-
Journal of Experimental & Clinical... Jan 2024MEK inhibitors (MEKi) were shown to be clinically insufficiently effective in patients suffering from BRAF wild-type (BRAF WT) melanoma, even if the MAPK pathway was...
BACKGROUND
MEK inhibitors (MEKi) were shown to be clinically insufficiently effective in patients suffering from BRAF wild-type (BRAF WT) melanoma, even if the MAPK pathway was constitutively activated due to mutations in NRAS or NF-1. Thus, novel combinations are needed to increase the efficacy and duration of response to MEKi in BRAF WT melanoma. Disulfiram and its metabolite diethyldithiocarbamate are known to have antitumor effects related to cellular stress, and induction of endoplasmic reticulum (ER) stress was found to synergize with MEK inhibitors in NRAS-mutated melanoma cells. Therefore, we investigated the combination of both therapeutics to test their effects on BRAF-WT melanoma cells and compared them with monotherapy using the MEKi trametinib.
METHODS
The effects of combined therapy with disulfiram or its metabolite diethyldithiocarbamate and the MEKi trametinib were evaluated in a series of BRAF-WT melanoma cell lines by measuring cell viability and apoptosis induction. Cytotoxicity was additionally assessed in 3D spheroids, ex vivo melanoma slice cultures, and in vivo xenograft mouse models. The response of melanoma cells to treatment was studied at the RNA and protein levels to decipher the mode of action. Intracellular and intratumoral copper measurements were performed to investigate the role of copper ions in the antitumor cytotoxicity of disulfiram and its combination with the MEKi.
RESULTS
Diethyldithiocarbamate enhanced trametinib-induced cytotoxicity and apoptosis induction in 2D and 3D melanoma culture models. Mechanistically, copper-dependent induction of oxidative stress and ER stress led to Janus kinase (JNK)-mediated apoptosis in melanoma cells. This mechanism was also detectable in patient-derived xenograft melanoma models and resulted in a significantly improved therapeutic effect compared to monotherapy with the MEKi trametinib.
CONCLUSIONS
Disulfiram and its metabolite represent an attractive pharmaceutical approach to induce ER stress in melanoma cells that potentiates the antitumor effect of MEK inhibition and may be an interesting candidate for combination therapy of BRAF WT melanoma.
Topics: Humans; Animals; Mice; Disulfiram; Proto-Oncogene Proteins B-raf; Copper; Melanoma; Ditiocarb; Disease Models, Animal; Mitogen-Activated Protein Kinase Kinases
PubMed: 38263136
DOI: 10.1186/s13046-023-02941-5 -
Revista de Neurologia Dec 2022Disulfiram-induced-encephalopathy is a rare complication that has been well described in adults. Although it usually occurs in acute intoxication with high doses of...
INTRODUCTION
Disulfiram-induced-encephalopathy is a rare complication that has been well described in adults. Although it usually occurs in acute intoxication with high doses of disulfiram, late onset encephalopathy has also been reported. Some authors propose the inhibition of dopamine beta-hydroxylase mediated by toxic metabolites of disulfiram as the main responsible, but the exact mechanism remains unclear. The aim of this report was to describe the clinical and neuroimaging findings in an unusual case of acute encephalitis due to disulfiram toxicity associated to chronic intranasal consume.
CASE REPORT
A chronic alcoholic who referred snorted use of a very high dose of disulfiram without simultaneous alcohol intake developed an acute encephalopathy with a rapidly progressive respiratory failure. A characteristic neuroimage finding consisting in extensive bilateral symmetric involvement of both pallidal nuclei was described. Recovery and neurologic improvement were slow. Two months after the intoxication, the patient still had slight intentional tremor and a scheduled magnetic resonance imaging. showed evolution of symmetrical areas of cytotoxic edema to necrosis.
CONCLUSION
Disulfiram-induced neurotoxicity must be suspect during chronic therapy with disulfiram or after acute ingestion of high doses. Symptoms such as symmetric sensory and motor neuropathy, confusion, catatonia, parkinsonism, ataxia, choreoathetosis, seizures and encephalopathy should make us rule out this disorder. A brain imaging test should be performed in these patients since a characteristic involvement of both nuclei pallidus has been described, but it is not present in all patients.
Topics: Adult; Humans; Disulfiram; Brain Diseases; Magnetic Resonance Imaging; Neuroimaging; Brain
PubMed: 36440748
DOI: 10.33588/rn.7511.2021415 -
Drug Discovery Today Sep 2022The current Coronavirus 2019 (COVID-19) pandemic has shown us that the pharmaceutical research community can organize and administer large nonprofit clinical trials...
The current Coronavirus 2019 (COVID-19) pandemic has shown us that the pharmaceutical research community can organize and administer large nonprofit clinical trials (RECOVERY and SOLIDARITY) and achieve the swift development of common, unpatentable drugs for a new indication: in this case an old, inexpensive drug, dexamethasone, for COVID-19. Why is it that such nonprofit efforts are so rare and are not organized as a systemic, routine part of drug development in the public interest? Based on my own experience with repurposing the alcohol-abuse drug disulfiram (Antabuse) for cancer, I identify at least four serious deadlocks to development of nonprofit drugs. All of these obstacles should be addressed to leverage the potential of the COVID-19 pandemic for better future healthcare systems in all countries around the world.
