-
Cancer Management and Research 2021Antabuse, generic name disulfiram, has been extensively used in daily clinical practice to treat alcohol abuse. In vivo and in vitro experiments have demonstrated that... (Review)
Review
Antabuse, generic name disulfiram, has been extensively used in daily clinical practice to treat alcohol abuse. In vivo and in vitro experiments have demonstrated that disulfiram was capable of inhibiting tumor cell proliferation; clinical studies have indicated that the administration of this drug was associated with favorable survival, whilst in vitro experiments have elucidated the anticancer mechanism of disulfiram. In addition, radiation and cancer biology studies have shown that disulfiram can protect normal cells and sensitize tumor cells during radiotherapy. This review aims at describing the antitumor activity of disulfiram in both preclinical studies and clinical trials, whilst focusing on the advances of this drug in radiation and cancer biology, and the promise of repurposing it as a novel sensitizer to, and protector against, radiation on the incoming clinical studies.
PubMed: 34045896
DOI: 10.2147/CMAR.S308168 -
JAMA Network Open Mar 2023Disulfiram has demonstrated broad antitumoral effect in several preclinical studies. One of the proposed indications is for the treatment of glioblastoma. (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Disulfiram has demonstrated broad antitumoral effect in several preclinical studies. One of the proposed indications is for the treatment of glioblastoma.
OBJECTIVE
To evaluate the efficacy and safety of disulfiram and copper as add-on to alkylating chemotherapy in patients with recurrent glioblastoma.
DESIGN, SETTING, AND PARTICIPANTS
This was a multicenter, open-label, randomized phase II/III clinical trial with parallel group design. Patients were recruited at 7 study sites in Sweden and 2 sites in Norway between January 2017 and November 2020. Eligible patients were 18 years or older, had a first recurrence of glioblastoma, and indication for treatment with alkylating chemotherapy. Patients were followed up until death or a maximum of 24 months. The date of final follow-up was January 15, 2021. Data analysis was performed from February to September 2022.
INTERVENTIONS
Patients were randomized 1:1 to receive either standard-of-care (SOC) alkylating chemotherapy alone, or SOC with the addition of disulfiram (400 mg daily) and copper (2.5 mg daily).
MAIN OUTCOMES AND MEASURES
The primary end point was survival at 6 months. Secondary end points included overall survival, progression-free survival, adverse events, and patient-reported quality of life.
RESULTS
Among the 88 patients randomized to either SOC (n = 45) or SOC plus disulfiram and copper (n = 43), 63 (72%) were male; the mean (SD) age was 55.4 (11.5) years. There was no significant difference between the study groups (SOC vs SOC plus disulfiram and copper) in 6 months survival (62% [26 of 42] vs 44% [19 of 43]; P = .10). Median overall survival was 8.2 months (95% CI, 5.4-10.2 months) with SOC and 5.5 months (95% CI, 3.9-9.3 months) with SOC plus disulfiram and copper, and median progression-free survival was 2.6 months (95% CI, 2.4-4.6 months) vs 2.3 months (95% CI, 1.7-2.6 months), respectively. More patients in the SOC plus disulfiram and copper group had adverse events grade 3 or higher (34% [14 of 41] vs 11% [5 of 44]; P = .02) and serious adverse events (41% [17 of 41] vs 16% [7 of 44]; P = .02), and 10 patients (24%) discontinued disulfiram treatment because of adverse effects.
CONCLUSIONS AND RELEVANCE
This randomized clinical trial found that among patients with recurrent glioblastoma, the addition of disulfiram and copper to chemotherapy, compared with chemotherapy alone, resulted in significantly increased toxic effects, but no significant difference in survival. These findings suggest that disulfiram and copper is without benefit in patients with recurrent glioblastoma.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02678975; EUDRACT Identifier: 2016-000167-16.
Topics: Humans; Male; Middle Aged; Female; Glioblastoma; Copper; Disulfiram; Quality of Life; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37000452
DOI: 10.1001/jamanetworkopen.2023.4149 -
The EMBO Journal Aug 2022Activation of the T-cell antigen receptor (TCR)-CD3 complex is critical to induce the anti-tumor response of CD8 T cells. Here, we found that disulfiram (DSF), an...
