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Cell Death & Disease Aug 2021Pediatric gliomas comprise a broad range of brain tumors derived from glial cells. While high-grade gliomas are often resistant to therapy and associated with a poor...
Pediatric gliomas comprise a broad range of brain tumors derived from glial cells. While high-grade gliomas are often resistant to therapy and associated with a poor outcome, children with low-grade gliomas face a better prognosis. However, the treatment of low-grade gliomas is often associated with severe long-term adverse effects. This shows that there is a strong need for improved treatment approaches. Here, we highlight the potential for repurposing disulfiram to treat pediatric gliomas. Disulfiram is a drug used to support the treatment of chronic alcoholism and was found to be effective against diverse cancer types in preclinical studies. Our results show that disulfiram efficiently kills pediatric glioma cell lines as well as patient-derived glioma stem cells. We propose a novel mechanism of action to explain disulfiram's anti-oncogenic activities by providing evidence that disulfiram induces the degradation of the oncoprotein MLL. Our results further reveal that disulfiram treatment and MLL downregulation induce similar responses at the level of histone modifications and gene expression, further strengthening that MLL is a key target of the drug and explaining its anti-oncogenic properties.
Topics: Alcoholism; Auranofin; Cell Line, Tumor; Cell Proliferation; Child; Disulfiram; Down-Regulation; Drug Repositioning; Drug Synergism; Gene Expression Regulation, Neoplastic; Glioma; Histone-Lysine N-Methyltransferase; Histones; Humans; Lysine; Methylation; Myeloid-Lymphoid Leukemia Protein; Neoplasm Grading; Protein Processing, Post-Translational; Proteolysis; Transcription, Genetic
PubMed: 34381018
DOI: 10.1038/s41419-021-04078-9 -
Molecules (Basel, Switzerland) Jul 2023Gold compounds form a new class of promising anticancer agents with innovative modes of action. It is generally believed that anticancer gold compounds, at variance with... (Review)
Review
Gold compounds form a new class of promising anticancer agents with innovative modes of action. It is generally believed that anticancer gold compounds, at variance with clinically established platinum drugs, preferentially target proteins rather than nucleic acids. The reactions of several gold compounds with a few model proteins have been systematically explored in recent years through ESI MS measurements to reveal adduct formation and identify the main features of those reactions. Here, we focus our attention on a group of five gold compounds of remarkable medicinal interest, i.e., Auranofin, Au(NHC)Cl, [Au(NHC)]PF, Aubipyc, and Auoxo6, and on their reactions with four different biomolecular targets, i.e., the proteins HEWL, hCA I, HSA and the C-terminal dodecapeptide of the enzyme thioredoxin reductase. Complete ESI MS data are available for those reactions due to previous experimental work conducted in our laboratory. From the comparative analysis of the ESI MS reaction profiles, some characteristic trends in the metallodrug-protein reactivity may be identified as detailed below. The main features are described and analyzed in this review. Overall, all these observations are broadly consistent with the concept that cytotoxic gold drugs preferentially target cancer cell proteins, with a remarkable selectivity for the cysteine and selenocysteine proteome. These interactions typically result in severe damage to cancer cell metabolism and profound alterations in the redox state, leading to eventual cancer cell death.
Topics: Gold Compounds; Gold; Auranofin; Antineoplastic Agents; Thioredoxin-Disulfide Reductase
PubMed: 37446857
DOI: 10.3390/molecules28135196 -
Transactions of the Royal Society of... Oct 2023Three obligate intracellular protozoan parasite species, which are responsible for significant morbidity and mortality and settle in macrophage cells, affect more than...
BACKGROUND
Three obligate intracellular protozoan parasite species, which are responsible for significant morbidity and mortality and settle in macrophage cells, affect more than one-half of the world's population, namely, Trypanosoma cruzi, Leishmania tropica and Toxoplasma gondii, which are causative agents of Chagas disease, leishmaniasis and toxoplasmosis, respectively. In the current study, it was aimed to investigate the in vitro and ex vivo antiprotozoal activity of auranofin on T. cruzi, L. tropica and T. gondii.
METHODS
The in vitro drug efficacy (IC50) of auranofin was investigated by haemocytometry and the CellTiter-Glo assay methods and the ex vivo drug efficacy (IC50) by light microscopic examination of Giemsa-stained slides. Also, the cytotoxic activity (CC50) of auranofin was examined by the CellTiter-Glo assay. The selectivity index (SI) was calculated for auranofin.
