Anti-fibrotic activity of gold and platinum complexes – Au(I) compounds as a new class of anti-fibrotic agents

Stratton, Matthew; Ramachandran, Akshaya; Camacho, Ehxciquiel Jaeroume M.; Patil, Shivaputra A.; Waris, Gulam; Grice, Kyle A.

doi:10.1016/j.jinorgbio.2020.111023

Cited by 10 publications

(12 citation statements)

References 62 publications

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“…Thus, it was described that several inorganic compounds and complexes present Ca 2+ -ATPases IC 50 inhibition values globally not so different from the above well-known Ca 2+ -ATPases drugs inhibitors, for example decavanadate (IC 50 = 15 µM), polyoxotungstates (IC 50 = 0.3-200 µM), polyoxovanadates (IC 50 =1 µM), and vanadium complexes such as BMOV (IC 50 = 40 µM), among others [31][32][33][34][35]. In summary, both gold(I) and gold(III) compounds 1-4 are strong inhibitors of the SR Ca 2+ -ATPase, pointing out this enzyme as a putative target for gold compounds with anticancer activity, described as promising agents for the future in medicinal chemistry [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18]23,29,[42][43][44].…”

Section: Abbreviationmentioning

confidence: 99%

“…In recent years, anti-cancer-active Au(I) complexes containing multidentate N-donor ligands (e.g., 2,2 -terpyridine; thiourea, triazole-peptide or other ligands were also studied for the same purpose [15]. Additionally, gold compounds have been a subject of research in terms of antibacterial, antivirus and anti-parasite activity [12,13,16,17] and in Alzheimer's disease [18]. Gold compounds, together with vanadium complexes and polyoxometalates, have been selected by some researchers as alternative anti-tumor substances with promising results in tumor growth suppression [19][20][21][22][23].…”

Section: Introductionmentioning

confidence: 99%

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The Ca2+-ATPase Inhibition Potential of Gold(I, III) Compounds

et al. 2020

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The therapeutic applications of gold are well-known for many centuries. The most used gold compounds contain Au(I). Herein, we report, for the first time, the ability of four Au(I) and Au(III) complexes, namely dichloro (2-pyridinecarboxylate) Au(III) (abbreviated as 1), chlorotrimethylphosphine Au(I) (2), 1,3-bis(2,6-diisopropylphenyl) imidazole-2-ylidene Au(I) chloride (3), and chlorotriphenylphosphine Au(I) (4), to affect the sarcoplasmic reticulum (SR) Ca2+-ATPase activity. The tested gold compounds strongly inhibit the Ca2+-ATPase activity with different effects, being Au(I) compounds 2 and 4 the strongest, with half maximal inhibitory concentration (IC50) values of 0.8 and 0.9 µM, respectively. For Au(III) compound 1 and Au(I) compound 3, higher IC50 values are found (4.5 µM and 16.3 µM, respectively). The type of enzymatic inhibition is also different, with gold compounds 1 and 2 showing a non-competitive inhibition regarding the native substrate MgATP, whereas for Au compounds 3 and 4, a mixed type of inhibition is observed. Our data reveal, for the first time, Au(I) compounds with powerful inhibitory capacity towards SR Ca2+ATPase function. These results also show, unprecedently, that Au (III) and Au(I) compounds can act as P-type ATPase inhibitors, unveiling a potential application of these complexes.

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Section: Abbreviationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Ca2+-ATPase Inhibition Potential of Gold(I, III) Compounds

et al. 2020

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“…The underlying mechanism comprised blockade of the NLRP3 inflammasome, which resulted in reduction of IL-1β secretion and induction of pyroptosis in macrophages, as well as reduction of HSC migratory ability. It has been very recently reported that high concentration (>1 µM) gold compounds inhibit TGFβ1 signaling in LX-2 cells 30 . However, we failed to show any significant effect of auranofin (<0.1 µM) on TGFβ1-stimulated Smad2/3 phosphorylation in primary HSCs.…”

