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Disulfiram/Cu induce ferroptosis in triple-negative breast cancer cells

ABSTRACT: To further explore the mechanism of DSF/Cu in TNBC, we conducted transcriptome sequencing experiments in MDA-MB-231 cells in response to 24 h treatment with DSF/Cu (0.2 µM). RNA-seq data revealed that 874 genes were upregulated and 764 genes were downregulated in DSF/Cu treated cells. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that TNBC cells death induced by DSF/Cu wais related to MAPK signaling pathway, p53 signaling pathway, mitophagy signaling pathway and ferroptosis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE209533 | GEO | 2022/12/30

REPOSITORIES: GEO

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Disulfiram/Copper induces immunogenic cell death via NPL4 in hepatocellular carcinoma

Project description:Some chemotherapeutic agents have been found to enhance the antitumor immunity by inducing immunogenic cell death (ICD). The combination of disulfiram (DSF) and copper (Cu) has demonstrated anti-tumor effects in a range of malignancies including hepatocellular carcinoma (HCC). However, the potential of DSF/Cu as an ICD inducer and whether it could enhance the efficacy of immune checkpoint blockade in HCC remains unknown. Here, we showed that DSF/Cu-treated HCC cells exhibited characteristics of ICD in vitro, such as calreticulin (CRT) exposure, ATP secretion, high mobility group box 1 (HMGB1) release. DSF/Cu treated HCC cells elicited significant immune memory in a vaccination assay. DSF/Cu treatment promoted dendritic cell activation and maturation. The combination of DSF/Cu and CD47 blockade further facilitated DC maturation and subsequently enhanced CD8+ T cell cytotoxicity. Mechanically, DSF/Cu promoted the nuclear accumulation and aggregation of nuclear protein localization protein 4 (NPL4) to inhibit the ubiquitin-proteasome system, thus induced endoplasmic reticulum (ER) stress. Inhibition of NPL4 induced ICD-associated damage-associated molecular patterns. Collectively, our findings demonstrated that DSF/Cu induced ICD-mediated immune activation in HCC and enhanced the efficacy of CD47 blockade.

2022-10-19 | GSE211734 | GEO

Expression data from meningioma cell after DSF and Cu treatment

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Disulfiram when combined with copper enhances the therapeutic effects of temozolomide for the treatment of Glioblastoma

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Disulfiram blocks inflammatory TLR4 signaling by targeting MD-2

Project description:Toll-like receptor 4 (TLR4) sensing of lipopolysaccharide (LPS), the most potent pathogen-associated molecular pattern of gram-negative bacteria, activates NF-κB and Irf3, which induces inflammatory cytokines and interferons that trigger an intense inflammatory response, which is critical for host defense but can also cause serious inflammatory pathology, including sepsis. Although TLR4 inhibition is an attractive therapeutic approach for suppressing overexuberant inflammatory signaling, previously identified TLR4 antagonists have not shown any clinical benefit. Here, we identify disulfiram (DSF), an FDA-approved drug for alcoholism, as a specific inhibitor of TLR4-mediated inflammatory signaling. TLR4 cell surface expression, LPS sensing, dimerization and signaling depend on TLR4 binding to MD-2. DSF and other cysteine-reactive drugs, previously shown to block LPS-triggered inflammatory cell death (pyroptosis), inhibit TLR4 signaling by covalently modifying Cys133 of MD-2, a key conserved residue that mediates TLR4 sensing and signaling. DSF blocks LPS-triggered inflammatory cytokine, chemokine, and interferon production by macrophages in vitro. In the aggressive N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease (PD) in which TLR4 plays an important role, DSF markedly suppresses neuroinflammation and dopaminergic neuron loss, and restores motor function. Our findings identify a role for DSF in curbing TLR4-mediated inflammation and suggest that DSF and other drugs that target MD-2 might be useful for treating PD and other diseases in which inflammation contributes importantly to pathogenesis.

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Expression data from meningioma cell after DSF and Cu treatment

Project description:Expression data from meningioma cell after DSF and Cu treatment

| PRJNA806864 | ENA

Effect of Disulfiram on T cell activation

Project description:To determine the effect of DSF on T cell activation ,we treated T cells with DSF and analyzed their functions.

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Antifungal activity of the repurposed drug disulfiram against Cryptococcus neoformans.

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Quantitative proteomics analysis reveals novel insights into mechanisms of action of Disulfiram (DSF)

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