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International Immunopharmacology Dec 2021Auranofin (AF), a gold compound, has been used to treat rheumatoid arthritis (RA) for more than 40 years; however, its mechanism of action remains unknown. We revealed... (Review)
Review
Auranofin (AF), a gold compound, has been used to treat rheumatoid arthritis (RA) for more than 40 years; however, its mechanism of action remains unknown. We revealed that AF inhibited the induction of proinflammatory proteins and their mRNAs by the inflammatory stimulants, cyclooxygenase-2 and inducible nitric oxide synthase, and their upstream regulator, NF-κB. AF also activated the proteins peroxyredoxin-1, Kelch-like ECH-associated protein 1, and NF-E2-related factor 2, and inhibited thioredoxin reductase, all of which are involved in oxidative or electrophilic stress under physiological conditions. Although the cell membrane was previously considered to be permeable to AF because of its hydrophobicity, the mechanisms responsible for transporting AF into and out of cells as well as its effects on the uptake and excretion of other drugs have not yet been elucidated. Antibodies for cytokines have recently been employed in the treatment of RA, which has had an impact on the use of AF. Trials to repurpose AF as a risk-controlled agent to treat cancers or infectious diseases, including severe acute respiratory syndrome coronavirus 2/coronavirus disease 2019, are ongoing. Novel gold compounds are also under development as anti-cancer and anti-infection agents.
Topics: Animals; Antirheumatic Agents; Arthritis, Rheumatoid; Auranofin; Communicable Diseases; Drug Repositioning; Humans; Neoplasms; SARS-CoV-2; Tuberculosis; COVID-19 Drug Treatment
PubMed: 34731781
DOI: 10.1016/j.intimp.2021.108272 -
Frontiers in Immunology 2021Auranofin 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... (Review)
Review
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 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 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 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.
Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Auranofin; Cytokine Release Syndrome; Drug Approval; Humans; Interleukin-6; SARS-CoV-2; Thioredoxins; COVID-19 Drug Treatment
PubMed: 34630379
DOI: 10.3389/fimmu.2021.683694 -
Clinical and Molecular Hepatology Oct 2022We aim to evaluate the effects of auranofin, a known antioxidant, on hepatic steatosis, inflammation, and fibrosis, contributing to non-alcoholic steatohepatitis (NASH)...
BACKGROUND/AIMS
We aim to evaluate the effects of auranofin, a known antioxidant, on hepatic steatosis, inflammation, and fibrosis, contributing to non-alcoholic steatohepatitis (NASH) development in vivo and in vitro.
METHODS
Transcriptome analysis of LX-2 cells was that expression patterns of genes changed by auranofin, and their related pathways were estimated. We used the gene set enrichment analysis (GSEA) program to determine the pathway involved in overall genetic change. In vitro, LX-2 and HepG2 cells were treated with transforming growth factor (TGF)-β1 and palmitic acid (PA), respectively, and the antifibrotic and antiadipogenic effect function of auranofin was evaluated.
RESULTS
Transcriptome analysis revealed that auranofin decreased the expression of 15 genes, including thrombospondin 1, endothelin 1 (ET-1), fibronectin 1, and LOX. The molecular functions of these genes are involved in collagen binding. GSEA of the overall gene expression pattern revealed that many genes increased in the reactive oxygen species pathway and decreased in the inflammatory response. Auranofin decreased nuclear factor kappa B (NF-κB) and IκBα in TGF-β1-induced LX-2 cells, thereby reducing ET-1 and fibrosis. Furthermore, increased pNRF2 in PA-induced HepG2 cells led to increased antioxidant marker expression and decreased lipid accumulation. In the bile duct ligation model mice, auranofin reduced the fibrosis area and increased the survival rate. Auranofin reduced liver fibrosis and lipid accumulation in NASH model mice fed on a Western diet.
CONCLUSION
Auranofin inhibits lipogenesis and fibrosis formation and is a proposed candidate for NASH treatment.
