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Oncogene Mar 2022The prognosis for B-cell precursor acute lymphoblastic leukemia patients with Mixed-Lineage Leukemia (MLL) gene rearrangements (MLLr BCP-ALL) is still extremely poor....
The prognosis for B-cell precursor acute lymphoblastic leukemia patients with Mixed-Lineage Leukemia (MLL) gene rearrangements (MLLr BCP-ALL) is still extremely poor. Inhibition of anti-apoptotic protein BCL-2 with venetoclax emerged as a promising strategy for this subtype of BCP-ALL, however, lack of sufficient responses in preclinical models and the possibility of developing resistance exclude using venetoclax as monotherapy. Herein, we aimed to uncover potential mechanisms responsible for limited venetoclax activity in MLLr BCP-ALL and to identify drugs that could be used in combination therapy. Using RNA-seq, we observed that long-term exposure to venetoclax in vivo in a patient-derived xenograft model leads to downregulation of several tumor protein 53 (TP53)-related genes. Interestingly, auranofin, a thioredoxin reductase inhibitor, sensitized MLLr BCP-ALL to venetoclax in various in vitro and in vivo models, independently of the p53 pathway functionality. Synergistic activity of these drugs resulted from auranofin-mediated upregulation of NOXA pro-apoptotic protein and potent induction of apoptotic cell death. More specifically, we observed that auranofin orchestrates upregulation of the NOXA-encoding gene Phorbol-12-Myristate-13-Acetate-Induced Protein 1 (PMAIP1) associated with chromatin remodeling and increased transcriptional accessibility. Altogether, these results present an efficacious drug combination that could be considered for the treatment of MLLr BCP-ALL patients, including those with TP53 mutations.
Topics: Apoptosis; Apoptosis Regulatory Proteins; Auranofin; Bridged Bicyclo Compounds, Heterocyclic; Burkitt Lymphoma; Cell Line, Tumor; Humans; Neoplasm Proteins; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Sulfonamides; Tumor Suppressor Protein p53
PubMed: 35091682
DOI: 10.1038/s41388-022-02196-y -
Proceedings of the National Academy of... Apr 2015Infections caused by antibiotic-resistant bacteria are a rising public health threat and make the identification of new antibiotics a priority. From a cell-based screen...
Infections caused by antibiotic-resistant bacteria are a rising public health threat and make the identification of new antibiotics a priority. From a cell-based screen for bactericidal compounds against Mycobacterium tuberculosis under nutrient-deprivation conditions we identified auranofin, an orally bioavailable FDA-approved antirheumatic drug, as having potent bactericidal activities against both replicating and nonreplicating M. tuberculosis. We also found that auranofin is active against other Gram-positive bacteria, including Bacillus subtilis and Enterococcus faecalis, and drug-sensitive and drug-resistant strains of Enterococcus faecium and Staphylococcus aureus. Our biochemical studies showed that auranofin inhibits the bacterial thioredoxin reductase, a protein essential in many Gram-positive bacteria for maintaining the thiol-redox balance and protecting against reactive oxidative species. Auranofin decreases the reducing capacity of target bacteria, thereby sensitizing them to oxidative stress. Finally, auranofin was efficacious in a murine model of methicillin-resistant S. aureus infection. These results suggest that the thioredoxin-mediated redox cascade of Gram-positive pathogens is a valid target for the development of antibacterial drugs, and that the existing clinical agent auranofin may be repurposed to aid in the treatment of several important antibiotic-resistant pathogens.
Topics: Animals; Anti-Bacterial Agents; Auranofin; Bacillus subtilis; Bacterial Proteins; Dose-Response Relationship, Drug; Enterococcus faecium; Female; Gene Deletion; Glutathione; Homeostasis; Mice; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Oxidation-Reduction; Oxidative Stress; Staphylococcus aureus; Stem Cells; Sulfhydryl Compounds; Thioredoxin-Disulfide Reductase
PubMed: 25831516
DOI: 10.1073/pnas.1504022112 -
Cellular Physiology and Biochemistry :... 2018Cardiac hypertrophy is a major outcome and compensatory response of the cardiovascular system to hemodynamic and additional stress responses that ultimately lead to...
BACKGROUND/AIMS
Cardiac hypertrophy is a major outcome and compensatory response of the cardiovascular system to hemodynamic and additional stress responses that ultimately lead to heart failure. Auranofin (Aur) has been used for treating rheumatic arthritis for several decades. Aur is a 19S proteasome-associated deubiquitinase inhibitor, and inhibition of the proteasome is speculated to reverse cardiac hypertrophy. However, the role of the deubiquitinases, especially 19S proteasome-associated deubiquitinases, in the regulation of cardiac remodeling remains poorly understood. The present study investigated the role of Aur in cardiac hypertrophy both in vitro and in vivo.
