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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 -
Journal of Molecular Medicine (Berlin,... Apr 2024Acute leukemia continues to be a major cause of death from disease worldwide and current chemotherapeutic agents are associated with significant morbidity in survivors....
Acute leukemia continues to be a major cause of death from disease worldwide and current chemotherapeutic agents are associated with significant morbidity in survivors. While better and safer treatments for acute leukemia are urgently needed, standard drug development pipelines are lengthy and drug repurposing therefore provides a promising approach. Our previous evaluation of FDA-approved drugs for their antileukemic activity identified disulfiram, used for the treatment of alcoholism, as a candidate hit compound. This study assessed the biological effects of disulfiram on leukemia cells and evaluated its potential as a treatment strategy. We found that disulfiram inhibits the viability of a diverse panel of acute lymphoblastic and myeloid leukemia cell lines (n = 16) and patient-derived xenograft cells from patients with poor outcome and treatment-resistant disease (n = 15). The drug induced oxidative stress and apoptosis in leukemia cells within hours of treatment and was able to potentiate the effects of daunorubicin, etoposide, topotecan, cytarabine, and mitoxantrone chemotherapy. Upon combining disulfiram with auranofin, a drug approved for the treatment of rheumatoid arthritis that was previously shown to exert antileukemic effects, strong and consistent synergy was observed across a diverse panel of acute leukemia cell lines, the mechanism of which was based on enhanced ROS induction. Acute leukemia cells were more sensitive to the cytotoxic activity of disulfiram than solid cancer cell lines and non-malignant cells. While disulfiram is currently under investigation in clinical trials for solid cancers, this study provides evidence for the potential of disulfiram for acute leukemia treatment. KEY MESSAGES: Disulfiram induces rapid apoptosis in leukemia cells by boosting oxidative stress. Disulfiram inhibits leukemia cell growth more potently than solid cancer cell growth. Disulfiram can enhance the antileukemic efficacy of chemotherapies. Disulfiram strongly synergises with auranofin in killing acute leukemia cells by ROS induction. We propose testing of disulfiram in clinical trial for patients with acute leukemia.
Topics: Humans; Disulfiram; Reactive Oxygen Species; Auranofin; Cell Line, Tumor; Leukemia, Myeloid, Acute
PubMed: 38349407
DOI: 10.1007/s00109-023-02414-4 -
The Cochrane Database of Systematic... 2000Auranofin is an oral gold compound used for the treatment of rheumatoid arthritis RA. The use of auranofin has declined in the past few years, perhaps due in part to... (Review)
Review
BACKGROUND
Auranofin is an oral gold compound used for the treatment of rheumatoid arthritis RA. The use of auranofin has declined in the past few years, perhaps due in part to conflicting results from different studies.
OBJECTIVES
To estimate the short-term efficacy and toxicity of auranofin for the treatment of (RA) SEARCH STRATEGY: We searched MEDLINE and EMBASE up to December 1998, the Cochrane Controlled Trials Register (CCTR) version 4, 1998, and the Cochrane Musculoskeletal Group Specialized Register. A hand search was also done of the reference lists of the trials retrieved from the electronic search.
SELECTION CRITERIA
All randomized controlled trials (RCTs) and controlled clinical trials (CCTs) comparing auranofin against placebo in patients with RA DATA COLLECTION AND ANALYSIS: The methodological quality of the trials was assessed using a validated assessment tool (Jadad 1996). Rheumatoid arthritis outcome measures were extracted from the publications for the 6-month endpoint. The pooled analysis was performed using standardized mean differences (SMDs) for joint counts, pain and global assessments. The weighted mean difference (WMD) was used for ESR. Toxicity was evaluated with pooled odds ratios for withdrawals and adverse reactions. A chi-square test was used to assess heterogeneity among trials. In the presence of heterogeneity, random effects models were used. Otherwise, the data was pooled assuming fixed effects.
