-
Frontiers in Bioscience (Landmark... Aug 2023The complex formed by disulfiram (DSF) and copper (Cu) is safe and effective for the prevention and treatment of triple-negative breast cancer (TNBC). Although previous...
BACKGROUND
The complex formed by disulfiram (DSF) and copper (Cu) is safe and effective for the prevention and treatment of triple-negative breast cancer (TNBC). Although previous studies have shown that DSF/Cu induces ferroptosis, the mechanism remains unclear.
METHODS
The mitochondrial morphology of TNBC treated with DSF/Cu was observed by transmission microscopy, and intracellular levels of iron, lipid reactive oxygen species (ROS), malondialdehyde, and glutathione were evaluated to detect the presence of ferroptosis. Target genes for the DSF/Cu-activated ferroptosis signaling pathway were examined by transcriptome sequencing analysis. Expression of the target gene, , was detected by qRT-PCR, immunofluorescence and western blot.
RESULTS
The mitochondria of TNBC cells were significantly atrophied following treatment with DSF/Cu for 24 h. Addition of DSF/Cu supplement resulted in significant up-regulation of intracellular iron, lipid ROS and malondialdehyde levels, and significant down-regulation of glutathione levels, all of which are important markers of ferroptosis. Transcriptome analysis confirmed that DSF/Cu activated the ferroptosis signaling pathway and up-regulated several ferroptosis target genes associated with redox regulation, especially heme oxygenase-1 (HMOX-1). Inhibition of ferroptosis by addition of the ROS scavenger N-acetyl-L-cysteine (NAC) significantly increased the viability of DSF/Cu-treated TNBC cells.
CONCLUSIONS
These results show that DSF/Cu increases lipid peroxidation and causes a sharp increase in HMOX1 activity, thereby inducing TNBC cell death through ferroptosis. DSF/Cu is a promising therapeutic drug for TNBC and could lead to ferroptosis-mediated therapeutic strategies for human cancer.
Topics: Humans; Triple Negative Breast Neoplasms; Copper; Disulfiram; Ferroptosis; Reactive Oxygen Species; Cell Line; Glutathione; Lipids
PubMed: 37664913
DOI: 10.31083/j.fbl2808186 -
Pharmacogenomics Oct 2020Alcohol use disorder (AUD) is highly prevalent and among the leading causes of morbidity and mortality in the United States. Pharmacotherapies for AUD are limited, thus... (Review)
Review
Alcohol use disorder (AUD) is highly prevalent and among the leading causes of morbidity and mortality in the United States. Pharmacotherapies for AUD are limited, thus making identification of patient subgroups that are most likely to respond favorably crucial. In this article, pharmacogenetic research on US FDA-approved and commonly prescribed off-label medications for the treatment of AUD is comprehensively reviewed. While the field has advanced in understanding pharmacotherapies for AUD and potential genetic moderators of treatment responses, the pharmacogenetic data to guide the prescribing clinician are limited and should be interpreted with caution. Precision medicine for AUD with more beneficial treatment responses and minimal side effects remains a high priority for further research.
Topics: Alcohol Deterrents; Alcoholism; Disulfiram; Humans; Naltrexone; Pharmacogenetics; Pharmacogenomic Testing; Precision Medicine
PubMed: 32807012
DOI: 10.2217/pgs-2020-0079 -
International Journal of Molecular... Feb 2024Disulfiram (DSF) is used to treat non‑small cell lung cancer (NSCLC). DSF significantly increases expression of programmed death‑ligand 1 (PD‑L1), which may...
Disulfiram (DSF) is used to treat non‑small cell lung cancer (NSCLC). DSF significantly increases expression of programmed death‑ligand 1 (PD‑L1), which may enhance immunosuppression and immune escape of tumors. Therefore, the present study aimed to investigate the role of combined treatment of DSF and anti‑PD‑L1 in NSCLC resistance. The viability and apoptosis of A549 cells were detected by the Cell Counting Kit‑8 assay and flow cytometry, respectively. The expression levels of ATPase copper‑transporting β (ATP7B) and PD‑L1 in A549 cells were detected by reverse transcription‑quantitative PCR and western blot analysis. The levels of reactive oxygen species (ROS), malondialdehyde (MDA) and superoxide dismutase (SOD) in A549 cells were detected by respective assay kits. The expression levels of cuproptosis‑associated proteins ferredoxin‑1 (FDX1), ATP7B, solute carrier family 31 member 1 (SLC31A1), succinate dehydrogenase B (SDHB), PD‑L1 and hypoxia inducible factor (HIF)‑1A were analyzed by western blotting in A549 cells. DSF inhibited the viability of A549 cells and promoted expression levels of ATP7B and PD‑L1 at both mRNA and protein levels in A549 cells. The viability of cisplatin (DPP)‑treated A549 cells was increased following DSF treatment. JQ‑1 (a PD‑L1 inhibitor) suppressed the viability of DPP‑treated A549 cells pretreated with DSF. DSF increased expression levels of ATP7B and PD‑L1. The combination treatment of DSF and JQ‑1 in A549 cells increased levels of ROS and MDA, as well as expression levels of FDX1 and SLC31A1; however, combination treatment decreased levels of SOD, as well as expression levels of ATP7B, SDHB, PD‑L1, and HIF‑1A. PX478 (an HIF‑1 inhibitor) acted with DSF to enhance the inhibitory effects on the viability and on the induction of apoptosis of A549 cells. PX478 upregulated the levels of ROS and MDA, while it downregulated levels of SOD in DSF‑treated A549 cells. PX478 promoted expression levels of FDX1 and SLC31A1, while it suppressed expression levels of ATP7B, PD‑L1, and HIF‑1A in DSF‑treated A549 cells. In conclusion, the combined treatment of A549 cells with anti‑PD‑L1 and DSF enhanced the effect of cuproptosis on the inhibition of NSCLC cell viability.
