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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE226162 | GEO | 2023/04/03

REPOSITORIES: GEO