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Chembiochem : a European Journal of... Aug 2020The success of metal-based anticancer therapeutics in the treatment of cancer is best exemplified by cisplatin. Currently used in 32/78 cancer regimens, metal-based... (Review)
Review
The success of metal-based anticancer therapeutics in the treatment of cancer is best exemplified by cisplatin. Currently used in 32/78 cancer regimens, metal-based drugs have a clear role in cancer therapy. Despite this, metal-based anticancer therapeutics are not without drawbacks, with issues such as toxic side effects and the development of resistance mechanisms. This has led to investigations of other metal-based drug candidates such as auranofin, a gold-based drug candidate as well as ruthenium-based candidates, NAMI-A, NKP-1339 and TLD-1433. All are currently undergoing clinical trials. Another class of complexes under study are rhenium-based; such complexes have undergone extensive in vitro testing but only nine have been reported to display antitumour in vivo activity, which is a necessary step before entering clinical trials. This review will document, chronologically, the rhenium-based drug candidates that have undergone in vivo testing and the outlook for such complexes.
Topics: Animals; Coordination Complexes; Drug Discovery; Drug Evaluation, Preclinical; Humans; Rhenium
PubMed: 32196894
DOI: 10.1002/cbic.202000117 -
Nature Communications Oct 2023Genome-scale metabolic models are widely used to enhance our understanding of metabolic features of organisms, host-pathogen interactions and to identify therapeutics...
Genome-scale metabolic models are widely used to enhance our understanding of metabolic features of organisms, host-pathogen interactions and to identify therapeutics for diseases. Here we present iTMU798, the genome-scale metabolic model of the mouse whipworm Trichuris muris. The model demonstrates the metabolic features of T. muris and allows the prediction of metabolic steps essential for its survival. Specifically, that Thioredoxin Reductase (TrxR) enzyme is essential, a prediction we validate in vitro with the drug auranofin. Furthermore, our observation that the T. muris genome lacks gsr-1 encoding Glutathione Reductase (GR) but has GR activity that can be inhibited by auranofin indicates a mechanism for the reduction of glutathione by the TrxR enzyme in T. muris. In addition, iTMU798 predicts seven essential amino acids that cannot be synthesised by T. muris, a prediction we validate for the amino acid tryptophan. Overall, iTMU798 is as a powerful tool to study not only the T. muris metabolism but also other Trichuris spp. in understanding host parasite interactions and the rationale design of new intervention strategies.
Topics: Animals; Mice; Trichuris; Auranofin; Glutathione; Glutathione Reductase; Host-Pathogen Interactions
PubMed: 37907472
DOI: 10.1038/s41467-023-42552-4 -
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 -
Cancers Jul 2019Recent study suggests that auranofin (AF), a US Food and Drug Administration (FDA)-approved drug for treatment of rheumatoid arthritis, has selective anticancer activity...
Recent study suggests that auranofin (AF), a US Food and Drug Administration (FDA)-approved drug for treatment of rheumatoid arthritis, has selective anticancer activity in various experimental models. Its clinical applications in cancer treatment, however, have been hampered due in part to its relatively moderate activity as a single agent. In this study, we performed a high-throughput screening of the FDA-approved drug library for clinical compounds that potentiate the anticancer activity auranofin, and unexpectedly identified an anti-inflammatory drug celecoxib (CE) that potently enhanced the therapeutic activity of AF in vitro and in vivo. Mechanistically, AF/CE combination induced severe oxidative stress that caused ROS-mediated inhibition of hexokinase (HK) and a disturbance of mitochondrial redox homeostasis, resulting in a significant decrease of ATP generation. The CE-induced ROS increase together with AF-medicated inhibition of thioredoxin reductase cause a shift of Trx2 to an oxidized state, leading to degradation of MTCO2 and dysfunction of the electron transport chain. Our study has identified a novel drug combination that effectively eliminates cancer cells in vivo. Since AF and CE are FDA-approved drugs that are currently used in the clinic, it is feasible to translate the findings of this study into clinical applications for cancer treatment.
