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International Journal of Molecular... Dec 2022Glioblastoma (GBM) is the most aggressive primary brain tumor. Recently, agents increasing the level of oxidative stress have been proposed as anticancer drugs. However,...
Glioblastoma (GBM) is the most aggressive primary brain tumor. Recently, agents increasing the level of oxidative stress have been proposed as anticancer drugs. However, their efficacy may be lowered by the cytoprotective activity of antioxidant enzymes, often upregulated in neoplastic cells. Here, we assessed the mRNA and protein expression of thioredoxin reductase 1 (TrxR1), a master regulator of cellular redox homeostasis, in GBM and non-tumor brain tissues. Next, we examined the influence of an inhibitor of TrxR1, auranofin (AF), alone or in combination with a prooxidant menadione (MEN), on growth of GBM cell lines, patient-derived GBM cells and normal human astrocytes. We detected considerable amount of TrxR1 in the majority of GBM tissues. Treatment with AF decreased viability of GBM cells and their potential to form colonies and neurospheres. Moreover, it increased the intracellular level of reactive oxygen species (ROS). Pre-treatment with ROS scavenger prevented the AF-induced cell death, pointing to the important role of ROS in the reduction of cell viability. The cytotoxic effect of AF was potentiated by treatment with MEN. In conclusion, our results identify TrxR1 as an attractive drug target and highlights AF as an off-patent drug candidate in GBM therapy.
Topics: Humans; Vitamin K 3; Reactive Oxygen Species; Auranofin; Glioblastoma; Cell Line, Tumor; Cell Death; Thioredoxin Reductase 1; Cell Survival
PubMed: 36555352
DOI: 10.3390/ijms232415712 -
Seminars in Radiation Oncology Jan 2019Dysregulated glucose and redox metabolism are near universal features of cancers. They therefore represent potential selectively toxic metabolic targets. This review... (Review)
Review
Dysregulated glucose and redox metabolism are near universal features of cancers. They therefore represent potential selectively toxic metabolic targets. This review outlines the preclinical and clinical data for targeting glucose and hydroperoxide metabolism in cancer, with a focus on drug strategies that have the most available evidence. In particular, inhibition of glycolysis using 2-deoxyglucose, and inhibition of redox metabolism using the glutathione pathway inhibitor buthionine sulfoximine and the thioredoxin pathway inhibitor auranofin, have shown promise in preclinical studies to increase sensitivity to chemotherapy and radiation by increasing intracellular oxidative stress. Combined inhibition of glycolysis, glutathione, and thioredoxin pathways sensitizes highly glycolytic, radioresistant cancer models in vitro and in vivo. Although the preclinical data support this approach, clinical data are limited to exploratory trials using a single drug in combination with either chemotherapy or radiation. Open research questions include optimizing drug strategies for targeting glycolysis and redox metabolism, determining the appropriate timing for administering this therapy with concurrent chemotherapy and radiation, and identifying biomarkers to determine the cancers that would benefit most from this approach. Given the quality of preclinical evidence, dual targeting of glycolysis and redox metabolism in combination with chemotherapy and radiation should be further evaluated in clinical trials.
Topics: Animals; Auranofin; Buthionine Sulfoximine; Deoxyglucose; Glucose; Glycolysis; Humans; Hydrogen Peroxide; Neoplasms; Oxidation-Reduction; Oxidative Stress; Radiation-Sensitizing Agents
PubMed: 30573182
DOI: 10.1016/j.semradonc.2018.10.007 -
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 -
Cancer Research Apr 2021is amplified in 20% to 25% of neuroblastoma, and -amplified neuroblastoma contributes to a large percent of pediatric cancer-related deaths. Therapy improvements for...
