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Journal of Controlled Release :... Jan 2022Disulfiram (DSF), a familiar FDA-approved drug used for alcohol withdrawal, has recently been verified with potent antitumor therapeutic effect by generating Cu(DTC),...
Disulfiram (DSF), a familiar FDA-approved drug used for alcohol withdrawal, has recently been verified with potent antitumor therapeutic effect by generating Cu(DTC), which is the complex of its metabolite diethyldithiocarbamate (DTC) and copper. However, its poor tumor selectivity and insufficient endogenous Cu concentration within tumor site largely hinders the application of DSF-based antitumor therapy. Therefore, a GSH-responsive coordination nanoparticles (Cu-IXZ@DSF) was established as a copper carrier to achieve synchronous but separate delivery of Cu and DSF without antitumor ability, further to realize selectively triggered tumor in situ Cu(DTC) generation for antitumor therapy. A widely-used proteasome inhibitor ixazomib (IXZ) was chosen as ligands and Cu was used as coordination nodes to form nanosized Cu-IXZ@DSF. The DSF encapsulated in Cu-IXZ@DSF could be reduced to DTC by intracellular GSH, which could contend for Cu and realize in situ high toxic Cu(DTC) generation. Meanwhile, the chelation could lead to the disassembly of Cu-IXZ@DSF and release of IXZ to eventually achieve tumor specific "transformation from low toxicity to high toxicity" chemotherapy. The results of in vitro and in vivo experiments demonstrated that the as-prepared nanoplatform Cu-IXZ@DSF showed good biosafety and excellent antitumor effect via endoplasmic reticulum stress (ERS) as well as reactive oxygen species (ROS) generation pathway. Therefore, this nanocarrier provides an inspiring strategy with specific-triggered antitumor Cu(DTC) generation for DSF-based chemotherapy with high therapeutic effect and biosafety and showing great potential of treating cancer.
Topics: Alcoholism; Cell Line, Tumor; Copper; Disulfiram; Glutathione; Humans; Nanoparticles; Substance Withdrawal Syndrome
PubMed: 34856225
DOI: 10.1016/j.jconrel.2021.11.041 -
International Review of Neurobiology 2024Repurposing drugs for the treatment of alcohol dependence involves the use of drugs that were initially developed for other conditions, but have shown promise in... (Review)
Review
Repurposing drugs for the treatment of alcohol dependence involves the use of drugs that were initially developed for other conditions, but have shown promise in reducing alcohol use or preventing relapse. This approach can offer a more cost-effective and time-efficient alternative to developing new drugs from scratch. Currently approved medications for alcohol use disorder (AUD) include acamprosate, disulfiram, naltrexone, nalmefene, baclofen, and sodium oxybate. Acamprosate was developed specifically for AUD, while disulfiram's alcohol-deterrent effects were discovered incidentally. Naltrexone and nalmefene were originally approved for opioids but found secondary applications in AUD. Baclofen and sodium oxybate were repurposed from neurological conditions. Other drugs show promise. Topiramate and zonisamide, anticonvulsants, demonstrate efficacy in reducing alcohol consumption. Another anticonvulsant, gabapentin has been disappointing overall, except in cases involving alcohol withdrawal symptoms. Varenicline, a nicotinic receptor agonist, benefits individuals with less severe AUD or concurrent nicotine use. Ondansetron, a 5-HT3 antagonist, has potential for early-onset AUD, especially when combined with naltrexone. Antipsychotic drugs like aripiprazole and quetiapine have limited efficacy. Further investigation is needed for potential repurposing of α1 adrenergic receptor antagonists prazosin and doxazosin, glucocorticoid receptor antagonist mifepristone, the phosphodiesterase inhibitor Ibudilast, the cysteine prodrug N-acetylcysteine, and the OX1R and OX2R blocker Suvorexant. This review supports repurposing drugs as an effective strategy for expanding treatment options for AUD.
Topics: Humans; Alcoholism; Acamprosate; Naltrexone; Disulfiram; Sodium Oxybate; Baclofen; Drug Repositioning; Substance Withdrawal Syndrome; Alcohol Drinking
PubMed: 38555115
DOI: 10.1016/bs.irn.2024.02.002 -
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 -
Acta Biomaterialia Jul 2023Theranostic nanoplatforms for combination tumor therapy have gained lots of attention recently due to the optimized therapeutic efficiency and simultaneous diagnosis...
