Repurposing disulfiram, an alcohol-abuse drug, in neuroblastoma causes KAT2A downregulation and in vivo activity with a water/oil emulsion
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA939111 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23628520_1.fastq.gz | Fastqsanger.gz | |||
| SRR23628520_2.fastq.gz | Fastqsanger.gz | |||
| SRR23628521_1.fastq.gz | Fastqsanger.gz | |||
| SRR23628521_2.fastq.gz | Fastqsanger.gz | |||
| SRR23628522_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 12 |
Similar Datasets
Project description:Neuroblastoma is the most common pediatric extracranial solid tumor accounting for 10% of cancer death in children. Despite intensive treatments involving surgery, chemotherapy, radiotherapy and stem cell transplantation, children with high-risk neuroblastoma still have a poor outcome. Thus, there is an urgent need to develop new therapeutic approaches that can be rapidly tested in clinical trials and with a safe long-term toxicity profile, particularly for children. A promising approach to meet those needs is drug repurposing. Here, we investigated disulfiram, an approved drug for chronic alcoholism treatment, with known anticancer and epigenetic effects. Disulfiram efficiently produced cell cycle arrest and decreased cell viability in five human neuroblastoma cell lines, with IC50 concentrations more than twenty times below its plasmatic level measured in patients treated for chronic alcoholism. We show that disulfiram induced a transcriptomic shift in neuroblastoma cells causing a decrease in cell replication and an increase in neuronal differentiation pathways. In line with these findings, disulfiram reduced significantly the protein level of the histone acetyltransferase KAT2A (GCN5), resulting in a drastic loss of histone acetylation in lysine residues (H3K9ac, H3K14ac, H3K27ac) targeted by KAT2A. To further investigate the anticancer effects of disulfiram in a high-risk neuroblastoma in vivo model, we developed a disulfiram-loaded emulsion suitable for the delivery of this highly liposoluble drug. Using this formulation, we showed that disulfiram significantly delayed the progression of neuroblastoma in mice. Overall, this study highlights a novel target of disulfiram, which directly impacts KAT2A expression and histone acetylation in neuroblastoma.
2023-04-03 | GSE226162 | GEO
Project description:Neuroblastoma, the most common type of pediatric extracranial solid tumor, causes 10% of childhood cancer deaths. Despite intensive multimodal treatment, the outcomes of high-risk neuroblastoma remain poor. We urgently need to develop new therapies with safe long-term toxicity profiles for rapid testing in clinical trials. Drug repurposing is a promising approach to meet these needs. Here, we investigated disulfiram, a safe and successful chronic alcoholism treatment with known anticancer and epigenetic effects. Disulfiram efficiently induced cell cycle arrest and decreased the viability of six human neuroblastoma cell lines at half-maximal inhibitory concentrations up to 20 times lower than its peak clinical plasma level in patients treated for chronic alcoholism. Disulfiram shifted neuroblastoma transcriptome, decreasing MYCN levels and activating neuronal differentiation. Consistently, disulfiram significantly reduced the protein level of lysine acetyltransferase 2A (KAT2A), drastically reducing acetylation of its target residues on histone H3. To investigate disulfiram's anticancer effects in an in vivo model of high-risk neuroblastoma, we developed a disulfiram-loaded emulsion to deliver the highly liposoluble drug. Treatment with the emulsion significantly delayed neuroblastoma progression in mice. These results identify KAT2A as a novel target of disulfiram, which directly impacts neuroblastoma epigenetics and is a promising candidate for repurposing to treat pediatric neuroblastoma.
| S-EPMC10543387 | biostudies-literature
Project description:Alcohol-abuse drug disulfiram targets pediatric glioma via MLL degradation
| PRJNA578095 | ENA
Project description:We sequenced mRNA from 24 samples extracted from mouse CA1 tissue to generate the first CA1-specific murine transcriptome and the first CA1-transcriptome in response to environmental novelty under normal and Kat2a-loss-of-function conditions. Samples were divded in 4 groups: A: Control naM-CM-/ve (n=6), B: control novelty-exposed (n=5), C: Kat2a cKO naM-CM-/ve (n=6), D: Kat2a cKO novelty-exposed (n=7). Pairwise comparisons for AvsB, AvsC, BvsD and CvsD were performed using DESeq2.
2014-07-16 | E-GEOD-53380 | biostudies-arrayexpress
Project description:Primary objective: Disease-control rate (complete response, partial response and/or stable disease >= 18 weeksTo investigate efficacy and safety of the treatment combination irinotecan, disulfiram and copper in patients with metastatic colorectal cancer having developed resistance to irinotecan.