is amplified in 20% to 25% of neuroblastoma, and -amplified neuroblastoma contributes to a large percent of pediatric cancer-related deaths. Therapy improvements for this subtype of cancer are a high priority. Here we uncover a MYCN-dependent therapeutic vulnerability in neuroblastoma. Namely, amplified rewires the cell through expression of key receptors, ultimately enhancing iron influx through increased expression of the iron import transferrin receptor 1. Accumulating iron causes reactive oxygen species (ROS) production, and -amplified neuroblastomas show enhanced reliance on the system Xc- cystine/glutamate antiporter for ROS detoxification through increased transcription of this receptor. This dependence creates a marked vulnerability to targeting the system Xc-/glutathione (GSH) pathway with ferroptosis inducers. This reliance can be exploited through therapy with FDA-approved rheumatoid arthritis drugs sulfasalazine (SAS) and auranofin: in -amplified, patient-derived xenograft models, both therapies blocked growth and induced ferroptosis. SAS and auranofin activity was largely mitigated by the ferroptosis inhibitor ferrostatin-1, antioxidants like N-acetyl-L-cysteine, or by the iron scavenger deferoxamine (DFO). DFO reduced auranofin-induced ROS, further linking increased iron capture in -amplified neuroblastoma to a therapeutic vulnerability to ROS-inducing drugs. These data uncover an oncogene vulnerability to ferroptosis caused by increased iron accumulation and subsequent reliance on the system Xc-/GSH pathway. SIGNIFICANCE: This study shows how MYCN increases intracellular iron levels and subsequent GSH pathway activity and demonstrates the antitumor activity of FDA-approved SAS and auranofin in patient-derived xenograft models of -amplified neuroblastoma.
Topics: Animals; Antioxidants; Auranofin; Cell Line, Tumor; Cell Proliferation; Cell Survival; Child; Enzyme Inhibitors; Ferroptosis; Gene Amplification; Gene Expression Regulation, Enzymologic; Glutathione; Humans; Iron; Male; Mice; Mice, Inbred NOD; Mice, Transgenic; N-Myc Proto-Oncogene Protein; Neuroblastoma; Oxazoles; Phospholipid Hydroperoxide Glutathione Peroxidase; Piperazines; Sulfasalazine; Xenograft Model Antitumor Assays
PubMed: 33483374
DOI: 10.1158/0008-5472.CAN-20-1641 -
The Cochrane Database of Systematic... 2000To assess the effects of salazopyrin, auranofin, etretinate, fumaric acid, IMI gold, azathioprine, and methotrexate, in psoriatic arthritis. (Review)
Review
OBJECTIVES
To assess the effects of salazopyrin, auranofin, etretinate, fumaric acid, IMI gold, azathioprine, and methotrexate, in psoriatic arthritis.
SEARCH STRATEGY
We searched Medline up to 1995, and Excerpta Medica (June 1974-95). Search terms were psoriasis, arthritis, therapy and/or controlled trial. This was supplemented by manually searching bibliographies of previously published reviews, conference proceedings and contacting drug companies. All languages were included in the initial search.
SELECTION CRITERIA
All randomized trials comparing salazopyrin, auranofin, etretinate, fumaric acid, IMI gold, azathioprine, and methotrexate, in psoriatic arthritis. The main outcome measures included individual component variables derived from Outcome Measures in Rheumatology Clinical Trials (OMERACT). These include Acute Phase Reactants, Disability, Pain, Patient Global Assessment, Physician Global Assessment, Swollen joint count, Tender joint count and radiographic changes of joints in any trial of 1 year or longer [Tugwell 1993], and the change in pooled disease index. Only English trials were included in the review.
DATA COLLECTION AND ANALYSIS
Data were independently extracted from the published reports by two of the reviewers. An independent blinded quality assessment was also performed.
MAIN RESULTS
Nineteen randomized trials were identified of which eleven were included in the quantitative analysis with data from 777 subjects. Although all agents were better than placebo, parenteral high dose methotrexate (not included), salazopyrin, azathioprine and etretinate were the agents that achieved statistical significance in a global index of disease activity (although it should be noted that only one component variable was available for azathioprine and only one trial was available for etretinate suggesting some caution is necessary in interpreting these results). Analysis of response in individual disease activity markers was more variable with considerable differences between different medications and responses. In all trials the placebo group improved over baseline (pooled improvement 0.43 DI units, 95% CI 0. 28-0.59). There was insufficient data to examine toxicity.
