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Translational Research : the Journal of... Feb 2024To investigate the role of S-palmitoylation in pyroptosis following acute myocardial infarction (AMI). Myocardial ischemic injury is mainly related to the death of...
To investigate the role of S-palmitoylation in pyroptosis following acute myocardial infarction (AMI). Myocardial ischemic injury is mainly related to the death of terminally differentiated cardiomyocytes. Pyroptosis is a new form of programmed cell death and recently is identified a potential mechanism of cardiomyocyte loss. However, the role of S-palmitoylation in pyroptosis following MI remains elusive. AMI was mimicked by permanent left anterior descending artery ligation. The palmitoylated proteins labeled by Click-iT palmitic acid were precipitated using streptavidin magnetic bead conjugate. The short-term palmitic acid dietary intake by modified western diet with palm oil for 7 days is compared with modified western diet with olive oil. Palmitoylation is increased in myocardial infarction and anoxic cardiomyocytes. Pyroptosis, but not apoptosis and necrosis, is more relevant with palmitoylation in the process of myocardial ischemia injury. The gasdermin D (GSDMD) Cys192 palmitoylation promotes its cytomembrane localization by ZDHHC14. GSDMD Cys192 palmitoylation aggravates in vitro cardiomyocyte pyroptosis. The short-term palmitic acid dietary intake or ML348 deteriorates myocardial pyroptosis, infarct size and cardiac function in AMI mice by GSDMD palmitoylation. Disulfiram antagonizes Cys192 palmitoylation of GSDMD-N-terminal and reduces myocardial pyroptosis and injury in AMI mice. We identifies ZHDDC14 induced palmitoylation as a crucial node for modulating GSDMD-N-terminal cytomembrane localization and establishes Disulfiram targeting GSDMD Cys192 palmitoylation as a potential clinical intervention for myocardial pyroptosis.
Topics: Mice; Animals; Disulfiram; Intracellular Signaling Peptides and Proteins; Gasdermins; Lipoylation; Palmitic Acid; Myocardial Infarction
PubMed: 37769810
DOI: 10.1016/j.trsl.2023.09.007 -
The Journal of Antimicrobial... Apr 2022To evaluate the in vitro and in vivo efficacy of the FDA-approved drug disulfiram in combination with meropenem against MBL-expressing carbapenem-resistant Acinetobacter...
OBJECTIVES
To evaluate the in vitro and in vivo efficacy of the FDA-approved drug disulfiram in combination with meropenem against MBL-expressing carbapenem-resistant Acinetobacter baumannii.
METHODS
Chequerboard and antibiotic resistance reversal analysis were performed using 25 clinical isolates producing different MBLs. Three representative strains harbouring NDM, IMP or non-MBL genes were subjected to a time-kill assay to further evaluate this synergistic interaction. Dose-dependent inhibition by disulfiram was assessed to determine IC50 for NDM-1, IMP-7, VIM-2 and KPC-2. Further, to test the efficacy of meropenem monotherapy and meropenem in combination with disulfiram against NDM- and IMP-harbouring A. baumannii, an experimental model of systemic infection and pneumonia was developed using BALB/c female mice.
RESULTS
Chequerboard and antibiotic reversal assay displayed a synergistic interaction against MBL-expressing A. baumannii strains with 4- to 32-fold reduction in MICs of meropenem. In time-kill analysis, meropenem and disulfiram exhibited synergy against NDM- and IMP-producing carbapenem-resistant A. baumannii (CRAb) isolates. In vitro dose-dependent inhibition analysis showed that disulfiram inhibits NDM-1 and IMP-7 with IC50 values of 1.5 ± 0.6 and 16.25 ± 1.6 μM, respectively, with slight or no inhibition of VIM-2 (<20%) and KPC-2. The combination performed better in the clearance of bacterial load from the liver and spleen of mice infected with IMP-expressing CRAb. In the pneumonia model, the combination significantly decreased the bacterial burden of NDM producers compared with monotherapy.
CONCLUSIONS
These results strongly suggest that the combination of disulfiram and meropenem represents an effective treatment option for NDM- and IMP-associated CRAb infections.