Activation of the T-cell antigen receptor (TCR)-CD3 complex is critical to induce the anti-tumor response of CD8 T cells. Here, we found that disulfiram (DSF), an FDA-approved drug previously used to treat alcohol dependency, directly activates TCR signaling. Mechanistically, DSF covalently binds to Cys20/Cys23 residues of lymphocyte-specific protein tyrosine kinase (LCK) and enhances its tyrosine 394 phosphorylation, thereby promoting LCK kinase activity and boosting effector T cell function, interleukin-2 production, metabolic reprogramming, and proliferation. Furthermore, our in vivo data revealed that DSF promotes anti-tumor immunity against both melanoma and colon cancer in mice by activating CD8 T cells, and this effect was enhanced by anti-PD-1 co-treatment. We conclude that DSF directly activates LCK-mediated TCR signaling to induce strong anti-tumor immunity, providing novel molecular insights into the therapeutic effect of DSF on cancer.
Topics: Animals; CD8-Positive T-Lymphocytes; Disulfiram; Lymphocyte Activation; Lymphocyte Specific Protein Tyrosine Kinase p56(lck); Mice; Phosphorylation; Receptors, Antigen, T-Cell; Signal Transduction
PubMed: 35638332
DOI: 10.15252/embj.2022110636 -
Frontiers in Pharmacology 2022Gliomas are the most common malignant brain tumors. High-grade gliomas, represented by glioblastoma multiforme (GBM), have a poor prognosis and are prone to recurrence.... (Review)
Review
Gliomas are the most common malignant brain tumors. High-grade gliomas, represented by glioblastoma multiforme (GBM), have a poor prognosis and are prone to recurrence. The standard treatment strategy is tumor removal combined with radiotherapy and chemotherapy, such as temozolomide (TMZ). However, even after conventional treatment, they still have a high recurrence rate, resulting in an increasing demand for effective anti-glioma drugs. Drug repurposing is a method of reusing drugs that have already been widely approved for new indication. It has the advantages of reduced research cost, safety, and increased efficiency. Disulfiram (DSF), originally approved for alcohol dependence, has been repurposed for adjuvant chemotherapy in glioma. This article reviews the drug repurposing method and the progress of research on disulfiram reuse for glioma treatment.
PubMed: 36091753
DOI: 10.3389/fphar.2022.933655 -
International Journal of Pharmaceutics Oct 2023The respiratory tract, as the first and most afflicted target of many viruses such as SARS-CoV-2, seems to be the logical choice for delivering antiviral agents against...
The respiratory tract, as the first and most afflicted target of many viruses such as SARS-CoV-2, seems to be the logical choice for delivering antiviral agents against this and other respiratory viruses. A combination of remdesivir and disulfiram, targeting two different steps in the viral replication cycle, has showed synergistic activity against SARS-CoV-2 in-vitro. In this study, we have developed an inhalable dry powder containing a combination of remdesivir and disulfiram utilizing the spray-drying technique, with the final goal of delivering this drug combination to the respiratory tract. The prepared dry powders were spherical, and crystalline. The particle size was between 1 and 5 μm indicating their suitability for inhalation. The spray-dried combinational dry powder containing remdesivir and disulfiram (RD) showed a higher emitted dose (ED) of >88% than single dry powder of remdesivir (R) (∼72%) and disulfiram (D) (∼84%), with a fine particle fraction (FPF) of ∼55%. Addition of L-leucine to RD showed >60% FPF with a similar ED. The in vitro aerosolization was not significantly affected after the stability study conducted at different humidity conditions. Interestingly, the single (R and D) and combined (RD) spray-dried powders showed limited cellular toxicity (CC values from 39.4 to >100 µM), while maintaining their anti-SARS-CoV-2 in vitro (EC values from 4.43 to 6.63 µM). In a summary, a combinational dry powder formulation containing remdesivir and disulfiram suitable for inhalation was developed by spray-drying technique which showed high cell viability in the respiratory cell line (Calu-3 cells) retaining their anti-SARS-CoV-2 property. In the future, in vivo studies will test the ability of these formulations to inhibit SARS-CoV-2 which is essential for clinical translation.
PubMed: 37703955
DOI: 10.1016/j.ijpharm.2023.123411 -
Journal of the American Heart... Apr 2024Pyroptosis executor GsdmD (gasdermin D) promotes atherosclerosis in mice and humans. Disulfiram was recently shown to potently inhibit GsdmD, but the in vivo efficacy...
