-
Nature Communications Sep 2023The poor efficacy of chimeric antigen receptor T-cell therapy (CAR T) for solid tumors is due to insufficient CAR T cell tumor infiltration, in vivo expansion,...
The poor efficacy of chimeric antigen receptor T-cell therapy (CAR T) for solid tumors is due to insufficient CAR T cell tumor infiltration, in vivo expansion, persistence, and effector function, as well as exhaustion, intrinsic target antigen heterogeneity or antigen loss of target cancer cells, and immunosuppressive tumor microenvironment (TME). Here we describe a broadly applicable nongenetic approach that simultaneously addresses the multiple challenges of CAR T as a therapy for solid tumors. The approach reprograms CAR T cells by exposing them to stressed target cancer cells which have been exposed to the cell stress inducer disulfiram (DSF) and copper (Cu)(DSF/Cu) plus ionizing irradiation (IR). The reprogrammed CAR T cells acquire early memory-like characteristics, potent cytotoxicity, enhanced in vivo expansion, persistence, and decreased exhaustion. Tumors stressed by DSF/Cu and IR also reprogram and reverse the immunosuppressive TME in humanized mice. The reprogrammed CAR T cells, derived from peripheral blood mononuclear cells of healthy donors or metastatic female breast cancer patients, induce robust, sustained memory and curative anti-solid tumor responses in multiple xenograft mouse models, establishing proof of concept for empowering CAR T by stressing tumor as a promising therapy for solid tumors.
Topics: Humans; Female; Animals; Mice; Leukocytes, Mononuclear; Receptors, Chimeric Antigen; Tumor Microenvironment; Breast Neoplasms; Disease Models, Animal; Immunosuppressive Agents; T-Lymphocytes
PubMed: 37714830
DOI: 10.1038/s41467-023-41282-x -
BMJ Case Reports Mar 2021Disulfiram has been widely used for over six decades in the treatment of alcohol dependence, as an aversive therapeutic agent. Despite having very few side effects when...
Disulfiram has been widely used for over six decades in the treatment of alcohol dependence, as an aversive therapeutic agent. Despite having very few side effects when taken without concurrent alcohol consumption, some of these may underlie serious clinical complications. Epileptic seizure induction is a rare adverse effect of disulfiram and its aetiological mechanism is unknown. We present a hospitalised 47-year-old male patient with two episodes of generalised tonic-clonic seizures during treatment with disulfiram while abstinent from alcohol.
Topics: Anticonvulsants; Carbamazepine; Disulfiram; Epilepsies, Partial; Epilepsy, Generalized; Epilepsy, Tonic-Clonic; Humans; Male; Middle Aged; Seizures
PubMed: 33731397
DOI: 10.1136/bcr-2020-236296 -
Blood Dec 2021
Topics: Disulfiram; Extracellular Traps; Humans; Pharmaceutical Preparations; Sepsis
PubMed: 34940816
DOI: 10.1182/blood.2021013438 -
International Journal of Biological... 2024Macrophage pyroptosis and neutrophil extracellular traps (NETs) play a critical role in sepsis pathophysiology; however, the role of macrophage pyroptosis in the...
Macrophage pyroptosis and neutrophil extracellular traps (NETs) play a critical role in sepsis pathophysiology; however, the role of macrophage pyroptosis in the regulation of NETs formation during sepsis is unknown. Here, we showed that macrophages transfer mitochondria to neutrophils through microvesicles following pyroptosis; this process induces mitochondrial dysfunction and triggers the induction of NETs formation through mitochondrial reactive oxygen species (mtROS)/Gasdermin D (GSDMD) axis. These pyroptotic macrophage-derived microvesicles can induce tissues damage, coagulation, and NETs formation . Disulfiram partly inhibits these effects in a mouse model of sepsis. Pyroptotic macrophage-derived microvesicles induce NETs formation through mitochondrial transfer, both and . Microvesicles-mediated NETs formation depends on the presence of GSDMD-N-expressing mitochondria in the microvesicles. This study elucidates a microvesicles-based pathway for NETs formation during sepsis and proposes a microvesicles-based intervention measure for sepsis management.
Topics: Mice; Animals; Extracellular Traps; Neutrophils; Mitochondria; Macrophages; Sepsis
PubMed: 38169726
DOI: 10.7150/ijbs.87646 -
Frontiers in Molecular Neuroscience 2022Alcohol use disorder (AUD) is highly prevalent and one of the leading causes of disability in the US and around the world. There are some molecular biomarkers of heavy... (Review)
Review
Alcohol use disorder (AUD) is highly prevalent and one of the leading causes of disability in the US and around the world. There are some molecular biomarkers of heavy alcohol use and liver damage which can suggest AUD, but these are lacking in sensitivity and specificity. AUD treatment involves psychosocial interventions and medications for managing alcohol withdrawal, assisting in abstinence and reduced drinking (naltrexone, acamprosate, disulfiram, and some off-label medications), and treating comorbid psychiatric conditions (e.g., depression and anxiety). It has been suggested that various patient groups within the heterogeneous AUD population would respond more favorably to specific treatment approaches. For example, there is some evidence that so-called reward-drinkers respond better to naltrexone than acamprosate. However, there are currently no objective molecular markers to separate patients into optimal treatment groups or any markers of treatment response. Objective molecular biomarkers could aid in AUD diagnosis and patient stratification, which could personalize treatment and improve outcomes through more targeted interventions. Biomarkers of treatment response could also improve AUD management and treatment development. Systems biology considers complex diseases and emergent behaviors as the outcome of interactions and crosstalk between biomolecular networks. A systems approach that uses transcriptomic (or other -omic data, e.g., methylome, proteome, metabolome) can capture genetic and environmental factors associated with AUD and potentially provide sensitive, specific, and objective biomarkers to guide patient stratification, prognosis of treatment response or relapse, and predict optimal treatments. This Review describes and highlights state-of-the-art research on employing transcriptomic data and artificial intelligence (AI) methods to serve as molecular biomarkers with the goal of improving the clinical management of AUD. Considerations about future directions are also discussed.