REVIEWER'S CONCLUSIONS
Parenteral high dose methotrexate and salazopyrin are the only two agents with well demonstrated published efficacy in psoriatic arthritis. The magnitude of the effect seen with azathioprine, etretinate, oral low dose methotrexate and perhaps colchicine suggests that they may be effective but that further multicentre clinical trials are required to establish their efficacy. Furthermore, the magnitude of the improvement observed in the placebo group strongly suggests that uncontrolled trials should not be used to guide management decisions in this condition.
Topics: Antirheumatic Agents; Arthritis, Psoriatic; Auranofin; Azathioprine; Dermatologic Agents; Etretinate; Fumarates; Humans; Immunosuppressive Agents; Methotrexate; Sulfasalazine
PubMed: 10796328
DOI: 10.1002/14651858.CD000212 -
International Journal of Molecular... Nov 2022Auranofin (AF), a gold(I) compound that is currently used for the treatment of rheumatoid arthritis and is in clinical trials for its promising anticancer activity, was...
Auranofin (AF), a gold(I) compound that is currently used for the treatment of rheumatoid arthritis and is in clinical trials for its promising anticancer activity, was encapsulated within the human H-chain and the horse spleen ferritin nanocages using the alkaline disassembly/reassembly protocol. The aim of the work was to highlight possible differences in their drug loading capacity and efficacy. The drug-loaded ferritins were characterized via UV-vis absorption spectroscopy and inductively coupled plasma-atomic emission spectroscopy to assess AF encapsulation and to define the exact amount of gold atoms trapped in the Ft cavity. The crystal structures allowed us to define the nature of AF interaction with both ferritins and to identify the gold binding sites. Moreover, the biological characterization let us to obtain preliminary information on the cytotoxic effect of AF when bound to the human H-chain.
Topics: Animals; Humans; Antineoplastic Agents; Auranofin; Binding Sites; Ferritins; Gold; Horses; Nanoparticle Drug Delivery System
PubMed: 36430642
DOI: 10.3390/ijms232214162 -
Gut Microbes 2013Recently, we developed a novel automated, high throughput screening (HTS) methodology for the anaerobic intestinal parasite Entamoeba histolytica. We validated this HTS... (Review)
Review
Recently, we developed a novel automated, high throughput screening (HTS) methodology for the anaerobic intestinal parasite Entamoeba histolytica. We validated this HTS platform by screening a chemical library containing US Food and Drug Administration (FDA)-approved drugs and bioactive compounds. We identified an FDA-approved drug, auranofin, as most active against E. histolytica both in vitro and in vivo. Our cell culture and animal studies indicated that thioredoxin reductase, an enzyme involved in reactive oxygen species detoxification, was the target for auranofin in E. histolytica. Here, we discuss the rationale for drug development for three parasites which are major causes of diarrhea worldwide, E. histolytica, Giardia lamblia and Cryptosporidium parvum and extend our current finding of antiparasitic activity of auranofin to Entamoeba cysts, G. lamblia and C. parvum. These studies support the use of HTS assays and reprofiling FDA-approved drugs for new therapy for neglected tropical diseases.
Topics: Antiprotozoal Agents; Auranofin; Cryptosporidium parvum; Drug Discovery; Entamoeba histolytica; Enzyme Inhibitors; Giardia lamblia; High-Throughput Screening Assays; Thioredoxin-Disulfide Reductase
PubMed: 23137963
DOI: 10.4161/gmic.22596 -
Molecular Therapy : the Journal of the... Mar 2023Approximately 50%-55% of high-grade serous ovarian carcinoma (HGSOC) patients have MYC oncogenic pathway activation. Because MYC is not directly targetable, we have...
