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Cancer Chemotherapy and Pharmacology Feb 2021Cancer is a major health issue worldwide and the global burden of cancer is expected to reduce the costs of treatment as well as prolong the survival time. One of the... (Review)
Review
Cancer is a major health issue worldwide and the global burden of cancer is expected to reduce the costs of treatment as well as prolong the survival time. One of the promising approaches is drug repurposing, because it reduces costs and shortens the production cycle of research and development. Disulfiram (DSF), which was originally approved as an anti-alcoholism drug, has been proven safe and shows the potential to target tumours. Its anti-tumour effect has been reported in many preclinical studies and recently on seven types of cancer in humans: non-small cell lung cancer (NSCLC), liver cancer, breast cancer, prostate cancer, pancreatic cancer, glioblastoma (GBM) and melanoma and has a successful breakthrough in the treatment of NSCLC and GBM. The mechanisms, particularly the intracellular signalling pathways, still remain to be completely elucidated. As shown in our previous study, DSF inhibits NF-kB signalling, proteasome activity, and aldehyde dehydrogenase (ALDH) activity. It induces endoplasmic reticulum (ER) stress and autophagy and has been used as an adjuvant therapy with irradiation or chemotherapy drugs. On the other hand, DSF not only kills the normal cancer cells but also has the ability to target cancer stem cells, which provides a new approach to prevent tumour recurrence and metastasis. Furthermore, other researchers have reported the ability of DSF to bind to nuclear protein localization protein 4 (NPL4), induce its immobilization and dysfunction, ultimately leading to cell death. Here, we provide an overview of DSF repurposing as a treatment in preclinical studies and clinical trials, and review studies describing the mechanisms underlying its anti-neoplastic effects.
Topics: Animals; Antineoplastic Agents; Disulfiram; Drug Repositioning; Humans; Neoplasms; Neoplastic Stem Cells
PubMed: 33426580
DOI: 10.1007/s00280-020-04216-8 -
Cellular & Molecular Immunology Mar 2024STING (also known as MITA) is an adaptor protein that mediates cytoplasmic DNA-triggered signaling, and aberrant activation of STING/MITA by cytosolic self-DNA or...
STING (also known as MITA) is an adaptor protein that mediates cytoplasmic DNA-triggered signaling, and aberrant activation of STING/MITA by cytosolic self-DNA or gain-of-function mutations causes severe inflammation. Here, we show that STING-mediated inflammation and autoimmunity are promoted by RNF115 and alleviated by the RNF115 inhibitor disulfiram (DSF). Knockout of RNF115 or treatment with DSF significantly inhibit systemic inflammation and autoimmune lethality and restore immune cell development in Trex1 mice and STING bone marrow chimeric mice. In addition, knockdown or pharmacological inhibition of RNF115 substantially downregulate the expression of IFN-α, IFN-γ and proinflammatory cytokines in PBMCs from patients with systemic lupus erythematosus (SLE) who exhibit high concentrations of dsDNA in peripheral blood. Mechanistically, knockout or inhibition of RNF115 impair the oligomerization and Golgi localization of STING in various types of cells transfected with cGAMP and in organs and cells from Trex1 mice. Interestingly, knockout of RNF115 inhibits the activation and Golgi localization of STING as well as the expression of proinflammatory cytokines in myeloid cells but not in endothelial cells or fibroblasts. Taken together, these findings highlight the RNF115-mediated cell type-specific regulation of STING and STING and provide potential targeted intervention strategies for STING-related autoimmune diseases.
Topics: Humans; Mice; Animals; Autoimmunity; Disulfiram; Endothelial Cells; Mice, Knockout; Inflammation; Autoimmune Diseases; Cytokines; DNA; Ubiquitin-Protein Ligases
PubMed: 38267694
DOI: 10.1038/s41423-024-01131-3 -
Drug Discovery Today Jun 2020Disulfiram (DSF) is a thiuram derivative that was developed to treat alcoholism but was also found to have antitumor activity. Copper (Cu), as a trace metal, has... (Review)
Review
Disulfiram (DSF) is a thiuram derivative that was developed to treat alcoholism but was also found to have antitumor activity. Copper (Cu), as a trace metal, has important roles in the body. Numerous studies have shown that the combination of DSF and copper (DSF/Cu) greatly enhances its antitumor efficacy. Given that the efficacy of DSF is well established and its safety profile is understood, repurposing DSF as a new anticancer drug is a promising strategy. Here, we summarize the pharmacological effects of DSF and the role of Cu in cancer, and focus on the antitumor effect of DSF/Cu, especially the mechanisms involved in enhancing drug sensibility by targeting specific molecules. We also provide rational strategies for using DSF as a cancer therapy.
