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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 -
Journal of Studies on Alcohol and Drugs Sep 2019U.S. Food and Drug Administration (FDA)-approved medications exist for the treatment of alcohol use disorders. However, their effectiveness depends on proper adherence... (Comparative Study)
Comparative Study
OBJECTIVE
U.S. Food and Drug Administration (FDA)-approved medications exist for the treatment of alcohol use disorders. However, their effectiveness depends on proper adherence to the prescribed regimen. Differences in adherence across medications may have implications for clinical outcomes and may provide helpful information in considering treatment options. This study aims to identify significant differences in adherence if present.
METHOD
A retrospective chart review was conducted in the Veterans Integrated Service Networks (VISN)-7 region of Veterans Affairs hospital and community-based outpatient clinics within South Carolina and Georgia. Prescriptions of FDA-approved alcohol use disorder medications from 2010 through 2015 were reviewed. Adherence was determined by the proportion of days the veteran had oral or injectable medication available over a 6-month period as noted by medication fills (reported as 0%-100% medication availability). We compared adherence for specific medications using chi-square, t test, logistic regression for dichotomous outcomes, and linear regression for continuous outcomes.
RESULTS
A total of 715 subjects and 807 medication trials were included. Mean adherence (percentage of days that medication was available) was 41.3% for disulfiram, 44.7% for acamprosate, 49.8% for oral naltrexone, and 54.6% for extended-release injectable naltrexone. The mean adherence was significantly different between disulfiram and oral naltrexone (p = .002) as well as disulfiram and extended-release injectable naltrexone (p = .004). Adherence of 80% was achieved in 11.9%, 19.4%, 22.7%, and 24.4% of treatment courses with disulfiram, acamprosate, naltrexone, and extended-release injectable naltrexone, respectively. These differences were significant for disulfiram versus oral naltrexone (p = .004) and disulfiram versus extended-release injectable naltrexone (p = .05).
CONCLUSIONS
These results demonstrate that overall adherence to medication-assisted treatment for alcohol use disorder is low across all medications. When directly compared, disulfiram had significantly lower adherence than both oral and extended-release injectable naltrexone.
Topics: Acamprosate; Alcohol Deterrents; Alcoholism; Disulfiram; Female; Humans; Male; Medication Adherence; Middle Aged; Naltrexone; Retrospective Studies; United States; United States Department of Veterans Affairs; United States Food and Drug Administration; Veterans
PubMed: 31603760
DOI: 10.15288/jsad.2019.80.572 -
The FEBS Journal Dec 2021SARM1, an executioner in axon degeneration, is an autoinhibitory NAD-consuming enzyme, composed of multiple domains. NMN and its analogs, CZ-48 and VMN, are the only...
SARM1, an executioner in axon degeneration, is an autoinhibitory NAD-consuming enzyme, composed of multiple domains. NMN and its analogs, CZ-48 and VMN, are the only known activators, which can release the inhibitory ARM domain from the enzymatic TIR domain. Here, we document that acid can also activate SARM1, even more efficiently than NMN, possibly via the protonation of the negative residues. Systematic mutagenesis revealed that a single mutation, E689Q in TIR, led to the constitutive activation of SARM1. It forms a salt bridge with R216 in the neighboring ARM, maintaining the autoinhibitory structure. Using this 'acid activation' protocol, mutation K597E was found to inhibit activation, while H685A eliminated SARM1 catalytic activity, revealing two distinct inhibitory mechanisms. The protocol has also been applied to differentiate two classes of chemical inhibitors. NAD, dHNN, disulfiram, CHAPS, and TRX-100 mainly inhibited the activation process, while nicotinamide and Tweens mainly inhibited SARM1 catalysis. Taken together, we demonstrate a new mechanism for SARM1 activation and decipher two distinct inhibitory mechanisms of SARM1.
Topics: Acids; Armadillo Domain Proteins; Biocatalysis; Cytoskeletal Proteins; Disulfiram; Enzyme Activation; Enzyme Inhibitors; HEK293 Cells; Humans; Hydrogen-Ion Concentration; Kinetics; Models, Molecular; Mutation; NAD; Niacinamide; Protein Domains
PubMed: 34213829
DOI: 10.1111/febs.16104 -
Cells Nov 2021Nephropathic cystinosis is a rare disease caused by mutations of the CTNS gene that encodes for cystinosin, a lysosomal cystine/H+ symporter. The disease is...