Topics: Humans; B7-H1 Antigen; Carcinoma, Non-Small-Cell Lung; Disulfiram; Reactive Oxygen Species; Lung Neoplasms; Signal Transduction; Superoxide Dismutase; 3,4-Methylenedioxyamphetamine
PubMed: 38186308
DOI: 10.3892/ijmm.2023.5343 -
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 -
Critical Care (London, England) Jul 2022The release of neutrophil extracellular traps (NETs) is associated with inflammation, coagulopathy, and organ damage found in severe cases of COVID-19. However, the...
BACKGROUND
The release of neutrophil extracellular traps (NETs) is associated with inflammation, coagulopathy, and organ damage found in severe cases of COVID-19. However, the molecular mechanisms underlying the release of NETs in COVID-19 remain unclear.
OBJECTIVES
We aim to investigate the role of the Gasdermin-D (GSDMD) pathway on NETs release and the development of organ damage during COVID-19.
METHODS
We performed a single-cell transcriptome analysis in public data of bronchoalveolar lavage. Then, we enrolled 63 hospitalized patients with moderate and severe COVID-19. We analyze in blood and lung tissue samples the expression of GSDMD, presence of NETs, and signaling pathways upstreaming. Furthermore, we analyzed the treatment with disulfiram in a mouse model of SARS-CoV-2 infection.
RESULTS
We found that the SARS-CoV-2 virus directly activates the pore-forming protein GSDMD that triggers NET production and organ damage in COVID-19. Single-cell transcriptome analysis revealed that the expression of GSDMD and inflammasome-related genes were increased in COVID-19 patients. High expression of active GSDMD associated with NETs structures was found in the lung tissue of COVID-19 patients. Furthermore, we showed that activation of GSDMD in neutrophils requires active caspase1/4 and live SARS-CoV-2, which infects neutrophils. In a mouse model of SARS-CoV-2 infection, the treatment with disulfiram inhibited NETs release and reduced organ damage.
CONCLUSION
These results demonstrated that GSDMD-dependent NETosis plays a critical role in COVID-19 immunopathology and suggests GSDMD as a novel potential target for improving the COVID-19 therapeutic strategy.
Topics: Animals; Disulfiram; Extracellular Traps; Mice; Neutrophils; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35799268
DOI: 10.1186/s13054-022-04062-5 -
Scientific Reports Nov 2023We report a multi-resonant terahertz (THz) metamaterial perfect absorber (MPA)-based biosensor in the working frequency range of [Formula: see text] for sensing of...
We report a multi-resonant terahertz (THz) metamaterial perfect absorber (MPA)-based biosensor in the working frequency range of [Formula: see text] for sensing of microorganisms (such as fungi, yeast) and wheat pesticides. Nearly [Formula: see text] absorption is realized at [Formula: see text] and [Formula: see text]. We designed our THz MPA sensor making resonators' gap area compatible with the microorganisms' size. To obtain optimum performance of the MPA, a mapping of amplitudes and shifts in the absorption resonance peaks with different structural parameters of the resonators is carried out. A very high-frequency shift is obtained for microorganisms such as Penicillium chrysogenum (fungi), yeast, and pesticides (Imidacloprid, N, N-Diethyldithiocarbamate sodium salt trihydrate, Daminozide, N, N-Diethyldithiocarbamate sodium salt hydrate, and Dicofol). An equivalent circuit model using Advance Design System (ADS) software is developed. The calculated results through the model show similar trends as obtained in the simulations using CST. Investigations of the effect of incidence angle of THz wave on the absorption spectra of the MPA are also carried out. It is found that incidence angle does not impact the stability of the lower resonance absorption peak (1.79THz). Due to the wide working frequency range, the proposed sensor is extremely suitable for the detection of all range of pesticides because their specific absorption fingerprint lies in the frequency range of 0-3.8THz. We believe that our sensor could be a potential detection tool for detecting pesticide residues in agriculture and food products. The THz MPA-based biosensor is capable of detecting a very small change in the effective dielectric constant of the MPA environment. Therefore, it can also offer huge opportunities in label-free biosensing for future biomedical applications.
