inhibition of multiple targets.…”

Section: Discussionmentioning

confidence: 99%

Auranofin resistance inToxoplasma gondiidecreases the accumulation of reactive oxygen species but does not target parasite thioredoxin reductase

Christopher¹,

Tirtorahardjo

Jan

et al. 2020

Preprint

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23Auranofin, a reprofiled FDA-approved drug originally designed to treat rheumatoid 24 arthritis, has emerged as a promising anti-parasitic drug. It induces the accumulation of 25 reactive oxygen species (ROS) in parasites, including Toxoplasma gondii. We generated 26 auranofin resistant T. gondii lines through chemical mutagenesis in order to identify the 27 molecular target of this drug. Resistant clones were confirmed with a competition assay 28 using wild-type T. gondii expressing yellow fluorescence protein (YFP) as a reference 29 strain. The predicted auranofin target, thioredoxin reductase, was not mutated in any of 30 our resistant lines. Subsequent whole genomic sequencing analysis (WGS) did not reveal 31 a consensus resistance locus, although many have point mutations in genes encoding 32 redox-relevant proteins such as superoxide dismutase (TgSOD2) and ribonucleotide 33 reductase. We investigated the SOD2 L201P mutation and found that it was not sufficient 34 to confer resistance when introduced into wild-type parasites. Resistant clones 35 accumulated less ROS than their wild type counterparts. Our results demonstrate that 36 resistance to auranofin in T. gondii enhances its ability to abate oxidative stress through 37 diverse mechanisms. This evidence supports a hypothesized mechanism of auranofin 38 anti-parasitic activity as disruption of redox homeostasis. 39 40 41 42 3 45While this is currently a critical therapeutic strategy, currently approved drugs cannot 46 eliminate latent parasites in cysts that are found in chronically infected individuals. 47Moreover, these drugs have significant bone marrow toxicity, are suspected teratogens 48 and the emergence of resistance remains a potential threat to treatment. Repurposing 49 FDA-approved drugs will accelerate drug discovery for neglected parasitic diseases. 50Most recently, auranofin, a reprofiled drug that is FDA-approved for treatment of 51 rheumatoid arthritis, has emerged as a promising anti-parasitic agent. It has 52 antiproliferative activity against Plasmodium falciparum (1) , Schistosoma mansoni (2), 53Leishmania infantum (3) and Entamoeba histolytica (4) as well as other parasites with 54 public health significance (5)(6)(7)(8)(9)(10)(11). Despite this promising broad spectrum of anti-parasitic 55 activity, the molecular target of auranofin has only been indirectly implicated as 56 thioredoxin reductase. 57Thioredoxin reductase enzymes are found in archaea, bacteria and diverse 58 eukaryotes and play a key role in reduction of disulfide bonds that is essential for cell 59 replication and survival. Inhibition of human thioredoxin reductase 1 induces expression 60 of heme oxygenase-1 to repress inflammation(12). We previously demonstrated that 61 auranofin reduces T. gondii infection of host cells in vitro and a single dose of auranofin 62 allows survival of chicken embryos infected with this parasite (13). It is hypothesized 63 that the anti-parasitic activity of auranofin comes from inhibition of the thioredoxin 64 reductase enzyme of thes...

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On the mechanism and rate of gold incorporation into thiol-dependent flavoreductases

Cited by 49 publications

References 36 publications

Auranofin-induced oxidative stress causes redistribution of the glutathione pool in Taenia crassiceps cysticerci

Auranofin-induced oxidative stress causes redistribution of the glutathione pool in Taenia crassiceps cysticerci

Potential Anticancer Activity of Auranofin

Auranofin resistance inToxoplasma gondiidecreases the accumulation of reactive oxygen species but does not target parasite thioredoxin reductase

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