PubMed: 31277230
DOI: 10.3390/cancers11070931 -
Activity of Auranofin against Multiple Genotypes of and Its Synergistic Effect with Amphotericin B .ACS Chemical Neuroscience Aug 2020Primary amebic meningoencephalitis, caused by brain infection with a free-living ameba, , leads to extensive inflammation of the brain and death within 3-7 days after...
Primary amebic meningoencephalitis, caused by brain infection with a free-living ameba, , leads to extensive inflammation of the brain and death within 3-7 days after symptoms begin. Treatment of primary amebic meningoencephalitis relies on amphotericin B in combination with other drugs, but use of amphotericin B is associated with severe adverse effects. Despite a fatality rate of over 97%, economic incentive to invest in development of antiamebic drugs by the pharmaceutical industry is lacking. Development of safe and rapidly acting drugs remains a critical unmet need to avert future deaths. Since FDA-approved anti-inflammatory and antiarthritic drug auranofin is a known inhibitor of selenoprotein synthesis and thioredoxin reductase and the genome of encodes genes for both selenocysteine biosynthesis and thioredoxin reductases, we tested the effect of auranofin against strains of different genotypes from the USA, Europe, and Australia. Auranofin was equipotent against all tested strains with an EC of 1-2 μM. Our growth inhibition study at different time points demonstrated that auranofin is fast-acting, and ∼90% growth inhibition was achieved within 16 h of drug exposure. A short exposure of to auranofin led to the accumulation of intracellular reactive oxygen species. This is consistent with auranofin's role in inhibiting antioxidant pathways. Further, combination of auranofin and amphotericin B led to 95% of growth inhibition with 2-9-fold dose reduction for amphotericin B and 3-20-fold dose reduction for auranofin. Auranofin has the potential to be repurposed for the treatment of primary amebic meningoencephalitis.
Topics: Amebiasis; Amphotericin B; Auranofin; Central Nervous System Protozoal Infections; Europe; Genotype; Humans; Naegleria fowleri
PubMed: 32392039
DOI: 10.1021/acschemneuro.0c00165 -
Gut Jul 1987Auranofin (SKF-D 39162) is an oral gold preparation for the treatment of rheumatoid arthritis. One of its major side effects is diarrhoea. To determine one possible...
Auranofin (SKF-D 39162) is an oral gold preparation for the treatment of rheumatoid arthritis. One of its major side effects is diarrhoea. To determine one possible mechanism for this we compared the effects of auranofin and myochrysine on intestinal water and solute transport in the rat. Jejunal perfusion with 2 mM auranofin (n = 5) induced fluid and electrolyte secretion and inhibited glucose absorption (p less than 0.01). Auranofin (0.2 mM) induced fluid secretion in the jejunum (n = 5; p less than 0.01) and colon (n = 6; p less than 0.01). In contrast, 2 mM myochrysine enhanced jejunal water and electrolyte absorption (n = 6; p less than 0.02). Both compounds enhanced absorption of mannitol (p less than 0.01). Perfusion of 0.2 mM auranofin for two hours had no significant effect on mucosal c-AMP levels (n = 4). After perfusion for two hours with 2 mM auranofin the jejunal mucosa showed severe injury by light and scanning electronmicroscopy while myochrysine had no apparent effect. The damage after perfusion with 0.2 mM auranofin for two hours was less severe. Auranofin was more rapidly absorbed than myochrysine (p less than 0.05). These effects provide an explanation for the diarrhoea associated with auranofin therapy.