BACKGROUND
Pyroptosis executor GsdmD (gasdermin D) promotes atherosclerosis in mice and humans. Disulfiram was recently shown to potently inhibit GsdmD, but the in vivo efficacy and mechanism of disulfiram's antiatherosclerotic activity is yet to be explored.
METHODS AND RESULTS
We used human/mouse macrophages, endothelial cells, and smooth muscle cells and a hyperlipidemic mouse model of atherosclerosis to determine disulfiram antiatherosclerotic efficacy and mechanism. The effects of disulfiram on several atheroprotective pathways such as autophagy, efferocytosis, phagocytosis, and gut microbiota were determined. Atomic force microscopy was used to determine the effects of disulfiram on the biophysical properties of the plasma membrane of macrophages. Disulfiram-fed hyperlipidemic apolipoprotein E mice showed significantly reduced interleukin-1β release upon in vivo Nlrp3 (NLR family pyrin domain containing 3) inflammasome activation. Disulfiram-fed mice showed smaller atherosclerotic lesions (~27% and 29% reduction in males and females, respectively) and necrotic core areas (~50% and 46% reduction in males and females, respectively). Disulfiram induced autophagy in macrophages, smooth muscle cells, endothelial cells, hepatocytes/liver, and atherosclerotic plaques. Disulfiram modulated other atheroprotective pathways (eg, efferocytosis, phagocytosis) and gut microbiota. Disulfiram-treated macrophages showed enhanced phagocytosis/efferocytosis, with the mechanism being a marked increase in cell-surface expression of efferocytic receptor MerTK. Atomic force microscopy analysis revealed altered biophysical properties of disulfiram-treated macrophages, showing increased order-state of plasma membrane and increased adhesion strength. Furthermore, 16sRNA sequencing of disulfiram-fed hyperlipidemic mice showed highly significant enrichment in atheroprotective gut microbiota and a reduction in atherogenic species.
CONCLUSIONS
Taken together, our data show that disulfiram can simultaneously modulate several atheroprotective pathways in a GsdmD-dependent as well as GsdmD-independent manner.
Topics: Male; Female; Mice; Humans; Animals; Disulfiram; Efferocytosis; Endothelial Cells; Gastrointestinal Microbiome; Atherosclerosis; Autophagy
PubMed: 38563369
DOI: 10.1161/JAHA.123.033881 -
Frontiers in Pharmacology 2022Radiation-induced intestinal injury (RIII) occurs after high doses of radiation exposure. RIII restricts the therapeutic efficacy of radiotherapy in cancer and increases...
Radiation-induced intestinal injury (RIII) occurs after high doses of radiation exposure. RIII restricts the therapeutic efficacy of radiotherapy in cancer and increases morbidity and mortality in nuclear disasters. Currently, there is no approved agent for the prevention or treatment of RIII. Here, we reported that the disulfiram, an FDA-approved alcohol deterrent, prolonged the survival in mice after lethal irradiation. Pretreatment with disulfiram inhibited proliferation within 24 h after irradiation, but improved crypt regeneration at 3.5 days post-irradiation. Mechanistically, disulfiram promoted Lgr5 intestinal stem cells (ISCs) survival and maintained their ability to regenerate intestinal epithelium after radiation. Moreover, disulfiram suppresses DNA damage accumulation, thus inhibits aberrant mitosis after radiation. Unexpectedly, disulfiram treatment did not inhibit crypt cell apoptosis 4 h after radiation and the regeneration of crypts from PUMA-deficient mice after irradiation was also promoted by disulfiram. In conclusion, our findings demonstrate that disulfiram regulates the DNA damage response and survival of ISCs through affecting the cell cycle. Given its radioprotective efficacy and decades of application in humans, disulfiram is a promising candidate to prevent RIII in cancer therapy and nuclear accident.