Theranostic nanoplatforms for combination tumor therapy have gained lots of attention recently due to the optimized therapeutic efficiency and simultaneous diagnosis performance. Herein, a novel tumor microenvironment (TME)-responsive core-shell tecto dendrimer (CSTD) was assembled by phenylboronic acid- and mannose-modified poly(amidoamine) dendrimers via the phenylboronic ester bonds that are responsive to low pH and reactive oxygen species (ROS), and efficiently loaded with copper ions and chemotherapeutic drug disulfiram (DSF) for tumor-targeted magnetic resonance (MR) imaging and cuproptosis-promoted chemo-chemodynamic therapy. The formed CSTD-Cu(II)@DSF could be specifically taken up by MCF-7 breast cancer cells, accumulated to the tumor model after circulation, and released drugs in response to the weakly acidic TME with overexpressed ROS. The enriched intracellular Cu(II) ions could induce the oligomerization of lipoylated proteins and proteotoxic stress for cuproptosis, and lipid peroxidation for chemodynamic therapy as well. Moreover, the CSTD-Cu(II)@DSF could cause the dysfunction of mitochondria and arrest the cell cycle at the G2/M phase, leading to enhanced DSF-mediated cell apoptosis. As a result, CSTD-Cu(II)@DSF could effectively inhibit the growth of MCF-7 tumors by a combination therapy strategy integrating chemotherapy with cuproptosis and chemodynamic therapy. Lastly, the CSTD-Cu(II)@DSF also displays Cu(II)-associated r relaxivity, allowing for T-weighted real-time MR imaging of tumors in vivo. The developed tumor-targeted and TME-responsive CSTD-based nanomedicine formulation may be developed for accurate diagnosis and synergistic treatment of other cancer types. STATEMENT OF SIGNIFICANCE: Constructing an effective nanoplatform for the combination of therapeutic effects and real-time tumor imaging remains a challenge. In this study, we reported for the first time an all-in-one tumor-targeted and tumor microenvironment (TME) responsive nanoplatform based on core-shell tecto dendrimer (CSTD) for the cuproptosis-promoted chemo-chemodynamic therapy and enhanced MR imaging. The efficient loading, selective tumor-targeting, and TME-responsive release of Cu(II) and disulfiram could enhance the intracellular accumulation of drugs, induce cuproptosis of cancer cells, and amplify the synergistic chemo-chemodynamic therapeutic effect, resulting in enhanced MR imaging and accelerated tumor eradication. This study sheds new light on the development of theranostic nanoplatforms for early accurate diagnosis and effective treatment of cancers.
Topics: Humans; Cell Line, Tumor; Dendrimers; Disulfiram; Magnetic Resonance Imaging; Nanoparticles; Neoplasms; Reactive Oxygen Species; Tumor Microenvironment; Copper; Apoptosis
PubMed: 37040813
DOI: 10.1016/j.actbio.2023.04.003 -
Current Oncology (Toronto, Ont.) Jun 2021Multiple myeloma (MM) is a malignant disease of the plasma cells representing approximately 10% of all hemato-oncological diseases. Detection of the disease is most... (Review)
Review
Multiple myeloma (MM) is a malignant disease of the plasma cells representing approximately 10% of all hemato-oncological diseases. Detection of the disease is most probable at around 65 years of age, and the average survival of patients is estimated to be 5-10 years, specifically due to frequent relapses and resistance to the therapy used. Thus, the search for new therapeutic approaches is becoming a big challenge. Disulfiram (DSF), a substance primarily known as a medication against alcoholism, has often been mentioned in recent years in relation to cancer treatment for its secondary anti-cancer effects. Recent studies performed on myeloma cell lines confirm high inhibition of the cell growth activity if a complex of disulfiram and copper is used. Its significant potential is now being seen in the cure of haematological malignities.
Topics: Cell Line, Tumor; Copper; Disulfiram; Humans; Multiple Myeloma; Neoplasm Recurrence, Local
PubMed: 34205025
DOI: 10.3390/curroncol28030193 -
Journal of Colloid and Interface Science Oct 2022Studies have shown that disulfiram (DSF) can combine with Cu to form bis(N, N-diethyldithiocarbamate) copper(II) complex (CuET) as antitumor drugs. However, there is...