Primary objective: Disease-control rate (complete response, partial response and/or stable disease >= 18 weeks
| 2539387 | ecrin-mdr-crc
Project description:We sequenced small RNAs from 12 samples extracted from mouse CA1 tissue to generate the first CA1-specific murine miRNome under normal and Kat2a-loss-of-function conditions. Samples were divded in 4 groups: A: Control (n=6), C: Kat2a cKO naïve (n=6)
2014-07-16 | E-GEOD-53427 | biostudies-arrayexpress
Project description:The NLRP3 inflammasome is dysregulated in autoinflammatory disorders caused by inherited mutations and contributes to the pathogenesis of several chronic inflammatory diseases. In this study, we discovered that disulfiram, a safe FDA-approved drug, specifically inhibits the NLRP3 inflammasome, but not the NLRC4 or AIM2 inflammasomes. Disulfiram suppresses caspase-1 activation, ASC speck formation, and pyroptosis induced by several stimuli that activate NLRP3. Mechanistically, NLRP3 is palmitoylated at cysteine 126, a modification required for its localization to the trans-Golgi network and inflammasome activation which was inhibited by disulfiram. Administration of disulfiram to animals inhibited the NLRP3, but not the NLRC4 inflammasome in vivo. Our study uncovers a mechanism by which disulfiram targets NLRP3 and provides a rationale for using a safe FDA-approved drug for the treatment of NLRP3-associated inflammatory diseases.
2024-07-25 | PXD054126 | Pride
Project description:KAT2A is a histone acetyl-transferase involved in stabilization of transcriptional activity through acetylation of lysine residue 9 of Histone 3. Mouse knockout models suggest that Kat2a is dispensable for haematopoietic stem and progenitor cell activity, despite a central role in survival and maintenance of Acute Myekoid Leukaemia cells through block of differentiation. Herein, we investigate KAT2A activity in human cord blood haematopoiesis and identify a specific requirement in the establishment of the erythroid lineage. KAT2A is required for specification and survival of Erythroid-Megakaryocytic progenitors, with regulation of expression of the erythropoietin receptor (EPOR) gene, which participates in lineage commitment, as well as of later effector genes in the platelet and erythroid lineages. Early and late lineage roles can be distinctly attributed to the ATAC and SAGA complexes in which context KAT2A exerts its activity. ATAC is active earlier in erythroid lineage development and mediates MEP specification from HSC, whilst SAGA activity is required post-commitment, including in expression of haemoglobin genes. We thus position KAT2A as a novel regulator of human erythropoiesis and separate early and later effects in lineage development with complex specificity. This has implications for putative therapeutic targeting of KAT2A complexes in leukaemia.
2021-09-28 | GSE128512 | GEO
Project description:Obesity has become a global health concern. A molecule that safely prevents and/or treats obesity is urgently needed. Here, we show that long-term diet supplementation of disulfiram (DSF, Antabuse®), an FDA-approved drug, abrogated the adverse impact of an obesogenic diet on insulin responsiveness, while mitigating liver steatosis, cardiovascular remodeling, and pancreatic islet hypertrophy in mice. Additionally, DSF treatment of already obese male and female mice reversed weight gain and alleviated metabolic dysfunctions. Loss of fat tissue and increase in liver fenestrations were also observed in rats on DSF. Transcriptomics and proteomics analyses of mouse and rat livers unveiled comparable signatures, as revealed by pathways associated with lipid and energy metabolism, redox, and detoxification. Mechanistically, markers of hepatic oxidative stress were abrogated in DSF-treated mice through activation of ALDH2 and GST activities in vivo and stimulation of autophagic flux in vitro. Thus, repurposing DSF may represent a new strategy to combat obesity and reverse the associated metabolic disorders in human.
2020-05-15 | PXD016793 | Pride
Project description:Comprehensive identification of acetylated proteins targeted by the lysine acetyltransferases KAT2A (GCN5) and KAT2B (PCAF), in human cells. KAT2A/B-dependent acetylated proteins were identified by comparing acetylated proteins in whole cell extract of control cells and cells in which KAT2A and KAT2B were simultaneously knocked down. The identification of acetylated proteins was performed using an enrichment-free approach. In order to do so, while facing the challenge of identifying low abundant acetylated peptides within a complex sample mixture, we have screened acetylated peptides starting from a large amount of material, equivalent to 50ug of protein digest (maximum loading capacity of our analytical chromatographic column). By analysing such a large amount of peptides, the level of acetylated peptides was then increased and thus acetylated peptides became easily detectable by mass spectrometry, without the need for enrichment.
2016-12-12 | PXD004669 | Pride