Nephropathic cystinosis is a rare disease caused by mutations of the CTNS gene that encodes for cystinosin, a lysosomal cystine/H+ symporter. The disease is characterized by early-onset chronic kidney failure and progressive development of extra-renal complications related to cystine accumulation in all tissues. At the cellular level, several alterations have been demonstrated, including enhanced apoptosis, altered autophagy, defective intracellular trafficking, and cell oxidation, among others. Current therapy with cysteamine only partially reverts some of these changes, highlighting the need to develop additional treatments. Among compounds that were identified in a previous drug-repositioning study, disulfiram (DSF) was selected for in vivo studies. The cystine depleting and anti-apoptotic properties of DSF were confirmed by secondary in vitro assays and after treating mice with 200 mg/kg/day of DSF for 3 months. However, at this dosage, growth impairment was observed. Long-term treatment with a lower dose (100 mg/kg/day) did not inhibit growth, but failed to reduce cystine accumulation, caused premature death, and did not prevent the development of renal lesions. In addition, DSF also caused adverse effects in cystinotic zebrafish larvae. DSF toxicity was significantly more pronounced in mice and zebrafish compared to wild-type animals, suggesting higher cell toxicity of DSF in cystinotic cells.
Topics: Acetylcysteine; Animals; Apoptosis; Cystine; Cystinosis; Disease Models, Animal; Disulfides; Disulfiram; Embryo, Nonmammalian; Humans; Kidney Diseases; Larva; Mice, Knockout; Toxicity Tests; Zebrafish; Mice
PubMed: 34943802
DOI: 10.3390/cells10123294 -
Journal of Addiction Medicine 2013Methadone and cocaine are each known to prolong the QTc interval, a risk factor for developing potentially fatal cardiac arrhythmias. Disulfiram, often administered in... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
Methadone and cocaine are each known to prolong the QTc interval, a risk factor for developing potentially fatal cardiac arrhythmias. Disulfiram, often administered in the context of methadone maintenance to facilitate alcohol abstinence, has been shown to have some efficacy for cocaine dependence. Disulfiram has differential effects on cocaine and methadone metabolism, but its impact on methadone- or cocaine-induced changes in QTc interval is unclear. Thus, the effects of disulfiram on QTc interval in a subset of cocaine-dependent patients participating in a 14-week, randomized, double-blind, placebo-controlled clinical trial of disulfiram were prospectively determined.
METHODS
Opioid-dependent participants were inducted onto methadone (weeks 1-2; MT) and both MT and non-opioid-dependent (UT) participants were randomized to receive disulfiram (weeks 3-14) at one of the following doses: 0, 250, 375, or 500 mg/d. Electrocardio-grams were obtained before study entry and during weeks 2 and 4.
RESULTS
Complete QTc-interval data in 23 MT and 18 UT participants were analyzed. QTc interval tended to be higher in MT participants relative to UT participants, regardless of disulfiram dose and time point, but disulfiram did not differentially alter QTc interval. QTc interval was, however, significantly greater in participants with recent cocaine use than in those with no recent use.
CONCLUSIONS
These results suggest that cocaine use and possibly MT status, but not disulfiram, are risk factors for QTc prolongation.
Topics: Adult; Alcohol Deterrents; Cocaine-Related Disorders; Disulfiram; Dose-Response Relationship, Drug; Electrocardiography; Female; Humans; Male; Methadone; Middle Aged; Opiate Substitution Treatment; Opioid-Related Disorders
PubMed: 23648640
DOI: 10.1097/ADM.0b013e3182928e02 -
International Journal of Pharmaceutics Apr 2020Disulfiram (DSF) is an inhibitor of P-glycoprotein (Pgp), the main obstacle limiting the success of doxorubicin (DOX), but it has poor solubility and stability. With the...