Studies have shown that disulfiram (DSF) can combine with Cu to form bis(N, N-diethyldithiocarbamate) copper(II) complex (CuET) as antitumor drugs. However, there is insufficient endogenous Cu dose to eradicate cancer cells selectively. Inspired by the buffet, we use Cu doped hollow zeolitic imidazolate framework nanoparticles (HZIF) as the carrier and equipped with DSF and indocyanine green (ICG) and targeted by folic acid (FA) (D&I@HZIF-FA) to enhance DSF-based cancer therapy. D&I@HZIF-FA could effectively supply Cu by a buffet-style, assisting the "DSF-to-CuET" transformation in the tumor. Additionally, self-supply Cu could convert HO into ·OH by triggering a Fenton-like reaction for chemo-dynamic therapy, and ICG achieves photothermal therapy for tumors under laser irradiation. This work provides a buffet-style for Cu to make DSF a strong candidate for cancer treatment by combining chemotherapy, chemo-dynamic therapy, and photothermal therapy and inspires more research about its applications in tumor therapy.
Topics: Antineoplastic Agents; Cell Line, Tumor; Copper; Disulfiram; Hydrogen Peroxide; Neoplasms
PubMed: 35696791
DOI: 10.1016/j.jcis.2022.06.009 -
The Lancet. Child & Adolescent Health Aug 2019The identification of preventive interventions that are safe and effective for cisplatin-induced ototoxicity is important, especially in children because hearing loss... (Review)
Review
The identification of preventive interventions that are safe and effective for cisplatin-induced ototoxicity is important, especially in children because hearing loss can impair speech-language acquisition development. Previous randomised trials assessed systemic drugs such as amifostine, sodium diethyldithiocarbamate or disulfiram, and sodium thiosulfate. Amifostine, sodium diethyldithiocarbamate, and disulfiram did not show hearing preservation. Paediatric trials assessing sodium thiosulfate showed efficacy in terms of hearing protection. The SIOPEL 6 trial consisted solely of patients with localised hepatoblastoma and no effects on survival were shown. In the ACCL0431 trial, which included heterogeneous patients, a post-hoc analysis showed significantly worse overall survival among patients who had disseminated disease receiving sodium thiosulfate than among controls, but not among those with localised disease. Intratympanically administered drugs have mainly been assessed in adults and include N-acetylcysteine and dexamethasone. Inconsistent effects of these drugs were identified but these studies were limited by design, small sample size, and statistical approach. Future studies of systemic drugs will need to consider the measurement of disease outcomes through study design and sample size, and ototoxicity endpoints should be harmonised to enhance comparability between trials.
Topics: Acetylcysteine; Adolescent; Amifostine; Anti-Inflammatory Agents; Antineoplastic Agents; Chelating Agents; Child; Cisplatin; Cytoprotection; Dexamethasone; Disulfiram; Ditiocarb; Humans; Neoplasms; Ototoxicity; Thiosulfates
PubMed: 31160205
DOI: 10.1016/S2352-4642(19)30115-4 -
Current Opinion in HIV and AIDS Jul 2016To provide an overview of the initial experiences with the use of latency-reversing agents (LRAs) in clinical trials in HIV and to discuss and contrast results arising... (Review)
Review
PURPOSE OF REVIEW
To provide an overview of the initial experiences with the use of latency-reversing agents (LRAs) in clinical trials in HIV and to discuss and contrast results arising from these studies.
RECENT FINDINGS
Although the clinical administration of histone deacetylase inhibitors (HDACis) and disulfiram to HIV-infected individuals on antiretroviral therapy significantly increased cell-associated HIV RNA in CD4 T cells and in some cases plasma HIV RNA, this did not reduce the frequency of latently infected cells in blood. Potential reasons for this include insufficient potency in latency reversal, lack of virus or immune-mediated cytolysis of virus-expressing cells and/or a high frequency of immune escape mutations in the recently activated virus. Analyses of HIV-specific T-cell responses in vivo did not demonstrate that HDACis impair immune cell effector functions.
SUMMARY
More effective latency-reversing interventions and additional strategies to eliminate virus-expressing cells are needed. Key challenges include testing combinations of LRAs and/or LRAs with immune modulation to optimize potency in the absence of adverse events. A better understanding of the mechanisms of action of LRAs as well as strategies to enhance potency and penetration in tissue are key challenges for future studies.