PubMed: 35517788
DOI: 10.3389/fphar.2022.852669 -
Frontiers in Molecular Biosciences 2021Copper (Cu) plays a pivotal role in cancer progression by acting as a co-factor that regulates the activity of many enzymes and structural proteins in cancer cells.... (Review)
Review
Copper (Cu) plays a pivotal role in cancer progression by acting as a co-factor that regulates the activity of many enzymes and structural proteins in cancer cells. Therefore, Cu-based complexes have been investigated as novel anticancer metallodrugs and are considered as a complementary strategy for currently used platinum agents with undesirable general toxicity. Due to the high failure rate and increased cost of new drugs, there is a global drive towards the repositioning of known drugs for cancer treatment in recent years. Disulfiram (DSF) is a first-line antialcoholism drug used in clinics for more than 65 yr. In combination with Cu, it has shown great potential as an anticancer drug by targeting a wide range of cancers. The reaction between DSF and Cu ions forms a copper diethyldithiocarbamate complex (Cu(DDC) also known as CuET) which is the active, potent anticancer ingredient through inhibition of NF-κB and ubiquitin-proteasome system as well as alteration of the intracellular reactive oxygen species (ROS). Importantly, DSF/Cu inhibits several molecular targets related to drug resistance, stemness, angiogenesis and metastasis and is thus considered as a novel strategy for overcoming tumour recurrence and relapse in patients. Despite its excellent anticancer efficacy, DSF has proven unsuccessful in several cancer clinical trials. This is likely due to the poor stability, rapid metabolism and/or short plasma half-life of the currently used oral version of DSF and the inability to form Cu(DDC) at relevant concentrations in tumour tissues. Here, we summarize the scientific rationale, molecular targets, and mechanisms of action of DSF/Cu in cancer cells and the outcomes of oral DSF ± Cu in cancer clinical trials. We will focus on the novel insights on harnessing the immune system and hypoxic microenvironment using DSF/Cu complex and discuss the emerging delivery strategies that can overcome the shortcomings of DSF-based anticancer therapies and provide opportunities for translation of DSF/Cu or its Cu(DDC) complex into cancer therapeutics.
PubMed: 34604310
DOI: 10.3389/fmolb.2021.741316 -
Clinical Psychopharmacology and... Feb 2017Disulfiram is the commonly prescribed drug for the treatment of alcohol dependence. It's major metabolite (diethyldithiocarbamate) is an inhibitor of...
Disulfiram is the commonly prescribed drug for the treatment of alcohol dependence. It's major metabolite (diethyldithiocarbamate) is an inhibitor of dopamine-betahydroxylase, an enzyme that catalyzes the metabolism of dopamine to norepinephrine resulting in psychosis. We recommend that disulfiram should be used at the lowest effective dose, possibly 250 mg daily and caution should be taken while prescribing disulfiram for patients with personal and familial antecedents of psychosis.
PubMed: 28138114
DOI: 10.9758/cpn.2017.15.1.68 -
Molecules (Basel, Switzerland) Jan 2022Aldehyde dehydrogenase-1a1 (ALDH1a1), the enzyme responsible for the oxidation of retinal into retinoic acid, represents a key therapeutic target for the treatment of...
Aldehyde dehydrogenase-1a1 (ALDH1a1), the enzyme responsible for the oxidation of retinal into retinoic acid, represents a key therapeutic target for the treatment of debilitating disorders such as cancer, obesity, and inflammation. Drugs that can inhibit ALDH1a1 include disulfiram, an FDA-approved drug to treat chronic alcoholism. Disulfiram, by carbamylation of the catalytic cysteines, irreversibly inhibits ALDH1a1 and ALDH2. The latter is the isozyme responsible for important physiological processes such as the second stage of alcohol metabolism. Given the fact that ALDH1a1 has a larger substrate tunnel than that in ALDH2, replacing disulfiram ethyl groups with larger motifs will yield selective ALDH1a1 inhibitors. We report herein the synthesis of new inhibitors of ALDH1a1 where (hetero)aromatic rings were introduced into the structure of disulfiram. Most of the developed compounds retained the anti-ALDH1a1 activity of disulfiram; however, they were completely devoid of inhibitory activity against ALDH2.
Topics: Acetaldehyde Dehydrogenase Inhibitors; Aldehyde Dehydrogenase 1 Family; Aldehyde Dehydrogenase, Mitochondrial; Disulfiram; Humans; Molecular Docking Simulation; Recombinant Proteins; Retinal Dehydrogenase
PubMed: 35056791
DOI: 10.3390/molecules27020480