RESULTS
According to IC50, CC50 and SI data, auranofin did not exhibit cytotoxic activity on Vero cells, but exhibited antiprotozoal activity on epimastigotes and intracellular amastigotes of T. cruzi, promastigotes and intracellular amastigotes of L. tropica and intracellular tachyzoites of T. gondii (p<0.05).
CONCLUSIONS
The detection antiprotozoal activity of auranofin on T. cruzi, L. tropica and T. gondii according to the IC50, CC50 and SI values is considered an important and promising development. This is significant because auranofin may be an effective alternative treatment for Chagas disease, leishmaniasis and toxoplasmosis in the future.
Topics: Humans; Animals; Chlorocebus aethiops; Trypanosoma cruzi; Toxoplasma; Leishmania tropica; Auranofin; Vero Cells; Chagas Disease; Toxoplasmosis; Leishmaniasis; Antiprotozoal Agents
PubMed: 37377375
DOI: 10.1093/trstmh/trad040 -
ACS Nano Sep 2022Nanomedicine-based and unmodified drug interventions to address COVID-19 have evolved over the course of the pandemic as more information is gleaned and virus variants...
Nanomedicine-based and unmodified drug interventions to address COVID-19 have evolved over the course of the pandemic as more information is gleaned and virus variants continue to emerge. For example, some early therapies (e.g., antibodies) have experienced markedly decreased efficacy. Due to a growing concern of future drug resistant variants, current drug development strategies are seeking to find effective drug combinations. In this study, we used IDentif.AI, an artificial intelligence-derived platform, to investigate the drug-drug and drug-dose interaction space of six promising experimental or currently deployed therapies at various concentrations: EIDD-1931, YH-53, nirmatrelvir, AT-511, favipiravir, and auranofin. The drugs were tested against a live B.1.1.529 (Omicron) virus first in monotherapy and then in 50 strategic combinations designed to interrogate the interaction space of 729 possible combinations. Key findings and interactions were then further explored and validated in an additional experimental round using an expanded concentration range. Overall, we found that few of the tested drugs showed moderate efficacy as monotherapies in the actionable concentration range, but combinatorial drug testing revealed significant dose-dependent drug-drug interactions, specifically between EIDD-1931 and YH-53, as well as nirmatrelvir and YH-53. Checkerboard validation analysis confirmed these synergistic interactions and also identified an interaction between EIDD-1931 and favipiravir in an expanded range. Based on the platform nature of IDentif.AI, these findings may support further explorations of the dose-dependent drug interactions between different drug classes in further pre-clinical and clinical trials as possible combinatorial therapies consisting of unmodified and nanomedicine-enabled drugs, to combat current and future COVID-19 strains and other emerging pathogens.
Topics: Amides; Artificial Intelligence; Auranofin; Guanosine Monophosphate; Humans; Phosphoramides; Pyrazines; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35977379
DOI: 10.1021/acsnano.2c06366 -
The Lancet. Respiratory Medicine Aug 2021Current tuberculosis treatments leave patients with clinically significant lung injury and increased all-cause mortality post-cure. Adjunctive host-directed therapies... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Current tuberculosis treatments leave patients with clinically significant lung injury and increased all-cause mortality post-cure. Adjunctive host-directed therapies could protect the lungs, improve long-term survival, and shorten treatment duration; however, few have been tested clinically. Therefore, we aimed to assess the safety and preliminary efficacy of four host-directed therapies for tuberculosis.
METHODS
In this prospective, open-label, phase 2, randomised controlled trial, patients with pulmonary tuberculosis were recruited at three clinical sites in South Africa. Eligible patients were aged 18-65 years, HIV-1-negative, and had rifampicin-susceptible Mycobacterium tuberculosis, a sputum Xpert cycle threshold of less than 20, and moderately advanced or far advanced disease on chest radiography. By use of numbers generated in blocks of ten and stratification by site, eligible patients were randomly assigned (1:1:1:1:1) to receive one of the four oral host-directed treatments plus standard tuberculosis treatment or standard treatment alone (the control group). Host-directed treatments were: CC-11050 (200 mg twice daily, taken with food; day 1-112); everolimus (0·5 mg/day; day 1-112); auranofin (3 mg/day for seven doses, then 6 mg/day; day 1-112); and ergocalciferol (5 mg on day 1, then 2·5 mg on day 28 and day 56). All study participants received oral rifabutin-substituted standard tuberculosis treatment for 180 days. Patients and clinicians were not masked to treatment assignment. Spirometry and sputum culture with solid and liquid media were done at baseline and up to 180 days at specified intervals throughout treatment. The primary endpoint was safety and tolerability up to day 210. Secondary preliminary efficacy endpoints were treatment effects on sputum microbiology (culture status at day 56 and the hazard ratio for stable culture conversion up to day 180) and lung function (FEV and forced vital capacity [FVC]) measured by spirometry at day 56, day 180, and day 540. Safety was analysed in the intention-to-treat population and preliminary efficacy primarily in the per-protocol population. The trial is registered at ClinicalTrials.gov, NCT02968927. Post-treatment follow-up was completed in 2020.