MAIN RESULTS
A statistically significant benefit was observed for auranofin when compared to placebo for tender joint scores, pain, patient and physician global assessments and ESR. The SMD between treatment and placebo was -0.39 (95% CI -0.54, -0.25) for tender joint scores, -0.08 (95% CI -0.22, -0.07) for swollen joint scores, and the WMD was -4.68 (95% CI -6.59, -2.77) for pain scores and -9.85mm (95% CI -16.46, -3.25) for ESR. Withdrawals from adverse reactions were 1.5 times higher in the auranofin group OR = 1.52 (95% CI 0.94, 2.46) but this result was not statistically significant. Patients receiving placebo were three times more likely to discontinue treatment because of lack of efficacy than patients receiving auranofin: OR=0.31 (95% CI: 0.21, 0.44).
REVIEWER'S CONCLUSIONS
Auranofin appears to have a small clinically and statistically significant benefit on the disease activity of patients with RA. The beneficial effects appear to be modest compared to drugs such as methotrexate or parenteral gold. Its effects on long term health status and radiological progression are not clear at this time.
Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Auranofin; Humans
PubMed: 10796461
DOI: 10.1002/14651858.CD002048 -
International Journal of Antimicrobial... Nov 2021Acanthamoebae are opportunistic pathogens that cause serious infections, including Acanthamoeba keratitis, a sight-threatening disease affecting mainly contact lens...
Acanthamoebae are opportunistic pathogens that cause serious infections, including Acanthamoeba keratitis, a sight-threatening disease affecting mainly contact lens wearers, and granulomatous amoebic encephalitis, an infection of the central nervous system that occurs mostly in immunocompromised individuals. Although these infections are rare, they are a challenge for healthcare providers. In the last decade, the search for and implementation of novel treatment approaches against these parasites and the infections they cause have intensified, but current options are still unsatisfactory. The aim of this study was to investigate the in vitro activity of the gold-based compound auranofin against Acanthamoeba spp. The study showed that auranofin has potent antimicrobial activity against Acanthamoeba spp., with an IC ranging from 2.9 to 3.48 µM, and thus may be useful in the prevention and control of Acanthamoeba infections.
Topics: Acanthamoeba; Acanthamoeba Keratitis; Amebiasis; Antiparasitic Agents; Auranofin; Encephalitis; Humans; Parasitic Sensitivity Tests
PubMed: 34419578
DOI: 10.1016/j.ijantimicag.2021.106425 -
Journal For Immunotherapy of Cancer Jun 2022Adoptive cell therapy using cytotoxic lymphocytes is an efficient immunotherapy against solid and hematological cancers. However, elevated levels of reactive oxygen...
BACKGROUND
Adoptive cell therapy using cytotoxic lymphocytes is an efficient immunotherapy against solid and hematological cancers. However, elevated levels of reactive oxygen species (ROS) in the hostile tumor microenvironment can impair NK cell and T cell function. Auranofin, a gold (I)-containing phosphine compound, is a strong activator of the transcription factor Nrf2. Nrf2 controls a wide range of downstream targets important for the cells to obtain increased resistance to ROS. In this study, we present a strategy using auranofin to render human cytotoxic lymphocytes resistant toward oxidative stress.
METHODS
Melanoma patient-derived tumor infiltrating lymphocytes (TIL) and healthy donor-derived NK cells and CD19-directed CAR T cells were pretreated with a low dose of auranofin. Their resistance toward oxidative stress was assessed by measuring antitumoral responses (killing-assay, degranulation/CD107a, cytokine production) and intracellular ROS levels (flow cytometry) in conditions of oxidative stress. To confirm that the effects were Nrf2 dependent, the transcription level of Nrf2-driven target genes was analyzed by qPCR.
RESULTS
Pretreatment of human TIL and NK cells ex vivo with a low-dose auranofin significantly lowered their accumulation of intracellular ROS and preserved their antitumoral activity despite high HO levels or monocyte-derived ROS. Furthermore, auranofin pretreatment of CD19 CAR-T cells or TIL increased their elimination of CD19 +tumor cells or autologous tumor spheroids, respectively, especially during ROS exposure. Analysis of Nrf2-driven target genes revealed that the increased resistance against ROS was Nrf2 dependent.