Topics: Mice; Humans; Animals; Non-alcoholic Fatty Liver Disease; NF-kappa B; NF-E2-Related Factor 2; Transforming Growth Factor beta1; Auranofin; NF-KappaB Inhibitor alpha; Thrombospondin 1; Fibronectins; Palmitic Acid; Reactive Oxygen Species; Endothelin-1; Antioxidants; Mice, Inbred C57BL; Signal Transduction; Liver Cirrhosis; Transforming Growth Factors; Collagen; Liver
PubMed: 35730208
DOI: 10.3350/cmh.2022.0068 -
Nature Communications Aug 2023UBA1 is the primary E1 ubiquitin-activating enzyme responsible for generation of activated ubiquitin required for ubiquitination, a process that regulates stability and...
UBA1 is the primary E1 ubiquitin-activating enzyme responsible for generation of activated ubiquitin required for ubiquitination, a process that regulates stability and function of numerous proteins. Decreased or insufficient ubiquitination can cause or drive aging and many diseases. Therefore, a small-molecule enhancing UBA1 activity could have broad therapeutic potential. Here we report that auranofin, a drug approved for the treatment of rheumatoid arthritis, is a potent UBA1 activity enhancer. Auranofin binds to the UBA1's ubiquitin fold domain and conjugates to Cys1039 residue. The binding enhances UBA1 interactions with at least 20 different E2 ubiquitin-conjugating enzymes, facilitating ubiquitin charging to E2 and increasing the activities of seven representative E3s in vitro. Auranofin promotes ubiquitination and degradation of misfolded ER proteins during ER-associated degradation in cells at low nanomolar concentrations. It also facilitates outer mitochondrial membrane-associated degradation. These findings suggest that auranofin can serve as a much-needed tool for UBA1 research and therapeutic exploration.
Topics: Ubiquitin; Ubiquitin-Conjugating Enzymes; Auranofin; Ubiquitination; Ubiquitin-Activating Enzymes
PubMed: 37558718
DOI: 10.1038/s41467-023-40537-x -
Chemical & Pharmaceutical Bulletin 2019Gold 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,... (Review)
Review
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.
Topics: Animals; Antineoplastic Agents; Apoptosis; Auranofin; Enzyme Inhibitors; Humans; Neoplasms; Oxidation-Reduction; Oxidative Stress; Thioredoxin-Disulfide Reductase; Thioredoxins
PubMed: 30827998
DOI: 10.1248/cpb.c18-00767 -
Yakugaku Zasshi : Journal of the... 2021Gold compounds have been employed throughout history to treat various types of disease, from ancient times to the present day. In the year 1985, auranofin, a... (Review)
Review
Gold compounds have been employed throughout history to treat various types of disease, from ancient times to the present day. In the year 1985, auranofin, a gold-containing compound, was approved by U.S. Food and Drug Administration (FDA) as a therapeutic agent to target rheumatoid arthritis that would facilitate easy oral drug administration as opposed to conventional intramuscular injection used in treatments. Furthermore, auranofin demonstrates promising results for the treatment of various diseases beyond rheumatoid arthritis, including cancer, neurodegenerative diseases, acquired immune deficiency syndrome, and bacterial and parasitic infections. Various potential novel applications for auranofin have been proposed for treating human diseases. Auranofin has previously been demonstrated to inhibit thioredoxin reductase (TrxR) involved within the thioredoxin (Trx) system that comprises one of the critical cellular redox systems within the body. TrxR comprises the sole known enzyme that catalyzes Trx reduction. With cancers in particular, TrxR inhibition facilitates an increase in cellular oxidative stress and suppresses tumor growth. In this review, we describe the potential of auranofin to serve as an anticancer agent and further drug repurposing to utilize this as a strategy for further appropriate drug developments.
Topics: Antineoplastic Agents; Arthritis, Rheumatoid; Auranofin; Drug Development; Drug Repositioning; Humans; Neoplasms; Oxidative Stress; Thioredoxin-Disulfide Reductase
PubMed: 33642497
DOI: 10.1248/yakushi.20-00179-2 -
British Journal of Rheumatology May 1997
Review
Topics: Adolescent; Adult; Aged; Antirheumatic Agents; Auranofin; Child; Child, Preschool; Humans; Infant; Joints; Middle Aged; Radiography; Randomized Controlled Trials as Topic; Rheumatic Diseases; Treatment Outcome
PubMed: 9189058
DOI: 10.1093/rheumatology/36.5.560 -
Bioorganic & Medicinal Chemistry Feb 2023Pseudomonas aeruginosa is widely attributed as the leading cause of hospital-acquired infections. Due to intrinsic antibiotic resistance mechanisms and the ability to...