METHODS
Male Sprague-Dawley rats underwent abdominal aortic constriction to induce left ventricular hypertrophy. The neonatal rat primary myocardial cell hypertrophy model was induced by Ang II. Echocardiography, hematoxylin-eosin staining, Masson's trichrome staining, immunochemistry, western blot analysis, a cell viability assay, and enzyme-linked immunosorbent assay were performed.
RESULTS
Aur significantly reduced the abdominal aortic constriction that led to left ventricular hypertrophy, reduced heart cavity expansion, and functional disorder, and thereby reduced fetal gene expression and attenuated cardiac fibrosis. Furthermore, Aur caused marked accumulation of ubiquitinated proteins and IκBα, as well as inactivation of NF-κB. This phenomenon was confirmed in the neonatal rat primary myocardial cell hypertrophy model.
CONCLUSIONS
The present study indicated that Aur blocks the development of left ventricular hypertrophy induced by abdominal aortic constriction. This phenomenon might be attributed to inhibition of the 19S proteasome-associated deubiquitinase that can lead to aggregation of IκBα and inactivation of the NF-κB pathway. Thus, Aur could be a potential anti-cardiac hypertrophy agent.
Topics: Animals; Antirheumatic Agents; Auranofin; Cardiomegaly; Cells, Cultured; Deubiquitinating Enzymes; Hypertrophy, Left Ventricular; Male; Myocytes, Cardiac; NF-kappa B; Proteasome Inhibitors; Rats, Sprague-Dawley; Signal Transduction
PubMed: 29554646
DOI: 10.1159/000488230 -
The Cochrane Database of Systematic... 2001Patients with chronic severe asthma are often dependent on the long term prescription of oral corticosteroids. The use of steroids is associated with serious side... (Review)
Review
BACKGROUND
Patients with chronic severe asthma are often dependent on the long term prescription of oral corticosteroids. The use of steroids is associated with serious side effects. Physicians treating such patients continue to search for alternative therapies that reduce the need for chronic dosing with oral steroids. Gold compounds are immunosuppressive agents and have benefits in the treatment of a number of inflammatory disorders. They have therefore been identified as an potentially useful agents in the treatment of chronic severe asthma both in terms of possible efficacy and as steroid sparing agents.
OBJECTIVES
The objective of this review was to assess the effects of adding gold to oral steroids in the treatment of chronic steroid dependent asthmatics.
SEARCH STRATEGY
The Cochrane Airways Group trials register and reference lists of identified articles were searched.
SELECTION CRITERIA
Randomised trials looking at the addition of gold compared to placebo in adult steroid dependent asthmatics.
DATA COLLECTION AND ANALYSIS
Trial quality was assessed and data extraction was carried out by two reviewers independently. Study authors were contacted for missing information.
MAIN RESULTS
Three trials fulfilled the criteria for inclusion in the review and a total of 376 patients were recruited into these studies. Data from 311 patients could be analysed. There was a small but significant treatment effect for gold in terms of steroid dose reduction (Peto Odds Ratio 0.51, 95% confidence intervals 0.31,0.83). No meta-analysis could be done for measures of lung function although overall there were few changes suggesting a positive benefit for gold. There were trends suggestive of adverse effects but no significant changes for gold treated patients with respect to proteinuria (Peto Odds Ratio 1.4, 95% confidence intervals 0.6, 3.3) dermatitis/eczema Peto Odds Ratio 2.1, 95% confidence intervals 0.9, 4.7).
REVIEWER'S CONCLUSIONS
The changes seen in these trials are small and probably of limited clinical significance. Given the side effects of gold and necessity for monitoring the use of gold as a steroid sparing agent in asthma cannot be recommended.
Topics: Adrenal Cortex Hormones; Anti-Asthmatic Agents; Asthma; Auranofin; Aurothioglucose; Humans; Randomized Controlled Trials as Topic
PubMed: 11406053
DOI: 10.1002/14651858.CD002985 -
Redox Biology May 2022Enzymes in the thiol redox systems of microbial pathogens are promising targets for drug development. In this study we characterized the thioredoxin reductase (TrxR)...