Disulfiram (DSF) is an inhibitor of P-glycoprotein (Pgp), the main obstacle limiting the success of doxorubicin (DOX), but it has poor solubility and stability. With the aim to overcome these limitations we prepared liposomes coencapsulating DSF and DOX (LipoDSF-DOX). Liposome stability, drugs release profile, effects on DOX cytotoxicity, Pgp activity and expression in breast cancer cells were evaluated. We observed that LipoDSF-DOX with a 1:3 weight ratio, with DSF in lipid bilayer and DOX in aqueous core, released DSF faster than DOX. LipoDSF-DOX increased DOX intracellular accumulation and cytotoxicity in Pgp-expressing breast cancer cells, with an efficacy superior to the mixture of free DSF and DOX, thanks to a differential kinetics of release of DSF and DOX when carried by liposomes. The mechanism of the increased DOX retention relied on the DSF-induced sulfhydraton of Pgp and followed by its ubiquitination. These events reduced Pgp expression and catalytic activity in LipoDSF-DOX-treated cells. Our results show that LipoDSF-DOX effectively reversed DOX resistance in Pgp-expressing breast cancer cells, exploiting the temporally different kinetics of release of DSF and DOX, optimized to decrease expression and activity of Pgp.
Topics: Breast Neoplasms; Cell Survival; Disulfiram; Doxorubicin; Drug Carriers; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Humans; Liposomes; MCF-7 Cells; Particle Size
PubMed: 32142738
DOI: 10.1016/j.ijpharm.2020.119191 -
Biological Psychiatry Feb 2013Disulfiram has been an effective cocaine addiction pharmacotherapy, and one of its possible mechanisms of efficacy is through copper chelation and inhibition of an... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Disulfiram has been an effective cocaine addiction pharmacotherapy, and one of its possible mechanisms of efficacy is through copper chelation and inhibition of an enzyme involved in catecholamine metabolism, dopamine β-hydroxylase (DβH), which converts dopamine to norepinephrine. A variant in the gene encoding DβH leads to reduced DβH activity, and as such, disulfiram might not be an effective treatment of cocaine dependence for individuals with this variant. This study explored that potential matching.
METHODS
Seventy-four cocaine- and opioid-codependent (DSM-V) subjects were stabilized on methadone for 2 weeks and subsequently randomized into disulfiram (250 mg/day, n = 34) and placebo groups (n = 40) for 10 weeks. We genotyped the DBH gene polymorphism, -1021C/T (rs1611115), that reduces DβH enzyme levels and evaluated its role for increasing cocaine free urines with disulfiram.
RESULTS
With repeated measures analysis of variance, corrected for population structure, disulfiram pharmacotherapy reduced cocaine-positive urines from 80% to 62% (p = .0001), and this disulfiram efficacy differed by DBH genotype group. Patients with the normal DβH level genotype dropped from 84% to 56% on disulfiram (p = .0001), whereas those with the low DBH level genotype showed no disulfiram effect.
CONCLUSIONS
This study indicates that the DBH genotype of a patient could be used to identify a subset of individuals for which disulfiram treatment might be an effective pharmacotherapy for cocaine dependence.
Topics: Adult; Cocaine-Related Disorders; Disulfiram; Dopamine beta-Hydroxylase; Drug Therapy, Combination; Female; Genotype; Humans; Male; Methadone; Middle Aged; Opioid-Related Disorders; Polymorphism, Single Nucleotide; Treatment Outcome
PubMed: 22906516
DOI: 10.1016/j.biopsych.2012.07.011 -
Acta Pharmacologica Sinica Aug 2014Alcohol use disorders (AUD) are defined as alcohol abuse and alcohol dependence, which create large problems both for society and for the drinkers themselves. To date,... (Review)
Review
Alcohol use disorders (AUD) are defined as alcohol abuse and alcohol dependence, which create large problems both for society and for the drinkers themselves. To date, no therapeutic can effectively solve these problems. Understanding the underlying mechanisms leading to AUD is critically important for developing effective and safe pharmacological therapies. Benzodiazepines (BZs) are used to reduce the symptoms of alcohol withdrawal syndrome. However, frequent use of BZs causes cross-tolerance, dependence, and cross-addiction to alcohol. The FDA-approved naltrexone and acamprosate have shown mixed results in clinical trials. Naltrexone is effective to treat alcohol dependence (decreased length and frequency of drinking bouts), but its severe side effects, including withdrawal symptoms, are difficult to overcome. Acamprosate showed efficacy for treating alcohol dependence in European trials, but two large US trials have failed to confirm the efficacy. Another FDA-approved medication, disulfiram, does not diminish craving, and it causes a peripheral neuropathy. Kudzu is the only natural medication mentioned by the National Institute on Alcohol Abuse and Alcoholism, but its mechanisms of action are not yet established. It has been recently shown that dihydromyricetin, a flavonoid purified from Hovenia, has unique effects on GABAA receptors and blocks ethanol intoxication and withdrawal in alcoholic animal models. In this article, we review the role of GABAA receptors in the treatment of AUD and currently available and potentially novel pharmacological agents.