CONCLUSION
These novel findings suggest that Nrf2 activation in human cytotoxic lymphocytes could be used to enhance the efficacy of adoptive cell therapy.
Topics: Antigens, CD19; Auranofin; Cytotoxicity, Immunologic; Humans; Hydrogen Peroxide; Immunotherapy; Killer Cells, Natural; Lymphocytes, Tumor-Infiltrating; Melanoma; NF-E2-Related Factor 2; Oxidative Stress; Reactive Oxygen Species; T-Lymphocytes; Tumor Microenvironment
PubMed: 35738800
DOI: 10.1136/jitc-2021-004458 -
Oxidative Medicine and Cellular... 2020Ferroptosis is an atypical form of regulated cell death, which is different from apoptosis, necrosis, pyroptosis, and autophagy. Ferroptosis is characterized by... (Review)
Review
Ferroptosis is an atypical form of regulated cell death, which is different from apoptosis, necrosis, pyroptosis, and autophagy. Ferroptosis is characterized by iron-dependent oxidative destruction of cellular membranes following the antioxidant system's failure. The sensitivity of ferroptosis is tightly regulated by a series of biological processes, the metabolism of iron, amino acids, and polyunsaturated fatty acids, and the interaction of glutathione (GSH), NADPH, coenzyme Q10 (CoQ10), and phospholipids. Elevated oxidative stress (ROS) level is a hallmark of cancer, and ferroptosis serves as a link between nutrition metabolism and redox biology. Targeting ferroptosis may be an effective and selective way for cancer therapy. The underlying molecular mechanism of ferroptosis occurrence is still not enough. This review will briefly summarize the process of ferroptosis and introduce critical molecules in the ferroptotic cascade. Furthermore, we reviewed the occurrence and regulation of reduction-oxidation (redox) for ferroptosis in cancer metabolism. The role of the tumor suppressor and the epigenetic regulator in tumor cell ferroptosis will also be described. Finally, old drugs that can be repurposed to induce ferroptosis will be characterized, aiming for drug repurposing and novel drug combinations for cancer therapy more efficiently and economically.
Topics: Acetaminophen; Antineoplastic Agents; Antioxidants; Apoptosis; Artemisinins; Auranofin; Cell Death; Cisplatin; Epigenesis, Genetic; Fatty Acids; Ferroptosis; Haloperidol; Humans; Indoles; Iron; Lapatinib; Mevalonic Acid; NADP; Neoplasms; Oxidation-Reduction; Oxidative Stress; Oxygen; Quinolines; Reactive Oxygen Species; Sorafenib; Spiro Compounds; Sulfasalazine; Trigonella
PubMed: 33425217
DOI: 10.1155/2020/8810785 -
Scientific Reports Jul 2022Anticancer drugs and molecular targeted therapies are used for refractory desmoid-type fibromatosis (DF), but occasionally cause severe side effects. The purpose of this...
Anticancer drugs and molecular targeted therapies are used for refractory desmoid-type fibromatosis (DF), but occasionally cause severe side effects. The purpose of this study was to identify an effective drug with fewer side effects against DF by drug repositioning, and evaluate its efficacy. FDA-approved drugs that inhibit the proliferation of DF cells harboring S45F mutations of CTNNB1 were screened. An identified drug was subjected to the investigation of apoptotic effects on DF cells with analysis of Caspase 3/7 activity. Expression of β-catenin was evaluated with western blot analysis, and immunofluorescence staining. Effects of the identified drug on in vivo DF were analyzed using Apc1638N mice. Auranofin was identified as a drug that effectively inhibits the proliferation of DF cells. Auranofin did not affect Caspase 3/7 activity compared to control. The expression level of β-catenin protein was not changed regardless of auranofin concentration. Auranofin effectively inhibited the development of tumorous tissues by both oral and intraperitoneal administration, particularly in male mice. Auranofin, an anti-rheumatic drug, was identified to have repositioning effects on DF. Since auranofin has been used for many years as an FDA-approved drug, it could be a promising drug with fewer side effects for DF.