Topics: Anti-HIV Agents; Clinical Trials as Topic; Disulfiram; HIV Infections; HIV-1; Histone Deacetylase Inhibitors; Humans; Transcription, Genetic; Treatment Outcome; Virus Activation; Virus Latency
PubMed: 26974532
DOI: 10.1097/COH.0000000000000279 -
The Cochrane Database of Systematic... May 2023Harmful alcohol use is defined as unhealthy alcohol use that results in adverse physical, psychological, social, or societal consequences and is among the leading risk... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Harmful alcohol use is defined as unhealthy alcohol use that results in adverse physical, psychological, social, or societal consequences and is among the leading risk factors for disease, disability and premature mortality globally. The burden of harmful alcohol use is increasing in low- and middle-income countries (LMICs) and there remains a large unmet need for indicated prevention and treatment interventions to reduce harmful alcohol use in these settings. Evidence regarding which interventions are effective and feasible for addressing harmful and other patterns of unhealthy alcohol use in LMICs is limited, which contributes to this gap in services.
OBJECTIVES
To assess the efficacy and safety of psychosocial and pharmacologic treatment and indicated prevention interventions compared with control conditions (wait list, placebo, no treatment, standard care, or active control condition) aimed at reducing harmful alcohol use in LMICs.
SEARCH METHODS
We searched for randomized controlled trials (RCTs) indexed in the Cochrane Drugs and Alcohol Group (CDAG) Specialized Register, the Cochrane Clinical Register of Controlled Trials (CENTRAL) in the Cochrane Library, PubMed, Embase, PsycINFO, CINAHL, and the Latin American and Caribbean Health Sciences Literature (LILACS) through 12 December 2021. We searched clinicaltrials.gov, the World Health Organization International Clinical Trials Registry Platform, Web of Science, and Opengrey database to identify unpublished or ongoing studies. We searched the reference lists of included studies and relevant review articles for eligible studies.
SELECTION CRITERIA
All RCTs comparing an indicated prevention or treatment intervention (pharmacologic or psychosocial) versus a control condition for people with harmful alcohol use in LMICs were included.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane.
MAIN RESULTS
We included 66 RCTs with 17,626 participants. Sixty-two of these trials contributed to the meta-analysis. Sixty-three studies were conducted in middle-income countries (MICs), and the remaining three studies were conducted in low-income countries (LICs). Twenty-five trials exclusively enrolled participants with alcohol use disorder. The remaining 51 trials enrolled participants with harmful alcohol use, some of which included both cases of alcohol use disorder and people reporting hazardous alcohol use patterns that did not meet criteria for disorder. Fifty-two RCTs assessed the efficacy of psychosocial interventions; 27 were brief interventions primarily based on motivational interviewing and were compared to brief advice, information, or assessment only. We are uncertain whether a reduction in harmful alcohol use is attributable to brief interventions given the high levels of heterogeneity among included studies (Studies reporting continuous outcomes: Tau² = 0.15, Q =139.64, df =16, P<.001, I² = 89%, 3913 participants, 17 trials, very low certainty; Studies reporting dichotomous outcomes: Tau²=0.18, Q=58.26, df=3, P<.001, I² =95%, 1349 participants, 4 trials, very low certainty). The other types of psychosocial interventions included a range of therapeutic approaches such as behavioral risk reduction, cognitive-behavioral therapy, contingency management, rational emotive therapy, and relapse prevention. These interventions were most commonly compared to usual care involving varying combinations of psychoeducation, counseling, and pharmacotherapy. We are uncertain whether a reduction in harmful alcohol use is attributable to psychosocial treatments due to high levels of heterogeneity among included studies (Heterogeneity: Tau² = 1.15; Q = 444.32, df = 11, P<.001; I²=98%, 2106 participants, 12 trials, very low certainty). Eight trials compared combined pharmacologic and psychosocial interventions with placebo, psychosocial intervention alone, or another pharmacologic treatment. The active pharmacologic study conditions included disulfiram, naltrexone, ondansetron, or topiramate. The psychosocial components of these interventions included