Pseudomonas aeruginosa is widely attributed as the leading cause of hospital-acquired infections. Due to intrinsic antibiotic resistance mechanisms and the ability to form biofilms, P. aeruginosa infections are challenging to treat. P. aeruginosa employs multiple virulence mechanisms to establish infections, many of which are controlled by the global virulence regulator Vfr. An attractive strategy to combat P. aeruginosa infections is thus the use of anti-virulence compounds. Here, we report the discovery that FDA-approved drug auranofin attenuates virulence pathways in P. aeruginosa, including quorum sensing (QS) and Type IV pili (TFP). We show that auranofin acts via multiple targets, one of which being Vfr. Consistent with inhibition of QS and TFP expression, we show that auranofin attenuates biofilm maturation, and when used in combination with colistin, displays strong synergy in eradicating P. aeruginosa biofilms. Auranofin may have immediate applications as an anti-virulence drug against P. aeruginosa infections.
Topics: Humans; Pseudomonas aeruginosa; Auranofin; Anti-Bacterial Agents; Virulence Factors; Pseudomonas Infections; Biofilms; Quorum Sensing; Bacterial Proteins
PubMed: 36682225
DOI: 10.1016/j.bmc.2023.117167 -
Drug Discovery Today Jul 2022Multidrug resistance (MDR) is a significant issue associated with the clinical application of antibiotics. It is also challenging to discover and develop new antibiotics... (Review)
Review
Multidrug resistance (MDR) is a significant issue associated with the clinical application of antibiotics. It is also challenging to discover and develop new antibiotics with novel scaffolds. Therefore, the repurposing of existing drugs has become a promising strategy for antibiotic drug discovery. Auranofin, an approved gold metallic drug, has been used for the treatment of rheumatoid arthritis (RA) for many years. Recent research revealed that auranofin has strong antibacterial activity against multiple Gram-positive bacteria by inhibiting thioredoxin reductase (TrxR). These results inspired the development of gold complexes as antibacterial agents. Herein, we discuss recent advances in the development of auranofin and other gold complexes as antibacterial agents, providing a new viewpoint for the treatment of bacterial infection.
Topics: Anti-Bacterial Agents; Auranofin; Drug Repositioning; Gold; Thioredoxin-Disulfide Reductase
PubMed: 35192926
DOI: 10.1016/j.drudis.2022.02.010 -
Journal of Applied Microbiology Sep 2022This study was performed to identify the potential for repurposing auranofin as an antibiotic adjuvant against carbapenemase-producing Acinetobacter baumannii.
AIMS
This study was performed to identify the potential for repurposing auranofin as an antibiotic adjuvant against carbapenemase-producing Acinetobacter baumannii.
METHODS AND RESULTS
The clinically isolated A. baumannii strains used in this study were all resistant to carbapenems and harboured the bla gene. The synergistic effect of auranofin and doripenem against carbapenemase-producing A. baumannii was confirmed through checkerboard and growth kinetic analyses. This study also demonstrated the inhibitory effects of auranofin against A. baumannii biofilms. The anti-biofilm effects of auranofin were visualized by confocal laser scanning microscopy (CLSM). Furthermore, auranofin inhibited motility, one of the virulence factors. Additionally, the changes in the expression of carbapenemase-, biofilm- and efflux pump-related genes induced by auranofin were confirmed via quantitative polymerase chain reaction (qPCR).
CONCLUSIONS
Our results demonstrated that auranofin has an antibacterial effect with doripenem and an inhibitory effect on several factors related to carbapenem resistance.
SIGNIFICANCE AND IMPACT OF THE STUDY
This study suggests that auranofin is a promising antibiotic adjuvant that can be used to prevent antibiotic resistance in carbapenem-resistant A. baumannii.
Topics: Acinetobacter Infections; Acinetobacter baumannii; Anti-Bacterial Agents; Auranofin; Bacterial Proteins; Carbapenems; Doripenem; Drug Resistance, Multiple, Bacterial; Humans; Microbial Sensitivity Tests; beta-Lactamases
PubMed: 35633297
DOI: 10.1111/jam.15644