Topics: COVID-19; Delivery of Health Care; Disulfiram; Humans; Organizations, Nonprofit; Pandemics
PubMed: 35667629
DOI: 10.1016/j.drudis.2022.06.001 -
British Medical Journal Jul 1977
Topics: Adult; Aged; Alcoholism; Chemical and Drug Induced Liver Injury; Disulfiram; Female; Humans; Liver; Male; Middle Aged
PubMed: 871808
DOI: 10.1136/bmj.2.6079.94 -
Antimicrobial Agents and Chemotherapy Nov 2022New anti-Entamoeba histolytica multistage drugs are needed because only one drug class, nitroimidazoles, is available for treating invasive disease, and it does not...
New anti-Entamoeba histolytica multistage drugs are needed because only one drug class, nitroimidazoles, is available for treating invasive disease, and it does not effectively eradicate the infective cyst stage. Zinc ditiocarb (ZnDTC), a main metabolite of the FDA-approved drug disulfiram, was recently shown to be highly effective against the invasive trophozoite stage. In this brief report, we show that ZnDTC is active against cysts, with similar potency to first-line cysticidal drug paromomycin.
Topics: Animals; Disulfiram; Parasites; Alcoholism; Entamoeba histolytica; Ditiocarb; Cysts
PubMed: 36255253
DOI: 10.1128/aac.00832-22 -
Oxidative Medicine and Cellular... 2022Glioma is the most common of all central nervous system (CNS) malignancies and is associated with a poor prognosis. Pyroptosis has been proven to be associated with the...
Glioma is the most common of all central nervous system (CNS) malignancies and is associated with a poor prognosis. Pyroptosis has been proven to be associated with the progression of multiple tumors and CNS diseases. However, the relationships between pyroptosis and clinical prognosis and immune cell infiltration are unclear in glioma. In this study, we conducted a comprehensive exploration of pyroptosis in glioma. First, prognosis-related genes were screened at each key regulatory locus in the pyroptosis pathway, and the prognostic ability and coexpression relationships of GSDMD and its upstream pathway genes NLRC4/CASP1/CASP4 were identified and well validated in multiple datasets. Tissue microarray-based immunohistochemistry results showed higher levels of NLRC4 and N-terminal GSDMD in high-grade gliomas, providing conclusive evidence of pyroptosis in gliomas. The robustness of the prognostic model based on these four genes was well validated in TCGA and CGGA cohorts. Bulk RNA-seq-based analysis showed that the group defined as the high-risk group according to the model showed activation of multiple inflammatory response pathways and impaired synaptic gene expression and had a higher infiltration of bone marrow-derived macrophages (BMDMs) and a hypersuppressed immune microenvironment. More importantly, three independent single-cell RNA-seq (scRNA-seq) datasets demonstrated that tumor-infiltrating macrophages, particularly BMDMs but not tissue-resident microglia, showed significant coexpression of the GSDMD and CASP genes, and BMDMs from high-grade gliomas accounted for a higher proportion of immune infiltrating cells and had higher expression of pyroptosis genes. Finally, we revealed the activation of pathways in response to LPS/bacteria and oxidative stress during BMDM development toward the pyroptosis cell fate by pseudotime trajectory analysis, suggesting potential BMDM pyroptosis initiators. The above results provide not only novel insights into the pathological mechanisms of glioma but also novel therapeutic targets for glioma, suggesting the potential application of pyroptosis inhibitors (e.g., disulfiram).
Topics: Disulfiram; Gene Expression Profiling; Glioma; Humans; Immunosuppression Therapy; Lipopolysaccharides; Macrophages; Pyroptosis; Single-Cell Analysis; Tumor Microenvironment
PubMed: 36199426
DOI: 10.1155/2022/1803544 -
PLoS Pathogens Sep 2020Understanding how the protozoan protein degradation pathway is regulated could uncover new parasite biology for drug discovery. We found the COP9 signalosome (CSN)...
Understanding how the protozoan protein degradation pathway is regulated could uncover new parasite biology for drug discovery. We found the COP9 signalosome (CSN) conserved in multiple pathogens such as Leishmania, Trypanosoma, Toxoplasma, and used the severe diarrhea-causing Entamoeba histolytica to study its function in medically significant protozoa. We show that CSN is an essential upstream regulator of parasite protein degradation. Genetic disruption of E. histolytica CSN by two distinct approaches inhibited cell proliferation and viability. Both CSN5 knockdown and dominant negative mutation trapped cullin in a neddylated state, disrupting UPS activity and protein degradation. In addition, zinc ditiocarb (ZnDTC), a main metabolite of the inexpensive FDA-approved globally-available drug disulfiram, was active against parasites acting in a COP9-dependent manner. ZnDTC, given as disulfiram-zinc, had oral efficacy in clearing parasites in vivo. Our findings provide insights into the regulation of parasite protein degradation, and supports the significant therapeutic potential of COP9 inhibition.
