Alcohol-abuse drug disulfiram targets pediatric glioma via MLL degradation
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ABSTRACT:
PROVIDER: PRJNA578095 | ENA |
REPOSITORIES: ENA
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Project description: Not available
| S-EPMC8358054 | biostudies-literature
Project description:RNA-seq analysis was performed to compare gene expression of glioma cells with MLL1 and MLL2 knockdown, and control glioma cells.
2019-12-20 | GSE139016 | GEO
Project description:Drugs of abuse including nicotine and alcohol elicit their effect by stimulating the mesocorticolimbic dopaminergic system. There is a high incidence of nicotine dependence in alcoholics. To date only limited data is available on the molecular mechanism underlying the action of alcohol and nicotine in the human brain. This study utilised gene expression screening to identify genes sensitive to chronic alcohol abuse within the ventral tegmental area of the human brain. Keywords: gene expression, brain, alcohol abuse, human, ventral tegmental area
2007-09-21 | GSE9058 | GEO
Project description:RNA-seq analysis was performed to compare gene expression between glioma cells treated with disulfiram and untreated glioma cells.
2019-10-16 | GSE138863 | GEO
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:Background: The incidence of alcohol and tobacco co-abuse is as high as 80%. The molecular mechanism underlying this comorbidity is virtually unknown but interactions between these drugs have important implications for the development of, and recovery from drug dependence. Methods: We investigated the effects of chronic tobacco and alcohol abuse and the interaction of the two behaviours on global gene expression in the human nucleus accumbens using cDNA microarrays and 20 alcoholic and control cases, with and without smoking comorbidity. Changes in gene expression were established by two-way ANOVA. Unsupervised hierarchical clustering was utilized to probe the strength of the data sets. Results: Subjecting the data sets derived from microarray gene expression screening to unsupervised hierarchical clustering tied the cases into distinct groups. When considering all alcohol-responsive genes, alcoholics were separated from non alcoholics with the exception of one control case. All smokers were distinguished from non smokers based on similarity in expression of smoking-sensitive genes. In the nucleus accumbens, alcohol-responsive genes were associated with transcription, lipid metabolism and signalling. Smoking-sensitive genes were predominantly assigned to functional groups concerned with RNA processing and the endoplasmic reticulum. Both drugs influenced the expression of genes involved in matrix remodelling, proliferation and cell morphogenesis. Additionally, a gene set encoding proteins involved in the canonical pathway ‘regulation of the actin cytoskeleton’ was induced in response to alcohol and tobacco co-abuse and included. Conclusions: The region-specific modulation of alcohol-sensitive gene expression by smoking may have important consequences for alcohol-induced aberrations within the mesolimbic dopaminergic system.
2010-07-01 | GSE20568 | GEO
Project description:Background: The incidence of alcohol and tobacco co-abuse is as high as 80%. The molecular mechanism underlying this comorbidity is virtually unknown but interactions between these drugs have important implications for the development of, and recovery from drug dependence. Methods: We investigated the effects of chronic tobacco and alcohol abuse and the interaction of the two behaviours on global gene expression in the human nucleus accumbens using cDNA microarrays and 20 alcoholic and control cases, with and without smoking comorbidity. Changes in gene expression were established by two-way ANOVA. Unsupervised hierarchical clustering was utilized to probe the strength of the data sets. Results: Subjecting the data sets derived from microarray gene expression screening to unsupervised hierarchical clustering tied the cases into distinct groups. When considering all alcohol-responsive genes, alcoholics were separated from non alcoholics with the exception of one control case. All smokers were distinguished from non smokers based on similarity in expression of smoking-sensitive genes. In the nucleus accumbens, alcohol-responsive genes were associated with transcription, lipid metabolism and signalling. Smoking-sensitive genes were predominantly assigned to functional groups concerned with RNA processing and the endoplasmic reticulum. Both drugs influenced the expression of genes involved in matrix remodelling, proliferation and cell morphogenesis. Additionally, a gene set encoding proteins involved in the canonical pathway ‘regulation of the actin cytoskeleton’ was induced in response to alcohol and tobacco co-abuse and included. Conclusions: The region-specific modulation of alcohol-sensitive gene expression by smoking may have important consequences for alcohol-induced aberrations within the mesolimbic dopaminergic system. The data set contained individual RNA samples extracted from the nucleus accumbens from 5 non smoking non drinking control case, 5 non smoking alcoholics, 5 non drinking smokers, and 5 smoking alcoholics. An aliquot if each sample was combined to generate a reference pool. Each sample was amplified individually and labelled with Cy3 in the process, the reference samples was amplified and labelled with Cy5. Each sample was hybridised competitively against the reference sample to 1 array.
2010-07-01 | E-GEOD-20568 | biostudies-arrayexpress
Project description:The new uses of the old drugs may reduce cost and shortens the production cycle of research and development, especially that approved by FDA for important clinical conditions. Alcohol abuse Disulfiram (DSF) has been proven safe and shows the promising anti-tumor effect in may preclinical studies. However, the potential side effects of DSF on tumor remain unknown. In this study, we explored the role of DSF in cancer cells and searched for the differential expressed protein after DSF treatment in the HeLa cells. To fully understand the mechanism of action of DSF with a systems perspective, we employed a quantitative proteomics strategy to systematically identify potential targets of DSF. In total, 201 proteins were dys-regulated significantly after DSF exposure, implying that they may be potential targets of DSF. Analysis of this data on a system level revealed major changes of proteins involved in diverse biological processes, including metabolic process and response to stimulus.
2021-11-27 | PXD024910 | Pride
Project description:Improving the poor prognosis of infant leukemias remains an unmet clinical need. This disease is a prototypical fusion oncoprotein-driven pediatric cancer, with MLL (KMT2A)-fusions present in most cases. Direct targeting of these driving oncoproteins represents a unique therapeutic opportunity. This rationale led us to initiate a drug screening with the aim of discovering drugs that can block MLL-fusion oncoproteins. A screen for inhibition of MLL-fusion proteins was developed that overcomes the traditional limitations of targeting transcription factors. This luciferase reporter-based screen, together with a secondary western blot screen, was used to prioritize compounds. We characterized the lead compound, Disulfiram, based on its efficient ablation of MLL fusion proteins. The consequences of drug-induced MLL-fusion inhibition was confirmed by cell proliferation, colony formation, apoptosis assays, RT-qPCR, in vivo assays, RNA-seq and CHIP-qPCR and CHIP-seq analysis. All statistical tests were two-sided. Drug-induced inhibition of MLL-fusion proteins by Disulfiram resulted in a specific block of colony formation in MLL-rearranged cells in vitro, induced differentiation and impeded leukemia progression in vivo. Mechanistically, Disulfiram abrogates MLL-fusion protein binding to DNA, resulting in epigenetic changes and down-regulation of leukemic programs setup by the MLL-fusion protein. Disulfiram can directly inhibit MLL-fusion proteins and demonstrates antitumor activity both in vitro and in vivo, providing, to our knowledge, the first evidence for a therapy that directly target the initiating oncogenic MLL-fusion protein.
2022-08-01 | GSE203203 | GEO
Project description:Effect of disulfiram treatment on pediatric high grade glioma
| PRJNA577636 | ENA