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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 -
Infection and Drug Resistance 2021infection poses a risk of the occurrence of gastrointestinal diseases, such as gastric cancer. Its incidence rate is significantly reduced by eradication, and thereby,...
BACKGROUND
infection poses a risk of the occurrence of gastrointestinal diseases, such as gastric cancer. Its incidence rate is significantly reduced by eradication, and thereby, eradication therapy is generally performed. Disulfiram is an oral prescription drug mainly used for the treatment of alcohol dependence. In recent years, reports have been made on its anticancer and antibacterial effects, and thus, it has recently become an interesting subject. This study aimed to examine the antibacterial activity of disulfiram, investigate the presence or absence of its antibacterial activity on , and determine whether it could be a new bactericidal drug against drug-resistant .
MATERIALS AND METHODS
Drug-sensitive strains of and amoxicillin-resistant, clarithromycin-resistant, and metronidazole-resistant strains were used, and a growth inhibition test of using disulfiram was performed. Furthermore, the expression of urease, vacuolating cytotoxin A (VacA), and CagA, the virulence proteins of , was quantitatively analyzed using the Western blotting method. In addition, for used in this study, the 16SrDNA sequence, a ribosomal gene involved in protein production, was analyzed to examine the presence or absence of gene mutation.
RESULTS
Disulfiram suppressed the growth of 7 out of 12 strains at 1 µg/mL, and no correlation was observed between their susceptibility/resistance to current eradication antimicrobial drugs and disulfiram resistance. Disulfiram reduced the expression levels of urease, VacA, and CagA proteins. , which showed resistance to disulfiram, tended to have fewer gene deletions/insertions in the 16S rDNA sequence; however, no specific mutation was detected.
CONCLUSION
Disulfiram has a bactericidal effect on at low concentrations, suggesting that it can be used as a supplement for current eradication drugs.
PubMed: 34012274
DOI: 10.2147/IDR.S299177 -
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 -
Bioactive Materials Jun 2024Endometrial cancer (EC) stands as one of the most prevalent gynecological malignancies affecting women, with its incidence and disease-related mortality steadily on the...
Endometrial cancer (EC) stands as one of the most prevalent gynecological malignancies affecting women, with its incidence and disease-related mortality steadily on the rise. Disulfiram (DSF), an FDA-approved medication primarily used for treating alcohol addiction, has exhibited promising anti-tumor properties. Studies have revealed DSF's capacity for enhanced anti-tumor activity, particularly when combined with copper. The novel Copper-Cysteamine (CuCy) compound, CuCl(SR) (R[bond, double bond]CHCHNH), showcases photodynamic effects and demonstrates significant anti-tumor potential under various conditions, including exposure to ultraviolet light, X-ray, microwave, and ultrasound. This study delves into exploring the synergistic anti-tumor effects and underlying mechanisms by utilizing copper-cysteamine in conjunction with DSF against endometrial cancer. The investigation involved comprehensive analyses encompassing experiments utilizing Ishikawa cells, studies, and transcriptomic analyses. Remarkably, the combined administration of both compounds at a low dose of 0.5 μM exhibited pronounced efficacy in impeding tumor growth, inhibiting blood vessel formation, and stimulating cell apoptosis. Notably, experiments involving transplanted tumors in nude mice vividly demonstrated the significant anti-tumor effects of this combination treatment. Detailed examination through transmission electron microscopy unveiled compelling evidence of mitochondrial damage, cellular swelling, and rupture, indicative of apoptotic changes in morphology due to the combined treatment. Moreover, transcriptomic analysis unveiled substantial downregulation of mitochondrial-related genes at the molecular level, coupled with a significant hindrance in the DNA repair pathway. These findings strongly suggest that the combined application of CuCy and DSF induces mitochondrial impairment in Ishikawa cells, thereby fostering apoptosis and ultimately yielding potent anti-tumor effects.
PubMed: 38440322
DOI: 10.1016/j.bioactmat.2024.02.009 -
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 -
Biomolecules May 2023Gasdermin D, a molecule downstream of the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing inflammasome, forms the membrane pore...
BACKGROUND
Gasdermin D, a molecule downstream of the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing inflammasome, forms the membrane pore for the secretion of interleukin (IL)-1β and IL-18, and also mediates pyroptosis. This study was to explore the influence of treatment with disulfiram, a small molecule inhibitor to gasdermin D, on the formation and progression of experimental abdominal aortic aneurysms (AAA).
METHODS
AAAs were induced in 10-week-old male apolipoprotein E deficient mice by subcutaneous infusion of angiotensin II (1000 ng/min/kg body weight) for 28 days via osmotic minipumps. Three days prior to angiotensin II infusion, disulfiram (50 mg/kg) or an equal volume of saline as the vehicle control was administered daily via oral gavage. The influence on experimental AAAs was analyzed by serial measurements of aortic diameters via ultrasonography, grading AAA severity and histopathology at sacrifice. Serum IL-1β and IL-18 levels, systolic blood pressure, total cholesterol, and triglyceride were also measured. Additional experiments assayed the influences on the cell viability and IL-1β secretion of in vitro activated macrophages.