counseling, encouragement to attend Alcoholics Anonymous, motivational interviewing, brief cognitive-behavioral therapy, or other psychotherapy (not specified). Analysis of studies comparing a combined pharmacologic and psychosocial intervention to psychosocial intervention alone found that the combined approach may be associated with a greater reduction in harmful alcohol use (standardized mean difference (standardized mean difference (SMD))=-0.43, 95% confidence interval (CI): -0.61 to -0.24; 475 participants; 4 trials; low certainty). Four trials compared pharmacologic intervention alone with placebo and three with another pharmacotherapy. Drugs assessed were: acamprosate, amitriptyline, baclofen disulfiram, gabapentin, mirtazapine, and naltrexone. None of these trials evaluated the primary clinical outcome of interest, harmful alcohol use. Thirty-one trials reported rates of retention in the intervention. Meta-analyses revealed that rates of retention between study conditions did not differ in any of the comparisons (pharmacologic risk ratio (RR) = 1.13, 95% CI: 0.89 to 1.44, 247 participants, 3 trials, low certainty; pharmacologic in addition to psychosocial intervention: RR = 1.15, 95% CI: 0.95 to 1.40, 363 participants, 3 trials, moderate certainty). Due to high levels of heterogeneity, we did not calculate pooled estimates comparing retention in brief (Heterogeneity: Tau² = 0.00; Q = 172.59, df = 11, P<.001; I = 94%; 5380 participants; 12 trials, very low certainty) or other psychosocial interventions (Heterogeneity: Tau² = 0.01; Q = 34.07, df = 8, P<.001; I = 77%; 1664 participants; 9 trials, very low certainty). Two pharmacologic trials and three combined pharmacologic and psychosocial trials reported on side effects. These studies found more side effects attributable to amitriptyline relative to mirtazapine, naltrexone and topiramate relative to placebo, yet no differences in side effects between placebo and either acamprosate or ondansetron. Across all intervention types there was substantial risk of bias. Primary threats to validity included lack of blinding and differential/high rates of attrition.
AUTHORS' CONCLUSIONS
In LMICs there is low-certainty evidence supporting the efficacy of combined psychosocial and pharmacologic interventions on reducing harmful alcohol use relative to psychosocial interventions alone. There is insufficient evidence to determine the efficacy of pharmacologic or psychosocial interventions on reducing harmful alcohol use largely due to the substantial heterogeneity in outcomes, comparisons, and interventions that precluded pooling of these data in meta-analyses. The majority of studies are brief interventions, primarily among men, and using measures that have not been validated in the target population. Confidence in these results is reduced by the risk of bias and significant heterogeneity among studies as well as the heterogeneity of results on different outcome measures within studies. More evidence on the efficacy of pharmacologic interventions, specific types of psychosocial interventions are needed to increase the certainty of these results.
Topics: Humans; Male; Acamprosate; Alcoholism; Amitriptyline; Developing Countries; Disulfiram; Mirtazapine; Naltrexone; Ondansetron; Topiramate
PubMed: 37158538
DOI: 10.1002/14651858.CD013350.pub2 -
Bioorganic & Medicinal Chemistry Letters May 2018Sixteen disulfides derived from disulfiram (Antabuse™) were evaluated as antibacterial agents. Derivatives with hydrocarbon chains of seven and eight carbons in length...
Sixteen disulfides derived from disulfiram (Antabuse™) were evaluated as antibacterial agents. Derivatives with hydrocarbon chains of seven and eight carbons in length exhibited antibacterial activity against Gram-positive Staphylococcus, Streptococcus, Enterococcus, Bacillus, and Listeria spp. A comparison of the cytotoxicity and microsomal stability with disulfiram further revealed that the eight carbon chain analog was of lower toxicity to human hepatocytes and has a longer metabolic half-life. In the final analysis, this investigation concluded that the S-octylthio derivative is a more effective growth inhibitor of Gram-positive bacteria than disulfiram and exhibits more favorable cytotoxic and metabolic parameters over disulfiram.
Topics: Animals; Anti-Bacterial Agents; Ciprofloxacin; Disulfiram; Gram-Negative Bacteria; Gram-Positive Bacteria; Half-Life; Hep G2 Cells; Humans; Microbial Sensitivity Tests; Microsomes, Liver; Molecular Structure; Rats; Vancomycin
PubMed: 29571571
DOI: 10.1016/j.bmcl.2018.03.023