Topics: Animals; Antineoplastic Agents; Copper; Disulfiram; Drug Therapy, Combination; Humans; Neoplasms
PubMed: 32320854
DOI: 10.1016/j.drudis.2020.04.003 -
Handbook of Experimental Pharmacology 2018For more than 25 years, researchers have made advances in developing medications to treat alcohol use disorder (AUD), highlighted by the US Food and Drug... (Review)
Review
For more than 25 years, researchers have made advances in developing medications to treat alcohol use disorder (AUD), highlighted by the US Food and Drug Administration's (FDA's) approval of disulfiram, naltrexone (oral and long-acting), and acamprosate. These medications are also approved in Europe, where the European Medicines Agency (EMA) recently added a fourth medication, nalmefene, for AUD. Despite these advances, today's medications have a small effect size, showing efficacy for only a limited number of individuals with AUD. However, a host of new medications, which act on variety of pharmacologic targets, are in the pipeline and have been evaluated in numerous human studies. This article reviews the efficacy and safety of medications currently being tested in human trials and looks at ongoing efforts to identify candidate compounds in human studies. As mentioned in the National Institute on Alcohol Abuse and Alcoholism's Strategic Plan 2017-2021 ( https://www.niaaa.nih.gov/sites/default/files/StrategicPlan_NIAAA_optimized_2017-2020.pdf ), medications development remains a high priority. By developing more effective and safe medications, and identifying those patients who will benefit the most from these treatments, we can provide clinicians with the tools they need to treat this devastating disorder, providing relief for patients and their families and markedly improving public health and safety.
Topics: Acamprosate; Alcohol Deterrents; Alcoholism; Disulfiram; Humans; Naltrexone
PubMed: 29294197
DOI: 10.1007/164_2017_79 -
Current Topics in Medicinal Chemistry 2016Although tremendous effort has been made over the past century to treat cancer effectively, the pace of drug development is far behind the increasing rate of cancer... (Review)
Review
Although tremendous effort has been made over the past century to treat cancer effectively, the pace of drug development is far behind the increasing rate of cancer incidence and mortality. There are two major hurdles in anticancer drug development: dose-limiting toxic side effects that reduce either drug effectiveness or the quality of life of patients and complicated drug development processes that are costly and time consuming. Drug repositioning has recently gained increasing attention among cancer researchers as this approach utilizes existing drugs and is significantly cost- and time-effective. Existing drugs, particularly non-cancer drugs, have favorable safety profiles in humans and serve as an ever-increasing source for new anticancer drug discovery. Here we review the recent examples of drug repositioning of existing non-cancer drugs for preclinical and clinical introductions of cancer therapy.
Topics: Antineoplastic Agents; Disulfiram; Doxycycline; Drug Repositioning; High-Throughput Screening Assays; Humans; Mebendazole; Neoplasms; Pyrvinium Compounds; Triclosan
PubMed: 26881712
DOI: 10.2174/1568026616666160216154441 -
British Journal of Pharmacology Nov 2021Treatment of cardiac arrhythmia remains challenging due to severe side effects of common anti-arrhythmic drugs. We previously demonstrated that mitochondrial Ca uptake...
BACKGROUND AND PURPOSE
Treatment of cardiac arrhythmia remains challenging due to severe side effects of common anti-arrhythmic drugs. We previously demonstrated that mitochondrial Ca uptake in cardiomyocytes represents a promising new candidate structure for safer drug therapy. However, druggable agonists of mitochondrial Ca uptake suitable for preclinical and clinical studies are still missing.
EXPERIMENTAL APPROACH
Herewe screened 727 compounds with a history of use in human clinical trials in a three-step screening approach. As a primary screening platform we used a permeabilized HeLa cell-based mitochondrial Ca uptake assay. Hits were validated in cultured HL-1 cardiomyocytes and finally tested for anti-arrhythmic efficacy in three translational models: a Ca overload zebrafish model and cardiomyocytes of both a mouse model for catecholaminergic polymorphic ventricular tachycardia (CPVT) and induced pluripotent stem cell derived cardiomyocytes from a CPVT patient.