RESULTS
Disulfiram significantly reduced the enlargement, incidence, and severity of angiotensin II-induced experimental AAAs with attenuation of medial elastin breaks, mural macrophage accumulation, and systolic blood pressure. The AAA suppression was also associated with reduced systemic levels of IL-1β but not IL-18. However, disulfiram treatment had no impact on body weight gain and lipid levels in aneurysmal mice. Additionally, disulfiram treatment also markedly reduced the secretion of IL-1β from activated macrophages with a limited effect on cell viability in vitro.
CONCLUSIONS
Gasdermin D inhibition by disulfiram attenuated angiotensin II-induced experimental AAAs with reduced systemic IL-1β levels and in vitro activated macrophage IL-1β secretion. Our study suggests that pharmacological gasdermin D inhibition may have translational potential for limiting clinical AAA progression.
Topics: Animals; Male; Mice; Angiotensin II; Aortic Aneurysm, Abdominal; Body Weight; Disease Models, Animal; Disulfiram; Gasdermins; Mice, Inbred C57BL
PubMed: 37371479
DOI: 10.3390/biom13060899 -
International Journal of Molecular... Sep 2018Gliomas are highly invasive brain tumors with short patient survival. One major pathogenic factor is aberrant tumor metabolism, which may be targeted with different... (Review)
Review
Gliomas are highly invasive brain tumors with short patient survival. One major pathogenic factor is aberrant tumor metabolism, which may be targeted with different specific and unspecific agents. Drug repurposing is of increasing interest in glioma research. Drugs interfering with the patient's metabolism may also influence glioma metabolism. In this review, we outline definitions and methods for drug repurposing. Furthermore, we give insights into important candidates for a metabolic drug repurposing, namely metformin, statins, non-steroidal anti-inflammatory drugs, disulfiram and lonidamine. Advantages and pitfalls of drug repurposing will finally be discussed.
Topics: Animals; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Drug Repositioning; Energy Metabolism; Glioma; Humans; Molecular Targeted Therapy; Treatment Outcome
PubMed: 30223473
DOI: 10.3390/ijms19092768 -
Metal Ions in Life Sciences Jan 2019Copper is an essential trace element that plays a critical role in a variety of basic biological functions, and serves as a key component in a number of copper-dependent... (Review)
Review
Copper is an essential trace element that plays a critical role in a variety of basic biological functions, and serves as a key component in a number of copper-dependent enzymes that regulate such processes as cell proliferation, angiogenesis, and motility. A growing body of preclinical work has demonstrated that copper is essential to metastatic cancer progression, and may have a role in tumor growth, epithelial-mesenchymal transition, and the formation of the tumor microenvironment and pre-metastatic niche. As a result, copper depletion has emerged as a novel therapeutic strategy in the treatment of metastatic cancer. We present a review of the physiologic role of copper with a discussion of relevant enzymes of the copper proteome in both normal tissue and in cancer. We conducted a comprehensive review of the available preclinical data of several copper chelation agents, including penicillamine, trientine, disulfiram, clioquinol, and tetrathiomolybdate (TM), across a variety of tumor types. We also present the existing early phase clinical trial data for the use of the copper chelator TM in the treatment of breast cancer and other malignancies.
Topics: Chelating Agents; Clinical Trials as Topic; Copper; Humans; Neoplasms; Proteome; Tumor Microenvironment
PubMed: 30855113
DOI: 10.1515/9783110527872-018 -
Annual Review of Medicine Jan 2018Antiretroviral therapy (ART) has rendered HIV-1 infection a treatable illness; however, ART is not curative owing to the persistence of replication-competent, latent... (Review)
Review
Antiretroviral therapy (ART) has rendered HIV-1 infection a treatable illness; however, ART is not curative owing to the persistence of replication-competent, latent proviruses in long-lived resting T cells. Strategies that target these latently infected cells and allow immune recognition and clearance of this reservoir will be necessary to eradicate HIV-1 in infected individuals. This review describes current pharmacologic approaches to reactivate the latent reservoir so that infected cells can be recognized and targeted, with the ultimate goal of achieving an HIV-1 cure.
Topics: Acetaldehyde Dehydrogenase Inhibitors; Adjuvants, Immunologic; Disulfiram; HIV Infections; HIV-1; Histone Deacetylase Inhibitors; Humans; Inflammation; Lymphocyte Activation; Protein Kinase C; T-Lymphocytes; Toll-Like Receptors; Virus Activation; Virus Latency
PubMed: 29099677
DOI: 10.1146/annurev-med-052716-031710