FINDINGS
Between Nov 18, 2016, and Sept 27, 2018, 200 patients were screened and randomly assigned to different treatment groups (n=40 per group, apart from n=39 in the everolimus group after one patient withdrew consent). 11 treatment-emergent serious adverse events occurred either during treatment or within 30 days after treatment discontinuation, of which three were attributable to a host-directed treatment. Life-threatening thrombocytopenia occurred in an auranofin recipient; apparent intra-abdominal sepsis leading to death occurred in another auranofin recipient and was classified as a suspected unexpected serious adverse reaction. Tuberculous spondylitis occurred as an apparent paradoxical reaction in a patient receiving ergocalciferol. Two patients in the control group had life-threatening, treatment-attributable liver injury. No treatment-emergent, treatment-attributable serious adverse events occurred in patients receiving CC-11050 or everolimus. Mean FEV in the control group was 61·7% of predicted (95% CI 56·3-67·1) at baseline and 69·1% (62·3-75·8) at day 180. Patients treated with CC-11050 and everolimus had increased recovery of FEV at day 180 relative to the control group (mean difference from control group 6·30%, 95% CI 0·06-12·54; p=0·048; and 6·56%, 0·18-12·95; p=0·044, respectively), whereas auranofin and ergocalciferol recipients did not. None of the treatments had an effect on FVC during 180 days of follow-up or on measures of sputum culture status over the course of the study.
INTERPRETATION
CC-11050 and everolimus were safe and reasonably well tolerated as adjunctive therapies for tuberculosis, and analysis of preliminary efficacy suggests they might also enhance the recovery of FEV, a key measure of lung function and predictor of all-cause mortality. Further studies of these candidates are warranted.
FUNDING
The Bill & Melinda Gates Foundation and the South African Medical Research Council.
Topics: Adult; Antitubercular Agents; Auranofin; Double-Blind Method; Drug Therapy, Combination; Ergocalciferols; Everolimus; Female; Forced Expiratory Volume; Humans; Indoles; Male; Middle Aged; Mycobacterium tuberculosis; Phosphodiesterase 4 Inhibitors; Prospective Studies; South Africa; Sputum; Sulfones; Tuberculosis, Pulmonary
PubMed: 33740465
DOI: 10.1016/S2213-2600(20)30448-3 -
Medicinal Research Reviews May 2022Auranofin is an oral gold(I) compound, initially developed for the treatment of rheumatoid arthritis. Currently, Auranofin is under investigation for oncological... (Review)
Review
Auranofin is an oral gold(I) compound, initially developed for the treatment of rheumatoid arthritis. Currently, Auranofin is under investigation for oncological application within a drug repurposing plan due to the relevant antineoplastic activity observed both in vitro and in vivo tumor models. In this review, we analysed studies in which Auranofin was used as a single drug or in combination with other molecules to enhance their anticancer activity or to overcome chemoresistance. The analysis of different targets/pathways affected by this drug in different cancer types has allowed us to highlight several interesting targets and effects of Auranofin besides the already well-known inhibition of thioredoxin reductase. Among these targets, inhibitory-κB kinase, deubiquitinates, protein kinase C iota have been frequently suggested. To rationalize the effects of Auranofin by a system biology-like approach, we exploited transcriptomic data obtained from a wide range of cell models, extrapolating the data deposited in the Connectivity Maps website and we attempted to provide a general conclusion and discussed the major points that need further investigation.
Topics: Antineoplastic Agents; Auranofin; Drug Resistance; Humans; Neoplasms; Thioredoxin-Disulfide Reductase
PubMed: 34850406
DOI: 10.1002/med.21872 -
Frontiers in Cellular and Infection... 2019Intravascular catheter related bloodstream infections (CRBSIs) are a leading cause of hospital-acquired infections worldwide, resulting not only in the burden of cost...