Topics: Animals; Female; Mice; Acinetobacter baumannii; Anti-Bacterial Agents; beta-Lactamases; Carbapenems; Disulfiram; Meropenem; Microbial Sensitivity Tests
PubMed: 35199158
DOI: 10.1093/jac/dkac057 -
Journal of Controlled Release :... Mar 2020Disulfiram (DSF) is an FDA-approved drug that has been repurposed for cancer treatment. It showed excellent anticancer efficacy in combination with copper ions (Cu).... (Review)
Review
Disulfiram (DSF) is an FDA-approved drug that has been repurposed for cancer treatment. It showed excellent anticancer efficacy in combination with copper ions (Cu). Several active clinical trials testing the anticancer efficacy of DSF against various cancers are underway. In this review article, we summarized different delivery strategies for DSF-based cancer therapy. In many studies, DSF and Cu were delivered in two separate formulations. DSF and Cu formed copper diethyldithiocarbamate [Cu(DDC)] complex which was reported as a major active anticancer ingredient for DSF/Cu combination therapy. Various delivery systems for DSF and Cu were developed to enhance their delivery into tumors. The administration of preformed Cu(DDC) complex was also explored to achieve better anticancer efficacy. Several studies developed formulations that were capable of delivering Cu(DDC) complex in a single formulation. These novel formulations will address drug delivery challenges and have great potential to improve the efficacy of DSF-based cancer therapy. DSF is an off-patent drug molecule. The novel drug formulations of DSF will also serve as a good strategy for developing intellectual properties which will be critical for product development and commercialization.
Topics: Copper; Disulfiram; Ditiocarb; Drug Delivery Systems; Humans; Neoplasms
PubMed: 31911155
DOI: 10.1016/j.jconrel.2020.01.001 -
Therapeutic Delivery Apr 2021
Topics: Antineoplastic Agents; Disulfiram; Drug Repositioning; Humans; Neoplasms
PubMed: 33657869
DOI: 10.4155/tde-2021-0009 -
International Journal of Pharmaceutics Oct 2022Disulfiram (DSF), a Food and Drug Administration (FDA)-approved drug for the treatment of alcoholism, has been found to have antitumor activity. DSF showed better... (Review)
Review
Disulfiram (DSF), a Food and Drug Administration (FDA)-approved drug for the treatment of alcoholism, has been found to have antitumor activity. DSF showed better antitumor efficiency when it was used in combination with certain antitumor drugs. DSF plays an important role in cancer treatment. It has been used as multidrug resistance (MDR) modulator to reverse MDR and can also combine with copper ions (Cu), which will produce copper diethyldithiocarbamate (Cu[DDC]) complex with antitumor activity. The synergistic targeted drug delivery for cancer treatment based on DSF, especially the combination with exogenous Cu and its forms of administration, has attracted extensive attention in the biomedical field. In this review, we summarize these synergistic delivery systems, in the hope that they will contribute to the continuous optimization and development of more advanced drug delivery systems. Furthermore, we discuss the current limitation and future directions of DSF-based drug delivery systems in the field of tumor therapy. Hopefully, our work may inspire further innovation of DSF-based antitumor drug delivery systems.
Topics: Antineoplastic Agents; Cell Line, Tumor; Copper; Disulfiram; Ditiocarb; Drug Delivery Systems; Humans; Neoplasms; United States; United States Food and Drug Administration
PubMed: 36007849
DOI: 10.1016/j.ijpharm.2022.122130 -
Journal of Leukocyte Biology Oct 2022T-cell malignancies, including T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoma (TCL), are characterized by inferior treatment effects, high...