KEY RESULTS
We identifiedtwo candidate compounds, the clinically approved drugs ezetimibe and disulfiram, which stimulate SR-mitochondria Ca transfer at nanomolar concentrations. This is significantly lower compared to the previously described mitochondrial Ca uptake enhancers (MiCUps) efsevin, a gating modifier of the voltage-dependent anion channel 2, and kaempferol, an agonist of the mitochondrial Ca uniporter. Both substances restored rhythmic cardiac contractions in a zebrafish cardiac arrhythmia model and significantly suppressed arrhythmogenesis in freshly isolated ventricular cardiomyocytes from a CPVT mouse model as well as induced pluripotent stem cell derived cardiomyocytes from a CPVT patient.
CONCLUSION AND IMPLICATIONS
Taken together we identified ezetimibe and disulfiram as novel MiCUps and efficient suppressors of arrhythmogenesis and as such as, promising candidates for future preclinical and clinical studies.
Topics: Animals; Arrhythmias, Cardiac; Calcium; Calcium Signaling; Disulfiram; Ezetimibe; HeLa Cells; Humans; Mice; Mitochondria; Myocytes, Cardiac; Pharmaceutical Preparations; Ryanodine Receptor Calcium Release Channel; Tachycardia, Ventricular; Zebrafish
PubMed: 34287836
DOI: 10.1111/bph.15630 -
Anti-cancer Agents in Medicinal... 2016Disulfiram (DSF), a derivative of thiuram, has been used in humans to treat alcoholism for more than 60 years. Over the past decade, however, increasing evidence... (Review)
Review
Disulfiram (DSF), a derivative of thiuram, has been used in humans to treat alcoholism for more than 60 years. Over the past decade, however, increasing evidence indicates that DSF possesses a great potential for the treatment of human cancers. DSF's anticancer activity has been demonstrated in both in vitro and in vivo model systems, and has been tested in human clinical trials for various cancer types. It is also evident that DSF can sensitize tumor cells to radiotherapy and enhance the cytotoxicity of anticancer drugs, thus DSF may serve as an adjuvant therapy. The key to DSF's anticancer action relates to its ability to suppress cancer stem cells by targeting aldehyde dehydrogenase (ALDH), a marker of cancer stem cells, and inhibit proteasome activity in cancer cells by forming complexes with metal ions. In addition, DSF targets epigenetic mechanisms and modulates cellular signaling pathways to slow down tumor progression. DSF also induces apoptosis, inhibits cancer cell proliferation, and suppresses cancer cell metastasis. Considering that the pharmacokinetics of DSF are well-established and a safety profile has been recorded, this compound is an attractive "old" drug that has great potential for rapid development into a new cancer therapeutic. This article provides a brief review of the history of DSF use in humans, evidence for its anticancer activities, the molecular mechanisms of DSF action that have been illustrated by recent studies, and the potential for repurposing DSF as a new chemotherapeutic drug in the near future.
Topics: Aldehyde Dehydrogenase; Animals; Antineoplastic Agents; Cell Proliferation; Disulfiram; Enzyme Inhibitors; Humans; Neoplasms; Neoplastic Stem Cells
PubMed: 27141876
DOI: 10.2174/1871520615666160504095040 -
AIDS (London, England) Jan 2022The aim of this study was to examine whether administering both vorinostat and disulfiram to people with HIV (PWH) on antiretroviral therapy (ART) is well tolerated and...
OBJECTIVE
The aim of this study was to examine whether administering both vorinostat and disulfiram to people with HIV (PWH) on antiretroviral therapy (ART) is well tolerated and can enhance HIV latency reversal.
DESIGN
Vorinostat and disulfiram can increase HIV transcription in PWH on ART. Together, these agents may lead to significant HIV latency reversal.
METHODS
Virologically suppressed PWH on ART received disulfiram 2000 mg daily for 28 days and vorinostat 400 mg daily on days 8-10 and 22-24. The primary endpoint was plasma HIV RNA on day 11 relative to baseline using a single copy assay. Assessments included cell-associated unspliced RNA as a marker of latency reversal, HIV DNA in CD4+ T-cells, plasma HIV RNA, and plasma concentrations of ART, vorinostat, and disulfiram.