Enzymes in the thiol redox systems of microbial pathogens are promising targets for drug development. In this study we characterized the thioredoxin reductase (TrxR) selenoproteins from Brugia malayi and Onchocerca volvulus, filarial nematode parasites and causative agents of lymphatic filariasis and onchocerciasis, respectively. The two filarial enzymes showed similar turnover numbers and affinities for different thioredoxin (Trx) proteins, but with a clear preference for the autologous Trx. Human TrxR1 (hTrxR1) had a high and similar specific activity versus the human and filarial Trxs, suggesting that, in vivo, hTrxR1 could possibly be the reducing agent of parasite Trxs once they are released into the host. Both filarial TrxRs were efficiently inhibited by auranofin and by a recently described inhibitor of human TrxR1 (TRi-1), but not as efficiently by the alternative compound TRi-2. The enzyme from B. malayi was structurally characterized also in complex with NADPH and auranofin, producing the first crystallographic structure of a nematode TrxR. The protein represents an unusual fusion of a mammalian-type TrxR protein architecture with an N-terminal glutaredoxin-like (Grx) domain lacking typical Grx motifs. Unlike thioredoxin glutathione reductases (TGRs) found in platyhelminths and mammals, which are also Grx-TrxR domain fusion proteins, the TrxRs from the filarial nematodes lacked glutathione disulfide reductase and Grx activities. The structural determinations revealed that the Grx domain of TrxR from B. malayi contains a cysteine (C22), conserved in TrxRs from clade IIIc nematodes, that directly interacts with the C-terminal cysteine-selenocysteine motif of the homo-dimeric subunit. Interestingly, despite this finding we found that altering C22 by mutation to serine did not affect enzyme catalysis. Thus, although the function of the Grx domain in these filarial TrxRs remains to be determined, the results obtained provide insights on key properties of this important family of selenoprotein flavoenzymes that are potential drug targets for treatment of filariasis.
Topics: Animals; Auranofin; Brugia malayi; Cysteine; Humans; Mammals; Onchocerca volvulus; Oxidation-Reduction; Parasites; Selenoproteins; Thioredoxin-Disulfide Reductase; Thioredoxins
PubMed: 35276442
DOI: 10.1016/j.redox.2022.102278 -
The Yale Journal of Biology and Medicine Apr 1954
Topics: Animals; Aurothioglucose; Gold; Mice; Obesity
PubMed: 13169910
DOI: No ID Found -
Postgraduate Medical Journal Jun 1983A 70-year-old female with seronegative rheumatoid arthritis developed interstitial pneumonitis while on chrysotherapy. The reversibility of lung disease and favourable...
A 70-year-old female with seronegative rheumatoid arthritis developed interstitial pneumonitis while on chrysotherapy. The reversibility of lung disease and favourable response to steroid treatment support the diagnosis of gold-induced lung disease and distinguish this entity from other forms of interstitial lung disease associated with rheumatoid arthritis. The relevant literature related to gold-induced lung disease is briefly reviewed.
Topics: Aged; Arthritis, Rheumatoid; Aurothioglucose; Female; Gold; Humans; Pulmonary Fibrosis
PubMed: 6415637
DOI: 10.1136/pgmj.59.692.368 -
International Journal of Antimicrobial... Mar 2016The scourge of multidrug-resistant bacterial infections necessitates the urgent development of novel antimicrobials to address this public health challenge. Drug...
The scourge of multidrug-resistant bacterial infections necessitates the urgent development of novel antimicrobials to address this public health challenge. Drug repurposing is a proven strategy to discover new antimicrobial agents; given that these agents have undergone extensive toxicological and pharmacological analysis, repurposing is an effective method to reduce the time, cost and risk associated with traditional antibiotic innovation. In this study, the in vitro and in vivo antibacterial activities of an antirheumatic drug, auranofin, was investigated against multidrug-resistant Staphylococcus aureus. The results indicated that auranofin possesses potent antibacterial activity against all tested strains of S. aureus, including meticillin-resistant S. aureus (MRSA), vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA), with minimum inhibitory concentrations (MICs) ranging from 0.0625μg/mL to 0.125μg/mL. In vivo, topical auranofin proved superior to conventional antimicrobials, including fusidic acid and mupirocin, in reducing the mean bacterial load in infected wounds in a murine model of MRSA skin infection. In addition to reducing the bacterial load, topical treatment of auranofin greatly reduced the production of inflammatory cytokines, including tumour necrosis factor-α (TNFα), interleukin-6 (IL-6), interleukin-1 beta (IL-1β) and monocyte chemoattractant protein-1 (MCP-1), in infected skin lesions. Moreover, auranofin significantly disrupted established in vitro biofilms of S. aureus and Staphylococcus epidermidis, more so than the traditional antimicrobials linezolid and vancomycin. Taken together, these results support that auranofin has potential to be repurposed as a topical antimicrobial agent for the treatment of staphylococcal skin and wound infections.