T-cell malignancies, including T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoma (TCL), are characterized by inferior treatment effects, high heterogeneity, poor prognosis, and a lack of specific therapeutic targets and drugs to improve outcome. Disulfiram (DSF) is a drug used to clinically control alcoholism that has recently been shown to be cytotoxic for multiple cancers. However, the underlying effects and mechanisms of DFS treatment in patients with T-cell malignancies are not well characterized. In this study, we report that DSF promotes apoptosis and inhibits the proliferation of malignant T-cell cell lines and primary T-ALL cells. We provide evidence that DSF exerts anticancer activity in T-cell malignancies by targeting the NPL4-mediated ubiquitin-proteasome pathway. Notably, high expression of NPL4 and 2 ubiquitin-proteasome pathway genes, anaphase-promoting complex subunit 1 (ANAPC1) and proteasome 26S subunit ubiquitin receptor, non-ATPase 2 (PSMD2), was significantly associated with unfavorable overall survival (OS) for patients with TCL and T-ALL (p < 0.05). More importantly, the weighted combination of NPL4, ANAPC1, and PSMD2 could visually display the 1-, 3-, and 5-year OS rates for patients with T-cell malignancies in a nomogram model and facilitate risk stratification. Specifically, risk stratification was an independent predictor of OS for patients with T-cell malignancies. In conclusion, DSF might induce apoptosis and inhibit the proliferation of malignant T-cells via the NPL4-mediated ubiquitin-proteasome pathway and offer a potential therapeutic option for T-cell malignancies.
Topics: Apc1 Subunit, Anaphase-Promoting Complex-Cyclosome; Disulfiram; Humans; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Proteasome Endopeptidase Complex; T-Lymphocytes; Ubiquitins
PubMed: 35363385
DOI: 10.1002/JLB.5MA1121-644R -
Journal of Substance Abuse Treatment Jan 2023Alcohol use disorder (AUD) represents the most prevalent addiction in the United States. Integration of AUD treatment in primary care settings would expand care access.... (Review)
Review
BACKGROUND
Alcohol use disorder (AUD) represents the most prevalent addiction in the United States. Integration of AUD treatment in primary care settings would expand care access. The objective of this scoping review is to examine models of AUD treatment in primary care that include pharmacotherapy (acamprosate, disulfiram, naltrexone).
METHODS
The team undertook a search across MEDLINE, PsycINFO, CINAHL, the Cochrane Central Register of Controlled Trials, and Web of Science on May 21, 2021. Eligibility criteria included: patient population ≥ 18 years old, primary care-based setting, US-based study, presence of an intervention to promote AUD treatment, and prescription of FDA-approved AUD pharmacotherapy. Study design was limited to controlled trials and observational studies. We assessed study bias using a modified Oxford Centre for Evidence-based Medicine Rating Framework quality rating scheme.
RESULTS
The qualitative synthesis included forty-seven papers, representing 25 primary studies. Primary study sample sizes ranged from 24 to 830,825 participants and many (44 %) were randomized controlled trials. Most studies (80 %) included a nonpharmacologic intervention for AUD: 56 % with brief intervention, 40 % with motivational interviewing, and 12 % with motivational enhancement therapy. A plurality of studies (48 %) included mixed pharmacologic interventions, with administration of any combination of naltrexone, acamprosate, and/or disulfiram. Of the 47 total studies included, 68 % assessed care initiation and engagement. Fewer studies (15 %) explored practices surrounding screening for or diagnosing AUD. Outcome measures included receipt of pharmacotherapy and alcohol consumption, which about half of studies included (53 % and 51 %, respectively). Many of these outcomes showed significant findings in favor of integrated care models for AUD.
CONCLUSIONS
The integration of AUD pharmacotherapy in primary care settings may be associated with improved process and outcome measures of care. Future research should seek to understand the varied experiences across care integration models.
Topics: Humans; United States; Adolescent; Alcoholism; Acamprosate; Naltrexone; Disulfiram; Alcohol Drinking; Primary Health Care; Randomized Controlled Trials as Topic
PubMed: 36332528
DOI: 10.1016/j.jsat.2022.108919 -
Systematic Reviews Jun 2022Cancer morbidity and mortality rates remain high, and thus, at present, considerable efforts are focused on finding drugs with higher sensitivity against tumor cells and...
BACKGROUND AND OBJECTIVES
Cancer morbidity and mortality rates remain high, and thus, at present, considerable efforts are focused on finding drugs with higher sensitivity against tumor cells and fewer side effects. Disulfiram (DSF), as an anti-alcoholic drug, kills the cancer cells by inducing apoptosis. Several preclinical and clinical studies have examined the potential of repurposing DSF as an anticancer treatment. This systematic review aimed to assess evidence regarding the antineoplastic activity of DSF in in vitro and in vivo models, as well as in humans.