Topics: Animals; COP9 Signalosome Complex; Disulfiram; Ditiocarb; Entamoeba histolytica; Mice; Proteolysis; Protozoan Proteins
PubMed: 32960936
DOI: 10.1371/journal.ppat.1008952 -
Journal of Orthopaedic Surgery and... Feb 2021Osteoarthritis (OA) is a kind of systemic musculoskeletal disorder and a most important factor for causing disability and physical painfulness. Nevertheless, due to the...
BACKGROUND
Osteoarthritis (OA) is a kind of systemic musculoskeletal disorder and a most important factor for causing disability and physical painfulness. Nevertheless, due to the fact that OA can be triggered by multiple etiological factors, this disease is hard to be cured. Therefore, it is of great necessity for us to find novel targets or drugs for OA treatment.
MATERIALS AND METHODS
The chondrocytes were treated with lipopolysaccharide (LPS) and adenosine triphosphate (ATP) to induce pyroptosis in OA. The cell proliferation was detected by Cell Counting Kit-8 assay (CCK-8 assay). Enzyme-linked immunosorbent assay (ELISA) was used for the detection of pyroptosis-related inflammatory factors. Then, the antagonists for gasdermin D (GSDMD) (disulfiram) and high mobility group box 1 (HMGB1) (glycyrrhizic acid) were used to treat the cell model to observe the effects of disulfiram and glycyrrhizic acid on the proliferation of chondrocytes in OA. The protein levels of pyroptosis-related inflammatory factors were measured by western blot, and the levels of aldehyde dehydrogenase (ALDH) and reactive oxygen species (ROS) were measured by corresponding commercial kits.
RESULTS
After chondrocytes were induced by LPS and ATP, the cell proliferation was decreased and the expressions of pyroptosis-related inflammatory factors were increased. Disulfiram and glycyrrhizic acid treatment led to enhanced cell proliferation and increased expressions of pyroptosis-related inflammatory factors, while disulfiram showed better alleviative effects on the inflammation in chondrocytes in OA. However, co-treatment with disulfiram at a high concentration and glycyrrhizic acid did not result in higher proliferation of chondrocytes and alleviated inflammation, but led to oxidative stress.
CONCLUSION
In conclusion, co-treatment with disulfiram and glycyrrhizic acid at a standard concentration suppresses the inflammatory response of chondrocytes, which may provide guidance for the use of the drugs in the treatment of OA.
Topics: Cell Proliferation; Cells, Cultured; Chondrocytes; Disulfiram; Dose-Response Relationship, Drug; Glycyrrhizic Acid; Humans; Inflammation; Osteoarthritis; Phytotherapy; Pyroptosis
PubMed: 33579316
DOI: 10.1186/s13018-021-02262-3 -
Report on Carcinogens : Carcinogen... 2011
Topics: Animals; Carcinogens; Chelating Agents; Ditiocarb; Herbicides; Humans; Neoplasms; Occupational Exposure
PubMed: 21863099
DOI: No ID Found -
Scientific Reports Sep 2023Neuroblastoma, the most common type of pediatric extracranial solid tumor, causes 10% of childhood cancer deaths. Despite intensive multimodal treatment, the outcomes of...
Neuroblastoma, the most common type of pediatric extracranial solid tumor, causes 10% of childhood cancer deaths. Despite intensive multimodal treatment, the outcomes of high-risk neuroblastoma remain poor. We urgently need to develop new therapies with safe long-term toxicity profiles for rapid testing in clinical trials. Drug repurposing is a promising approach to meet these needs. Here, we investigated disulfiram, a safe and successful chronic alcoholism treatment with known anticancer and epigenetic effects. Disulfiram efficiently induced cell cycle arrest and decreased the viability of six human neuroblastoma cell lines at half-maximal inhibitory concentrations up to 20 times lower than its peak clinical plasma level in patients treated for chronic alcoholism. Disulfiram shifted neuroblastoma transcriptome, decreasing MYCN levels and activating neuronal differentiation. Consistently, disulfiram significantly reduced the protein level of lysine acetyltransferase 2A (KAT2A), drastically reducing acetylation of its target residues on histone H3. To investigate disulfiram's anticancer effects in an in vivo model of high-risk neuroblastoma, we developed a disulfiram-loaded emulsion to deliver the highly liposoluble drug. Treatment with the emulsion significantly delayed neuroblastoma progression in mice. These results identify KAT2A as a novel target of disulfiram, which directly impacts neuroblastoma epigenetics and is a promising candidate for repurposing to treat pediatric neuroblastoma.
Topics: Animals; Child; Humans; Mice; Alcohol Deterrents; Cell Line, Tumor; Disulfiram; Down-Regulation; Drug Repositioning; Emulsions; Histone Acetyltransferases; Neuroblastoma
PubMed: 37777587
DOI: 10.1038/s41598-023-43219-2