Intravascular catheter related bloodstream infections (CRBSIs) are a leading cause of hospital-acquired infections worldwide, resulting not only in the burden of cost and morbidity for patients but also in the over-consumption of medical resources for hospitals and health care organizations. In this study, a novel auranofin releasing antibacterial and antibiofilm polyurethane (PU) catheter coating was developed and investigated for future use in preventing CRBSIs. Auranofin is an antirheumatic drug with recently identified antimicrobial properties. The drug carrier, PU, acts as a barrier surrounding the antibacterial agent, auranofin, to extend the drug release profile and improve its long-term antibacterial and antibiofilm efficacy and potentially the length of catheter implantation within a patient. The PU+auranofin coatings developed here were found to be highly stretchable (exhibiting ~500% percent elongation), which is important for the compliance of the material on a flexible catheter. PU+auranofin coated catheters were able to inhibit the growth of methicillin-resistant (MRSA) for 8 to 26 days depending on the specific drug concentration utilized during the dip coating process. The PU+auranofin coated catheters were also able to completely inhibit MRSA biofilm formation , an effect that was not observed with auranofin or PU alone. Lastly, these coatings were found to be hemocompatible with human erythrocytes and maintain liver cell viability.
Topics: Anti-Infective Agents; Auranofin; Biofilms; Catheters; Chemical Phenomena; Coated Materials, Biocompatible; Drug Carriers; Methicillin-Resistant Staphylococcus aureus; Polyurethanes
PubMed: 30873389
DOI: 10.3389/fcimb.2019.00037 -
Frontiers in Cellular and Infection... 2021To assess the efficacy of aztreonam-avibactam-auranofin (ATM-AVI-AUR) against a collection of 88 carbapenemase-producing (CPE) clinical isolates and 6 selected...
OBJECTIVES
To assess the efficacy of aztreonam-avibactam-auranofin (ATM-AVI-AUR) against a collection of 88 carbapenemase-producing (CPE) clinical isolates and 6 selected ATM-AVI-resistant CPE with CMY-16 Tyr150Ser and Asn346His mutants or transformants.
METHODS
MICs of imipenem, ceftazidime-avibact8am (CAZ-AVI), ATM-AVI, CAZ-AVI-AUR and ATM-AVI-AUR were determined the broth microdilution method. Genetic background and carbapenemase genes were determined by PCR and Sanger sequencing.
RESULTS
AUR alone showed little antibacterial activity with AUR MICs were greater than 64 μg/mL for all the 88 clinical CPE isolates. The addition of AUR (16 μg/mL) resulted in an 3-folding dilutions MIC reduction of ATM-AVI MIC (0.5 to 0.0625 μg/mL) and a 2-folding dilutions MIC reduction of MIC (1 to 0.25 μg/mL) against all 88 clinical CPE isolates, respectively. Notably, the reduced ATM-AVI MIC values were mainly found in MBL-producers, and the MIC and MIC reduced by 2-folding dilutions (0.25 to 0.0625 μg/mL) and 3-folding dilutions (2 to 0.25 μg/mL) respectively by AUR among the 51 MBL-producers. By contrast, the addition of AUR did not showed significant effects on ATM-AVI MIC (0.0625 μg/mL) and MIC (0.125 μg/mL) among single KPC-producers. Interestingly, the addition of AUR restored the ATM-AVI susceptibility against the 6 selected ATM-AVI-resistant CMY-16 Tyr150Ser and Asn346His mutants or transfromants, with the MICs reduced from ≥32 μg/mL (32->256 μg/mL) to ≤8 μg/mL (0.0625-8 μg/mL).
CONCLUSIONS
Our results demonstrated that AUR potentiated the activities of CAZ-AVI and ATM-AVI against MBL-producing isolates . Importantly, AUR restored the ATM-AVI activity against ATM-AVI resistant mutant strains. As a clinically approved drug, AUR might be repurposed in combination with ATM-AVI to treat infections caused by highly resistant MBL-producing
Topics: Auranofin; Azabicyclo Compounds; Aztreonam; beta-Lactamases
PubMed: 34778107
DOI: 10.3389/fcimb.2021.755763 -
International Journal of Molecular... Jun 2022The biological properties of sixteen structurally related monoanionic gold (III) bis(dithiolene/ diselenolene) complexes were evaluated. The complexes differ in the...
