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Repurposing disulfiram, an alcohol-abuse drug, in neuroblastoma causes KAT2A downregulation and in vivo activity with a water/oil emulsion

ABSTRACT: Repurposing disulfiram, an alcohol-abuse drug, in neuroblastoma causes KAT2A downregulation and in vivo activity with a water/oil emulsion

PROVIDER: PRJNA939111 | ENA |

REPOSITORIES: ENA

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			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

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Repurposing disulfiram, an alcohol-abuse drug, in neuroblastoma causes KAT2A downregulation and in vivo activity with a water/oil emulsion

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

Alcohol-abuse drug disulfiram targets pediatric glioma via MLL degradation

Project description:Alcohol-abuse drug disulfiram targets pediatric glioma via MLL degradation

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Repurposing disulfiram, an alcohol-abuse drug, in neuroblastoma causes KAT2A downregulation and in vivo activity with a water/oil emulsion.

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

Intestinal alcohol abuse sorted dendritic cells proteomics

Project description:Consumption of ethanol has detrimental effects on gastric organs such as the intestine. To demonstrate the deleterious effect of alcohol, we sacrificed isobaric feeding or ethanol feeding mice and sorted the dendritic cells from their intestine organ. The dendritic cells were analyzed by a small-scale global proteomics approach. We achieved to obtain the biological signatures in the alcohol abuse mice group using bioinformatics analysis.

2024-06-16 | PXD033700 | Pride

Gene expression in the human VTA of cases with alcohol abuse

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

Kat2a regulates hippocampal memory formation [RNA-seq]

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

Repurposing disulfiram as treatment for metastatic colorectal cancerAn investigator initiated clinical phase II trial

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

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Alcohol-abuse drug disulfiram targets pediatric glioma via MLL degradation

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

Kat2a regulates hippocampal memory formation [small RNA-seq]

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 naÃ¯ve (n=6)

2014-07-16 | E-GEOD-53427 | biostudies-arrayexpress

Alcohol-abuse drug disulfiram targets pediatric glioma via MLL degradation.

Project description:Pediatric gliomas comprise a broad range of brain tumors derived from glial cells. While high-grade gliomas are often resistant to therapy and associated with a poor outcome, children with low-grade gliomas face a better prognosis. However, the treatment of low-grade gliomas is often associated with severe long-term adverse effects. This shows that there is a strong need for improved treatment approaches. Here, we highlight the potential for repurposing disulfiram to treat pediatric gliomas. Disulfiram is a drug used to support the treatment of chronic alcoholism and was found to be effective against diverse cancer types in preclinical studies. Our results show that disulfiram efficiently kills pediatric glioma cell lines as well as patient-derived glioma stem cells. We propose a novel mechanism of action to explain disulfiram's anti-oncogenic activities by providing evidence that disulfiram induces the degradation of the oncoprotein MLL. Our results further reveal that disulfiram treatment and MLL downregulation induce similar responses at the level of histone modifications and gene expression, further strengthening that MLL is a key target of the drug and explaining its anti-oncogenic properties.

| S-EPMC8358054 | biostudies-literature

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