Topics: Acamprosate; Alcohol Deterrents; Alcohol Drinking; Alcoholism; Animals; Benzodiazepines; Disulfiram; Ethanol; Fructose; Humans; Naltrexone; Narcotic Antagonists; Neuroprotective Agents; Plant Preparations; Receptors, GABA-A; Taurine; Topiramate
PubMed: 25066321
DOI: 10.1038/aps.2014.50 -
Journal of Medical Case Reports Mar 2016Neuropathy is a rare adverse side effect of disulfiram therapy and is under-recognized. There have been few case reports documenting this side effect.
BACKGROUND
Neuropathy is a rare adverse side effect of disulfiram therapy and is under-recognized. There have been few case reports documenting this side effect.
CASE PRESENTATION
Two cases of disulfiram peripheral neuropathy are discussed. The first case is that of a 25-year-old Caucasian woman who was exposed to disulfiram therapy for a total of 8 months and developed pain and stiffness that prevented her from walking. The second case is that of a 46-year-old Caucasian woman who developed sudden-onset numbness in her lower extremities with progression to pain. Her symptoms improved over the course of 2 months after cessation of disulfiram therapy. In both cases, symptoms improved after cessation of disulfiram therapy.
CONCLUSIONS
Disulfiram neuropathy occurs in persons with a history of chronic alcohol use. It is under-recognized and often attributed to alcoholic neuropathy given its comorbidity with alcoholic neuropathy. A greater understanding of this side effect may reduce neurologic complications related to disulfiram neuropathy and aid in early withdrawal of this offending agent.
Topics: Adult; Alcohol Deterrents; Alcoholism; Disulfiram; Female; Humans; Hypesthesia; Middle Aged; Neuralgia; Peripheral Nervous System Diseases
PubMed: 27029711
DOI: 10.1186/s13256-016-0865-z -
The American Journal of Drug and... Sep 2016Anxiety is common among persons with alcohol use disorder during early abstinence from alcohol. Although benzodiazepines are effective for short-term treatment of... (Clinical Trial)
Clinical Trial
BACKGROUND
Anxiety is common among persons with alcohol use disorder during early abstinence from alcohol. Although benzodiazepines are effective for short-term treatment of anxiety, they are rarely used beyond acute detoxification due to concerns about misuse or interactions with alcohol.
OBJECTIVES
We conducted an open-label trial to explore the effects of coadministering lorazepam and disulfiram to alcohol-dependent patients with anxiety disorder symptoms. The rationale for this model is to minimize the risks of the benzodiazepine, while also potentially enhancing adherence to disulfiram.
METHODS
Forty-one participants with DSM-IV alcohol dependence who also met syndromal criteria for anxiety disorder with or without co-occurring major depressive syndrome initiated treatment with lorazepam (starting dose 0.5 mg three times daily) and disulfiram (starting dose 500 mg three times weekly). Participants received 16 weeks of monitored pharmacotherapy with manualized medical management.
RESULTS
Adherence to treatment decreased steadily with time (85.4% at 4 weeks, 36.6% at 16 weeks). Participants showed significant increases in percent abstinent days during treatment and at 24 weeks follow-up. Large reductions in anxiety, depression, and craving were observed during treatment, and improvement remained significant at 24 weeks. Duration of adherence with disulfiram strongly predicted abstinence at 16 weeks. There was no evidence of misuse of lorazepam or dose escalation during the study.
CONCLUSION
Lorazepam can be safely used for short-term treatment of anxiety in combination with disulfiram treatment of alcohol use disorder. However, it is not clear that making lorazepam dispensing contingent on adherence to disulfiram enhances retention in disulfiram treatment.
Topics: Adult; Alcoholism; Anxiety Disorders; Craving; Depressive Disorder, Major; Disulfiram; Drug Therapy, Combination; Female; Humans; Lorazepam; Male; Medication Adherence; Pilot Projects; Treatment Outcome; Young Adult
PubMed: 27184605
DOI: 10.3109/00952990.2016.1168430