The biological properties of sixteen structurally related monoanionic gold (III) bis(dithiolene/ diselenolene) complexes were evaluated. The complexes differ in the nature of the heteroatom connected to the gold atom (AuS for dithiolene, AuSe for diselenolene), the substituent on the nitrogen atom of the thiazoline ring (Me, Et, Pr, iPr and Bu), the nature of the exocyclic atom or group of atoms (O, S, Se, C(CN)) and the counter-ion (PhP or EtN). The anticancer and antimicrobial activities of all the complexes were investigated, while the anti-HIV activity was evaluated only for selected complexes. Most complexes showed relevant anticancer activities against Cisplatin-sensitive and Cisplatin-resistant ovarian cancer cells A2780 and OVCAR8, respectively. After 48 h of incubation, the IC values ranged from 0.1-8 μM (A2780) and 0.8-29 μM (OVCAR8). The complexes with the PhP ([]) counter-ion are in general more active than their EtN ([]) analogues, presenting IC values in the same order of magnitude or even lower than Auranofin. Studies in the zebrafish embryo model further showed that, despite their marked anticancer effect, the complexes with [] counter-ion exhibited low in vivo toxicity. In general, the exocyclic exchange of sulfur by oxygen or ylidenemalononitrile (C(CN)) enhanced the compounds toxicity. Most complexes containing the [] counter ion exhibited exceptional antiplasmodial activity against the parasite liver stages, with submicromolar IC values ranging from 400-700 nM. In contrast, antibacterial/fungi activities were highest for most complexes with the [] counter-ion. Auranofin and two selected complexes [][AuSBu(=S)] and [][AuSEt(=S)] did not present anti-HIV activity in TZM-bl cells. Mechanistic studies for selected complexes support the idea that thioredoxin reductase, but not DNA, is a possible target for some of these complexes. The complexes [] [AuSBu(=S)], [] [AuSEt(=S)], [] [AuSEt(=Se)] and [] [AuSeiPr(=S)] displayed a strong quenching of the fluorescence intensity of human serum albumin (HSA), which indicates a strong interaction with this protein. Overall, the results highlight the promising biological activities of these complexes, warranting their further evaluation as future drug candidates with clinical applicability.
Topics: Animals; Antineoplastic Agents; Auranofin; Cell Line, Tumor; Cisplatin; Female; Gold; Humans; Ovarian Neoplasms; Zebrafish
PubMed: 35806151
DOI: 10.3390/ijms23137146 -
Biochemical and Biophysical Research... Dec 2022Osteoarthritis, a prevalent orthopedic disease, can affect the elderly and causes impairment. The degradation and aberrant homeostasis of cartilage extracellular matrix...
Osteoarthritis, a prevalent orthopedic disease, can affect the elderly and causes impairment. The degradation and aberrant homeostasis of cartilage extracellular matrix figure pivotally in the progression of osteoarthritis. Thioredoxin systems plays a role in a wide range of biological processes, including cell proliferation, apoptosis, and oxidative stress. The present study aimed to investigate the unique function and underlying pathophysiological mechanism of TXNRD1 in chondrocytes. An upregulated expression of TXNRD1 was observed in the articular cartilage of osteoarthritis patients compared with normal articular cartilage. Furthermore, in vitro experiments showed that the expression of TXNRD1 was also abnormally increased in IL-1β-induced primary mouse chondrocytes. Silencing TXNRD1 using siRNA in chondrocytes could effectively inhibit the expression of ADAMTS5 and MMP13, and enhance the expression of COL2A1 and SOX9. The same was true for auranofin, an inhibitor of TXNRD1. This phenomenon indicated that inhibition of TXNRD1 attenuated il-1β-induced metabolic imbalance of extracellular matrix (ECM) and the progression of chondrocyte osteoarthritis. Further mechanism analysis revealed that the activation of Nrf2 signaling pathway and the expression of heme oxygenase-1 (HO-1) were increased upon TXNRD1 inhibition. Furthermore, auranofin was found to attenuate DMM-induced osteoarthritis progression in vivo. Therefore, the pharmacological downregulation of TXNRD1 may provide an effective novel therapy for OA.
Topics: Animals; Mice; Auranofin; Cartilage, Articular; Chondrocytes; Extracellular Matrix; Interleukin-1beta; NF-E2-Related Factor 2; Osteoarthritis; Thioredoxin Reductase 1
PubMed: 36308906
DOI: 10.1016/j.bbrc.2022.10.059