RESULTS
The first two participants (P1 and P2) experienced grade 3 neurotoxicity leading to trial suspension. After 24 days, P1 presented with confusion, lethargy, and ataxia having stopped disulfiram and ART. Symptoms resolved by day 29. After 11 days, P2 presented with paranoia, emotional lability, lethargy, ataxia, and study drugs were ceased. Symptoms resolved by day 23. CA-US RNA increased by 1.4-fold and 1.3-fold for P1 and P2 respectively. Plasma HIV RNA was detectable from day 8 to 37 (peak 81 copies ml-1) for P2 but was not increased in P1 Antiretroviral levels were therapeutic and neuronal injury markers were elevated in P1.
CONCLUSION
The combination of prolonged high-dose disulfiram and vorinostat was not safe in PWH on ART and should not be pursued despite evidence of latency reversal.
Topics: Disulfiram; Drug Therapy, Combination; HIV Infections; Humans; Virus Latency; Vorinostat
PubMed: 34586085
DOI: 10.1097/QAD.0000000000003091 -
Current Medicinal Chemistry Feb 2018Considerable evidence demonstrates the importance of dithiocarbamates especially disulfiram as anticancer drugs. However there are no systematic reviews outlining how... (Review)
Review
BACKGROUND
Considerable evidence demonstrates the importance of dithiocarbamates especially disulfiram as anticancer drugs. However there are no systematic reviews outlining how their metal-binding ability is related to their anticancer activity. This review aims to summarize chemical features and metal-binding activity of disulfiram and its metabolite DEDTC, and discuss different mechanisms of action of disulfiram and their contributions to the drug's anticancer activity.
METHODS
We undertook a disulfiram-related search on bibliographic databases of peerreviewed research literature, including many historic papers and in vitro, in vivo, preclinical and clinical studies. The selected papers were carefully reviewed and summarized.
RESULTS
More than five hundreds of papers were obtained in the initial search and one hundred eighteen (118) papers were included in the review, most of which deal with chemical and biological aspects of Disulfiram and the relationship of its chemical and biological properties. Eighty one (81) papers outline biological aspects of dithiocarbamates, and fifty seven (57) papers report biological activity of Disulfiram as an inhibitor of proteasomes or inhibitor of aldehyde dehydrogenase enzymes, interaction with other anticancer drugs, or mechanism of action related to reactive oxygen species. Other papers reviewed focus on chemical aspects of dithiocarbamates.
CONCLUSION
This review confirms the importance of chemical features of compounds such as Disulfiram to their biological activities, and supports repurposing DSF as a potential anticancer agent.
Topics: Acetaldehyde Dehydrogenase Inhibitors; Antineoplastic Agents; Disulfiram; Drug Repositioning; Humans; Metals; Neoplasms
PubMed: 29065820
DOI: 10.2174/0929867324666171023161121 -
Chinese Medical Journal Jun 2024Cancer is a major global health issue. Effective therapeutic strategies can prolong patients' survival and reduce the costs of treatment. Drug repurposing, which... (Review)
Review
Cancer is a major global health issue. Effective therapeutic strategies can prolong patients' survival and reduce the costs of treatment. Drug repurposing, which identifies new therapeutic uses for approved drugs, is a promising approach with the advantages of reducing research costs, shortening development time, and increasing efficiency and safety. Disulfiram (DSF), a Food and Drug Administration (FDA)-approved drug used to treat chronic alcoholism, has a great potential as an anticancer drug by targeting diverse human malignancies. Several studies show the antitumor effects of DSF, particularly the combination of DSF and copper (DSF/Cu), on a wide range of cancers such as glioblastoma (GBM), breast cancer, liver cancer, pancreatic cancer, and melanoma. In this review, we summarize the antitumor mechanisms of DSF/Cu, including induction of intracellular reactive oxygen species (ROS) and various cell death signaling pathways, and inhibition of proteasome activity, as well as inhibition of nuclear factor-kappa B (NF-κB) signaling. Furthermore, we highlight the ability of DSF/Cu to target cancer stem cells (CSCs), which provides a new approach to prevent tumor recurrence and metastasis. Strikingly, DSF/Cu inhibits several molecular targets associated with drug resistance, and therefore it is becoming a novel option to increase the sensitivity of chemo-resistant and radio-resistant patients. Studies of DSF/Cu may shed light on its improved application to clinical tumor treatment.
Topics: Disulfiram; Humans; Drug Repositioning; Neoplasms; Antineoplastic Agents; Reactive Oxygen Species; Neoplastic Stem Cells; Signal Transduction; NF-kappa B
PubMed: 38275022
DOI: 10.1097/CM9.0000000000002909