METHODS
Two authors independently conducted this systematic review of English and Chinese articles from the PubMed, Embase, and the Cochrane Library databases up to July 2019. Eligible in vitro studies needed to include assessments of the apoptosis rate by flow cytometry using annexin V/propidium iodide, and studies in animal models and clinical trials needed to examine tumor inhibition rates, and progression-free survival (PFS) and overall survival (OS), respectively. Data were analyzed using descriptive statistics.
RESULTS
Overall, 35 studies, i.e., 21 performed in vitro, 11 based on animal models, and three clinical trials, were finally included. In vitro and animal studies indicated that DSF was associated with enhanced apoptosis and tumor inhibition rates, separately. Human studies showed that DSF prolongs PFS and OS. The greatest anti-tumor activity was observed when DSF was used as combination therapy or as a nanoparticle-encapsulated molecule. There was no noticeable body weight loss after DSF treatment, which indicated that there was no major toxicity of DSF.
CONCLUSIONS
This systematic review provides evidence regarding the anti-tumor activity of DSF in vitro, in animals, and in humans and indicates the optimal forms of treatment to be evaluated in future research.
Topics: Animals; Antineoplastic Agents; Disulfiram; Humans; Neoplasms
PubMed: 35655266
DOI: 10.1186/s13643-021-01858-4 -
European Journal of Pharmacology Aug 2021Disulfiram (DSF) is a well-known anti-alcohol agent that inhibits aldehyde dehydrogenase and results in extreme 'hangover' symptoms when consumed with alcohol. This... (Review)
Review
Disulfiram (DSF) is a well-known anti-alcohol agent that inhibits aldehyde dehydrogenase and results in extreme 'hangover' symptoms when consumed with alcohol. This drug, however, has been suggested as useful in other forms of drug addiction due to its beneficial potential in both drug abuse reduction and withdrawal. However, among other drugs used in alcohol dependence, it carries the greatest risk of pharmacological interactions. Concomitant use of DSF and central nervous system stimulants usually leads to harmful, undesirable effects. To date, there is still limited data regarding the detailed safety profile of DSF as a concomitant drug. In this review article, we outline the current state of knowledge about DSF, its broad pharmacological action, as well as therapeutic effects, with a particular emphasis on the molecular understanding of its potential pharmacodynamic interactions with common addictive substances (e.g., alcohol, cocaine, cannabinoids, opioids) supported by relevant examples.
Topics: Acetaldehyde Dehydrogenase Inhibitors; Alcohol Drinking; Alcoholism; Animals; Disulfiram; Drug Interactions; Humans; Substance-Related Disorders
PubMed: 33971180
DOI: 10.1016/j.ejphar.2021.174143 -
Alcohol and Alcoholism (Oxford,... Mar 2017Disulfiram (DSF) causes the ALDH-mediated deterrence of alcohol consumption. We review recent meta-analyses showing the superior effectiveness of supervised disulfiram... (Meta-Analysis)
Meta-Analysis Review
Disulfiram (DSF) causes the ALDH-mediated deterrence of alcohol consumption. We review recent meta-analyses showing the superior effectiveness of supervised disulfiram (SD) in alcoholism treatment compared with oral naltrexone or acamprosate (ACP). The success of SD is also consistent with the almost complete absence of alcoholism in Japanese homozygotes for 'inefficient' ALDH. However, SD is an underused treatment and some clinicians have ethical objections to DSF. We examine these objections and argue that they are based on a misunderstanding of how DSF works. In particular, we argue that SD is not as is often claimed a variety of aversion therapy but aids cognitive, behavioural, educational and psychosocial interventions. It has some unique features that need to be better understood if it is to be properly compared with other treatments and effectively employed to help alcoholic patients, especially those who have not responded to other evidence-based interventions.
Topics: Acamprosate; Alcohol Deterrents; Alcoholism; Bioethical Issues; Disulfiram; Humans; Naltrexone; Taurine
PubMed: 28064151
DOI: 10.1093/alcalc/agw093