Topics: Animals; Auranofin; Biological Transport; Glucose; Gold Sodium Thiomalate; Intestinal Absorption; Intestinal Mucosa; Intestines; Male; Mannitol; Microscopy, Electron, Scanning; Rats; Rats, Inbred Strains; Water-Electrolyte Balance
PubMed: 3115869
DOI: 10.1136/gut.28.7.829 -
Scientific Reports Mar 2020Neisseria gonorrhoeae represents an urgent public health threat due to the rapid emergence of resistance to current antibiotics and the limited number of anti-gonococcal...
Neisseria gonorrhoeae represents an urgent public health threat due to the rapid emergence of resistance to current antibiotics and the limited number of anti-gonococcal agents currently in clinical trials. This study utilized a drug repositioning strategy to investigate FDA-approved gold-containing drugs against N. gonorrhoeae. Auranofin, sodium aurothiomalate and aurothioglucose inhibited 48 clinical isolates of N. gonorrhoeae including multidrug-resistant strains at a concentration as low as 0.03 µg/mL. A time-kill assay revealed that auranofin exhibited rapid bactericidal activity against N. gonorrhoeae. Moreover, both sodium aurothiomalate and aurothioglucose did not inhibit growth of vaginal protective commensal lactobacilli. Auranofin, in combination with azithromycin, ceftriaxone, cefixime or tetracycline showed an additive effect against four N. gonorrhoeae strains, suggesting the possibility of using auranofin in dual therapy. Moreover, auranofin reduced the burden of intracellular N. gonorrhoeae by over 99% outperforming the drug of choice ceftriaxone. Auranofin was found superior to ceftriaxone in reducing the secretion of the pro-inflammatory cytokine IL-8 by endocervical cells infected with N. gonorrhoeae. Furthermore, auranofin exhibited a prolonged post-antibiotic effect over 10 h, as well as inability to generate resistant mutants. Overall, the current study suggests that repurposing gold-containing drugs, like auranofin, for treatment of gonorrhea warrants further investigation.
Topics: Anti-Bacterial Agents; Auranofin; Ceftriaxone; Drug Resistance, Multiple, Bacterial; Gold; Gonorrhea; Humans; Microbial Sensitivity Tests; Neisseria gonorrhoeae
PubMed: 32221472
DOI: 10.1038/s41598-020-62696-3 -
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 -
International Journal of Antimicrobial... Mar 2020Vancomycin-resistant enterococci (VRE) are a leading cause of nosocomial infections because of the limited number of effective therapeutic options. In an effort to...
INTRODUCTION
Vancomycin-resistant enterococci (VRE) are a leading cause of nosocomial infections because of the limited number of effective therapeutic options. In an effort to repurpose FDA-approved drugs against antibiotic-resistant bacteria, auranofin has been identified as a potent drug against VRE.
METHODS AND RESULTS
The present study determined that auranofin's antibacterial activity was not affected when evaluated against a higher inoculum size of VRE (~10 CFU/mL), and auranofin successfully reduced the burden of stationary phase VRE cells via a time-kill assay. In addition, auranofin reduced VRE production of key virulence factors, including proteases, lipase and haemagglutinin. The promising features of auranofin prompted evaluation of its in vivo efficacy in a lethal mouse model of VRE septicaemia. All mice receiving auranofin at 0.125 mg/kg orally, 0.125 mg/kg subcutaneously (SC) or 0.0625 mg/kg (SC) survived the lethal VRE challenge. Additionally, auranofin was superior to linezolid, the current drug of choice, in reducing VRE burden in the liver, kidneys and spleen of mice. Remarkably, auranofin successfully reduced VRE below the limit of detection in murine internal organs after 4 days of oral or subcutaneous treatment.
CONCLUSION
These results indicate that auranofin warrants further investigation as a new treatment for systemic VRE infections.
Topics: Animals; Anti-Bacterial Agents; Antirheumatic Agents; Auranofin; Gram-Positive Bacterial Infections; Linezolid; Mice; Microbial Sensitivity Tests; Vancomycin-Resistant Enterococci
PubMed: 31669742
DOI: 10.1016/j.ijantimicag.2019.10.009 -
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