Topics: Animals; Auranofin; Caspase 3; Fibromatosis, Aggressive; Male; Mice; Mutation; beta Catenin
PubMed: 35831372
DOI: 10.1038/s41598-022-15756-9 -
Nature Communications Oct 2020Global emergence of Gram-negative bacteria carrying the plasmid-borne resistance genes, bla and mcr, raises a significant challenge to the treatment of life-threatening...
Global emergence of Gram-negative bacteria carrying the plasmid-borne resistance genes, bla and mcr, raises a significant challenge to the treatment of life-threatening infections by the antibiotics, carbapenem and colistin (COL). Here, we identify an antirheumatic drug, auranofin (AUR) as a dual inhibitor of metallo-β-lactamases (MBLs) and mobilized colistin resistance (MCRs), two resistance enzymes that have distinct structures and substrates. We demonstrate that AUR irreversibly abrogates both enzyme activity via the displacement of Zn(II) cofactors from their active sites. We further show that AUR synergizes with antibiotics on killing a broad spectrum of carbapenem and/or COL resistant bacterial strains, and slows down the development of β-lactam and COL resistance. Combination of AUR and COL rescues all mice infected by Escherichia coli co-expressing MCR-1 and New Delhi metallo-β-lactamase 5 (NDM-5). Our findings provide potential therapeutic strategy to combine AUR with antibiotics for combating superbugs co-producing MBLs and MCRs.
Topics: Animals; Anti-Bacterial Agents; Auranofin; Carbapenems; Colistin; Drug Resistance, Multiple, Bacterial; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Female; Humans; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; beta-Lactamase Inhibitors; beta-Lactamases
PubMed: 33067430
DOI: 10.1038/s41467-020-18939-y -
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 -
Redox Biology Jul 2020The failure of insulin-producing β-cells is the underlying cause of hyperglycemia in diabetes mellitus. β-cell decay has been linked to hypoxia, chronic inflammation,...
The failure of insulin-producing β-cells is the underlying cause of hyperglycemia in diabetes mellitus. β-cell decay has been linked to hypoxia, chronic inflammation, and oxidative stress. Thioredoxin (Trx) proteins are major actors in redox signaling and essential for signal transduction and the cellular stress response. We have analyzed the cytosolic, mitochondrial, and extracellular Trx system proteins in hypoxic and cytokine-induced stress using β-cell culture, isolated pancreatic islets, and pancreatic islet transplantation modelling low oxygen supply. Protein levels of cytosolic Trx1 and Trx reductase (TrxR) 1 significantly decreased, while mitochondrial Trx2 and TrxR2 increased upon hypoxia and reoxygenation. Interestingly, Trx1 was secreted by β-cells during hypoxia. Moreover, murine and human pancreatic islet grafts released Trx1 upon glucose stimulation. Survival of transplanted islets was substantially impaired by the TrxR inhibitor auranofin. Since a release was prominent upon hypoxia, putative paracrine effects of Trx1 on β-cells were examined. In fact, exogenously added recombinant hTrx1 mitigated apoptosis and preserved glucose sensitivity in pancreatic islets subjected to hypoxia and inflammatory stimuli, dependent on its redox activity. Human subjects were studied, demonstrating a transient increase in extracellular Trx1 in serum after glucose challenge. This increase correlated with better pancreatic islet function. Moreover, hTrx1 inhibited the migration of primary murine macrophages. In conclusion, our study offers evidence for paracrine functions of extracellular Trx1 that improve the survival and function of pancreatic β-cells.
Topics: Animals; Auranofin; Humans; Mice; Oxidation-Reduction; Oxidative Stress; Thioredoxin-Disulfide Reductase; Thioredoxins
PubMed: 32473461
DOI: 10.1016/j.redox.2020.101570