Section: Discussionmentioning

confidence: 99%

Auranofin prevents liver fibrosis by system Xc-mediated inhibition of NLRP3 inflammasome

et al. 2021

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Demand for a cure of liver fibrosis is rising with its increasing morbidity and mortality. Therefore, it is an urgent issue to investigate its therapeutic candidates. Liver fibrosis progresses following ‘multi-hit’ processes involving hepatic stellate cells, macrophages, and hepatocytes. The NOD-like receptor protein 3 (NLRP3) inflammasome is emerging as a therapeutic target in liver fibrosis. Previous studies showed that the anti-rheumatic agent auranofin inhibits the NLRP3 inflammasome; thus, this study evaluates the antifibrotic effect of auranofin in vivo and explores the underlying molecular mechanism. The antifibrotic effect of auranofin is assessed in thioacetamide- and carbon tetrachloride-induced liver fibrosis models. Moreover, hepatic stellate cell (HSC), bone marrow-derived macrophage (BMDM), kupffer cell, and hepatocyte are used to examine the underlying mechanism of auranofin. Auranofin potently inhibits activation of the NLRP3 inflammasome in BMDM and kupffer cell. It also reduces the migration of HSC. The underlying molecular mechanism was inhibition of cystine-glutamate antiporter, system Xc. Auranofin inhibits system Xc activity and instantly induced oxidative burst, which mediated inhibition of the NLRP3 inflammasome in macrophages and HSCs. Therefore, to the best of our knowledge, we propose the use of auranofin as an anti-liver fibrotic agent.

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“…Because IL-6 is linked to pulmonary fibrosis, for example, during idiopathic pulmonary fibrosis ( 46 ), high IL-6 levels during COVID-19 could promote pulmonary fibrosis; this hypothesis would need further investigation. Since auranofin inhibits fibrosis in human hepatic stellate cells ( 47 ), auranofin could hypothetically have the same inhibitory effect on SARS-CoV-2-associated pulmonary fibrosis; this hypothesis will need to be further investigated.…”

Section: Mechanisms Of Action Of Auranofinmentioning

confidence: 99%

Will Auranofin Become a Golden New Treatment Against COVID-19?

Sonzogni-Desautels

Ndao

2021

Front. Immunol.

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Auranofin is an FDA-approved disease-modifying anti-rheumatic drug that has been used for decades for treatment of rheumatoid arthritis. This gold(I) compound has anti-inflammatory properties because it reduces IL-6 expression via inhibition of the NF-κB-IL-6-STAT3 signaling pathway. Also, by inhibiting redox enzymes such as thioredoxin reductase, auranofin increases cellular oxidative stress and promotes apoptosis. Auranofin also possesses antiviral properties. Recently, it was reported that auranofin reduced by 95% SARS-CoV-2 RNA in infected human cells in vitro and decreased SARS-CoV-2-induced cytokine expression, including IL-6. During SARS-CoV-2 infection, a cytokine storm involving IL-6 increases severity of illness and worsens prognosis. Therefore, auranofin could, in our point of view, reduce pathology due to SARS-CoV-2-induced IL-6. COVID-19 is a rapidly-evolving respiratory disease now distributed worldwide. Strikingly high numbers of new COVID-19 cases are reported daily. We have begun a race to vaccinate people, but due to the complex logistics of this effort, the virus will continue to spread before all humans can be immunized, and new variants that may be less well contained by current vaccines are of concern. The COVID-19 pandemic has overwhelmed health care systems and new treatments to reduce mortality are urgently needed. We encourage to further evaluate the potential of auranofin in the treatment of COVID-19 in vitro and in animal models of SARS-CoV-2 infection and, if preliminary data are promising, in clinical trials with COVID-19 patients. In our opinion, auranofin has the potential to become a valuable addition to available therapies in this pandemic.

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Anti-fibrotic activity of gold and platinum complexes – Au(I) compounds as a new class of anti-fibrotic agents

Cited by 10 publications

References 62 publications

The Ca2+-ATPase Inhibition Potential of Gold(I, III) Compounds

The Ca2+-ATPase Inhibition Potential of Gold(I, III) Compounds

Auranofin prevents liver fibrosis by system Xc-mediated inhibition of NLRP3 inflammasome

Will Auranofin Become a Golden New Treatment Against COVID-19?

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