Topics: Saccharomyces cerevisiae; Pesticides; Yeast, Dried; Ditiocarb; Sodium
PubMed: 37952035
DOI: 10.1038/s41598-023-46787-5 -
Molecules (Basel, Switzerland) Oct 2020The therapeutic utility of the copper ionophore disulfiram was investigated in a diet-induced obesity mouse model (C57BL/6J background), both through administration in...
The therapeutic utility of the copper ionophore disulfiram was investigated in a diet-induced obesity mouse model (C57BL/6J background), both through administration in feed (0.05 to 1% ()) and via oral gavage (150 mg/kg) for up to eight weeks. Mice were monitored for body weight, fat deposition (perigonadal fat pads), metabolic changes (e.g., glucose dyshomeostasis) and pathologies (e.g., hepatic steatosis, hyperglycaemia and hypertriglyceridemia) associated with a high-fat diet. Metal-related pharmacological effects across major organs and serums were investigated using inductively coupled plasma mass spectrometry (ICP-MS). Disulfiram treatments (all modes) augmented hepatic copper in mice, markedly moderated body weight and abolished the deleterious systemic changes associated with a high-fat diet. Likewise, another chemically distinct copper ionophore H(gtsm), administered daily (oral gavage), also augmented hepatic copper and moderated mouse body weight. Postmortem histological examinations of the liver and other major organs, together with serum aminotransferases, supported the reported therapeutic safety of disulfiram. Disulfiram specifically altered systemic copper in mice and altered hepatic copper metabolism, perturbing the incorporation of copper into ceruloplasmin (holo-ceruloplasmin biosynthesis) and subsequently reducing serum copper concentrations. Serum ceruloplasmin represents a biomarker for disulfiram activity. Our results establish copper ionophores as a potential class of antiobesity agents.
Topics: Animals; Anti-Obesity Agents; Body Weight; Copper; Disulfiram; Dose-Response Relationship, Drug; Ionophores; Liver; Mice; Mice, Inbred C57BL; Permeability
PubMed: 33120881
DOI: 10.3390/molecules25214957 -
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 -
Cell Death and Differentiation Jul 2023Drug repurposing is a versatile strategy to improve current therapies. Disulfiram has long been used in the treatment of alcohol dependency and multiple clinical trials...
Drug repurposing is a versatile strategy to improve current therapies. Disulfiram has long been used in the treatment of alcohol dependency and multiple clinical trials to evaluate its clinical value in oncology are ongoing. We have recently reported that the disulfiram metabolite diethyldithiocarbamate, when combined with copper (CuET), targets the NPL4 adapter of the p97VCP segregase to suppress the growth of a spectrum of cancer cell lines and xenograft models in vivo. CuET induces proteotoxic stress and genotoxic effects, however important issues concerning the full range of the CuET-evoked tumor cell phenotypes, their temporal order, and mechanistic basis have remained largely unexplored. Here, we have addressed these outstanding questions and show that in diverse human cancer cell models, CuET causes a very early translational arrest through the integrated stress response (ISR), later followed by features of nucleolar stress. Furthermore, we report that CuET entraps p53 in NPL4-rich aggregates leading to elevated p53 protein and its functional inhibition, consistent with the possibility of CuET-triggered cell death being p53-independent. Our transcriptomics profiling revealed activation of pro-survival adaptive pathways of ribosomal biogenesis (RiBi) and autophagy upon prolonged exposure to CuET, indicating potential feedback responses to CuET treatment. The latter concept was validated here by simultaneous pharmacological inhibition of RiBi and/or autophagy that further enhanced CuET's tumor cytotoxicity, using both cell culture and zebrafish in vivo preclinical models. Overall, these findings expand the mechanistic repertoire of CuET's anti-cancer activity, inform about the temporal order of responses and identify an unorthodox new mechanism of targeting p53. Our results are discussed in light of cancer-associated endogenous stresses as exploitable tumor vulnerabilities and may inspire future clinical applications of CuET in oncology, including combinatorial treatments and focus on potential advantages of using certain validated drug metabolites, rather than old, approved drugs with their, often complex, metabolic profiles.
Topics: Animals; Humans; Cell Line, Tumor; Disulfiram; Neoplasms; Ribosomes; Tumor Suppressor Protein p53; Zebrafish
PubMed: 37142656
DOI: 10.1038/s41418-023-01167-4 -
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