Approximately 50%-55% of high-grade serous ovarian carcinoma (HGSOC) patients have MYC oncogenic pathway activation. Because MYC is not directly targetable, we have analyzed molecular pathways enriched in MYC-high HGSOC tumors to identify potential therapeutic targets. Here, we report that MYC-high HGSOC tumors show enrichment in genes controlled by NRF2, an antioxidant signaling pathway, along with increased thioredoxin redox activity. Treatment of MYC-high HGSOC tumors cells with US Food and Drug Administration (FDA)-approved thioredoxin reductase 1 (TrxR1) inhibitor auranofin resulted in significant growth suppression and apoptosis in MYC-high HGSOC cells in vitro and also significantly reduced tumor growth in an MYC-high HGSOC patient-derived tumor xenograft. We found that auranofin treatment inhibited glycolysis in MYC-high cells via oxidation-induced GAPDH inhibition. Interestingly, in response to auranofin-induced glycolysis inhibition, MYC-high HGSOC cells switched to glutamine metabolism for survival. Depletion of glutamine with either glutamine starvation or glutaminase (GLS1) inhibitor CB-839 exerted synergistic anti-tumor activity with auranofin in HGSOC cells and OVCAR-8 cell line xenograft. These findings suggest that applying a combined therapy of GLS1 inhibitor and TrxR1 inhibitor could effectively treat MYC-high HGSOC patients.
Topics: Female; Humans; Auranofin; Cell Line, Tumor; Genes, myc; Glutaminase; Glutamine; Ovarian Neoplasms; Thioredoxin-Disulfide Reductase; Thioredoxins
PubMed: 36560881
DOI: 10.1016/j.ymthe.2022.12.011 -
Yakugaku Zasshi : Journal of the... 2021
Topics: Antirheumatic Agents; Auranofin; Biopharmaceutics; Chemistry, Bioinorganic; Chemistry, Pharmaceutical; Drug Repositioning; Gold; Humans; Nanoparticles
PubMed: 33642495
DOI: 10.1248/yakushi.20-00179-F -
American Journal of Physiology. Lung... Jun 2020Bronchopulmonary dysplasia (BPD), a long-term respiratory morbidity of prematurity, is characterized by attenuated alveolar and vascular development. Supplemental oxygen...
Bronchopulmonary dysplasia (BPD), a long-term respiratory morbidity of prematurity, is characterized by attenuated alveolar and vascular development. Supplemental oxygen and immature antioxidant defenses contribute to BPD development. Our group identified thioredoxin reductase-1 (TXNRD1) as a therapeutic target to prevent BPD. The present studies evaluated the impact of the TXNRD1 inhibitor aurothioglucose (ATG) on pulmonary responses and gene expression in newborn C57BL/6 pups treated with saline or ATG (25 mg/kg ip) within 12 h of birth and exposed to room air (21% O) or hyperoxia (>95% O) for 72 h. Purified RNA from lung tissues was sequenced, and differential expression was evaluated. Hyperoxic exposure altered ~2,000 genes, including pathways involved in glutathione metabolism, intrinsic apoptosis signaling, and cell cycle regulation. The isolated effect of ATG treatment was limited primarily to genes that regulate angiogenesis and vascularization. In separate studies, pups were treated as described above and returned to room air until 14 days. Vascular density analyses were performed, and ANOVA indicated an independent effect of hyperoxia on vascular density and alveolar architecture at 14 days. Consistent with RNA-seq analyses, ATG significantly increased vascular density in room air, but not in hyperoxia-exposed pups. These findings provide insights into the mechanisms by which TXNRD1 inhibitors may enhance lung development.
Topics: Acute Disease; Air; Animals; Animals, Newborn; Apoptosis; Aurothioglucose; DNA; Glutathione; Hyperoxia; Lung; Mice, Inbred C57BL; Neovascularization, Physiologic; Pulmonary Alveoli; Signal Transduction; Transcription, Genetic; Transcriptome; Up-Regulation
PubMed: 32292070
DOI: 10.1152/ajplung.00086.2020