Topics: Animals; Anti-Bacterial Agents; Auranofin; Biofilms; Cell Line; Chemokine CCL2; Drug Repositioning; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Female; Fusidic Acid; Humans; Interleukin-1beta; Interleukin-6; Methicillin-Resistant Staphylococcus aureus; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Mupirocin; Staphylococcal Skin Infections; Staphylococcus epidermidis; Tumor Necrosis Factor-alpha
PubMed: 26895605
DOI: 10.1016/j.ijantimicag.2015.12.016 -
Biochemical Pharmacology Jan 2020Brain tumours are among the deadliest tumours being highly resistant to currently available therapies. The proliferative behaviour of gliomas is strongly influenced by...
Brain tumours are among the deadliest tumours being highly resistant to currently available therapies. The proliferative behaviour of gliomas is strongly influenced by ion channel activity. Small-conductance calcium-activated potassium (SK/K) channels are a family of ion channels that are associated with cell proliferation and cell survival. A combined treatment of classical anti-cancer agents and pharmacological SK channel modulators has not been addressed yet. We used the gold-derivative auranofin to induce cancer cell death by targeting thioredoxin reductases in combination with CyPPA to activate SK channels in neuro- and glioblastoma cells. Combined treatment with auranofin and CyPPA induced massive mitochondrial damage and potentiated auranofin-induced toxicity in neuroblastoma cells in vitro. In particular, mitochondrial integrity, respiration and associated energy generation were impaired. These findings were recapitulated in patient-derived glioblastoma neurospheres yet not observed in non-cancerous HT22 cells. Taken together, integrating auranofin and SK channel openers to affect mitochondrial health was identified as a promising strategy to increase the effectiveness of anti-cancer agents and potentially overcome resistance.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Auranofin; Brain Neoplasms; Cell Death; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Synergism; Glioblastoma; Humans; Mice; Mitochondria; Neuroblastoma; Pyrazoles; Pyrimidines; Small-Conductance Calcium-Activated Potassium Channels; Spheroids, Cellular; Thioredoxin-Disulfide Reductase
PubMed: 31738894
DOI: 10.1016/j.bcp.2019.113714 -
PloS One 2012Increased glutathione (GSH) and thioredoxin (Trx) metabolism are mechanisms that are widely implicated in resistance of cancer cells to chemotherapy. The current study...
Increased glutathione (GSH) and thioredoxin (Trx) metabolism are mechanisms that are widely implicated in resistance of cancer cells to chemotherapy. The current study determined if simultaneous inhibition of GSH and Trx metabolism enhanced cell killing of human head and neck squamous cell carcinoma (HNSCC) cells by a mechanism involving oxidative stress. Inhibition of GSH and Trx metabolism with buthionine sulfoximine (BSO) and auranofin (AUR), respectively, induced significant decreases in clonogenic survival compared to either drug alone in FaDu, Cal-27 and SCC-25 HNSCC cells in vitro and in vivo in Cal-27 xenografts. BSO+AUR significantly increased glutathione and thioredoxin oxidation and suppressed peroxiredoxin activity in vitro. Pre-treatment with N-acetylcysteine completely reversed BSO+AUR-induced cell killing in FaDu and Cal-27 cells, while catalase and selenium supplementation only inhibited BSO+AUR-induced cell killing in FaDu cells. BSO+AUR decreased caspase 3/7 activity in HNSCC cells and significantly reduced the viability of both Bax/Bak double knockout (DKO) and DKO-Bax reconstituted hematopoietic cells suggesting that necrosis was involved. BSO+AUR also significantly sensitized FaDu, Cal-27, SCC-25 and SQ20B cells to cell killing induced by the EGFR inhibitor Erlotinib in vitro. These results support the conclusion that simultaneous inhibition of GSH and Trx metabolism pathways induces oxidative stress and clonogenic killing in HNSCCs and this strategy may be useful in sensitizing HNSCCs to EGFR inhibitors.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Auranofin; Buthionine Sulfoximine; Carcinoma, Squamous Cell; Catalase; Cell Line, Tumor; Cell Survival; Drug Synergism; Erlotinib Hydrochloride; Female; Gene Knockdown Techniques; Glutathione; Glutathione Peroxidase; Glutathione Reductase; Head and Neck Neoplasms; Humans; Mice; Mice, Nude; Necrosis; Oxidation-Reduction; Oxidative Stress; Peroxiredoxins; Quinazolines; RNA, Small Interfering; Thioredoxin-Disulfide Reductase; Thioredoxins; Xenograft Model Antitumor Assays
PubMed: 23118946
DOI: 10.1371/journal.pone.0048175