PubMed: 36407766
DOI: 10.3389/fnmol.2022.1032362 -
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 -
Frontiers in Pharmacology 2021Disulfiram has been used clinically for decades as an anti-alcoholic drug. Recently, several studies have demonstrated the anti-inflammatory effects of disulfiram and... (Review)
Review
Disulfiram has been used clinically for decades as an anti-alcoholic drug. Recently, several studies have demonstrated the anti-inflammatory effects of disulfiram and its metabolism, which can alleviate the progression of inflammation and . In the current study, we summarize the anti-inflammatory mechanisms of disulfiram and its metabolism, including inhibition of pyroptosis by either covalently modifying gasdermin D or inactivating nod-like receptor protein 3 inflammasome, dual effects of intracellular reactive oxygen species production, and inhibition of angiogenesis. Furthermore, we review the potential application of disulfiram and its metabolism in treatment of inflammatory disorders, such as inflammatory bowel disease, inflammatory injury of kidney and liver, type 2 diabetes mellitus, sepsis, uveitis, and osteoarthritis.
PubMed: 35185542
DOI: 10.3389/fphar.2021.795078 -
JCI Insight Mar 2022Severe acute lung injury has few treatment options and a high mortality rate. Upon injury, neutrophils infiltrate the lungs and form neutrophil extracellular traps... (Review)
Review
Severe acute lung injury has few treatment options and a high mortality rate. Upon injury, neutrophils infiltrate the lungs and form neutrophil extracellular traps (NETs), damaging the lungs and driving an exacerbated immune response. Unfortunately, no drug preventing NET formation has completed clinical development. Here, we report that disulfiram - an FDA-approved drug for alcohol use disorder - dramatically reduced NETs, increased survival, improved blood oxygenation, and reduced lung edema in a transfusion-related acute lung injury (TRALI) mouse model. We then tested whether disulfiram could confer protection in the context of SARS-CoV-2 infection, as NETs are elevated in patients with severe COVID-19. In SARS-CoV-2-infected golden hamsters, disulfiram reduced NETs and perivascular fibrosis in the lungs, and it downregulated innate immune and complement/coagulation pathways, suggesting that it could be beneficial for patients with COVID-19. In conclusion, an existing FDA-approved drug can block NET formation and improve disease course in 2 rodent models of lung injury for which treatment options are limited.
Topics: Acetaldehyde Dehydrogenase Inhibitors; Acute Lung Injury; Animals; COVID-19; Disease Models, Animal; Disulfiram; Extracellular Traps; Lung; Rodentia; SARS-CoV-2
PubMed: 35133984
DOI: 10.1172/jci.insight.157342 -
Redox Biology Feb 2024Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors and the fourth leading cause of cancer-related death globally, which is characterized by...
Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors and the fourth leading cause of cancer-related death globally, which is characterized by complicated pathophysiology, high recurrence rate, and poor prognosis. Our previous study has demonstrated that disulfiram (DSF)/Cu could be repurposed for the treatment of HCC by inducing ferroptosis. However, the effectiveness of DSF/Cu may be compromised by compensatory mechanisms that weaken its sensitivity. The mechanisms underlying these compensatory responses are currently unknown. Herein, we found DSF/Cu induces endoplasmic reticulum stress with disrupted ER structures, increased Ca level and activated expression of ATF4. Further studies verified that DSF/Cu induces both ferroptosis and cuproptosis, accompanied by the depletion of GSH, elevation of lipid peroxides, and compensatory increase of xCT. Comparing ferroptosis and cuproptosis, it is interesting to note that GSH acts at the crossing point of the regulation network and therefore, we hypothesized that compensatory elevation of xCT may be a key aspect of the therapeutic target. Mechanically, knockdown of ATF4 facilitated the DSF/Cu-induced cell death and exacerbated the generation of lipid peroxides under the challenge of DSF/Cu. However, ATF4 knockdown was unable to block the compensatory elevation of xCT and the GSH reduction. Notably, we found that DSF/Cu induced the accumulation of ubiquitinated proteins, promoted the half-life of xCT protein, and dramatically dampened the ubiquitination-proteasome mediated degradation of xCT. Moreover, both pharmacologically and genetically suppressing xCT exacerbated DSF/Cu-induced cell death. In conclusion, the current work provides an in-depth study of the mechanism of DSF/Cu-induced cell death and describes a framework for the further understanding of the crosstalk between ferroptosis and cuproptosis. Inhibiting the compensatory increase of xCT renders HCC cells more susceptible to DSF/Cu, which may provide a promising synergistic strategy to sensitize tumor therapy and overcome drug resistance, as it activates different programmed cell death.
Topics: Humans; Disulfiram; Copper; Carcinoma, Hepatocellular; Cell Line, Tumor; Ferroptosis; Lipid Peroxides; Liver Neoplasms
PubMed: 38150993
DOI: 10.1016/j.redox.2023.103007 -
The Primary Care Companion For CNS... Nov 2023
Topics: Humans; Disulfiram; Acetic Acid; Ethanol; Alcohol Deterrents; Alcoholism
PubMed: 38055873
DOI: 10.4088/PCC.23cr03537