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Beaudry, Annie; Jacques-Ricard, Simon; Darracq, Anaïs; Sgarioto, Nicolas; Garcia, Araceli; García, Teresita Rode; Lemieux, William; Béland, Kathie; Haddad, Elie; Cordeiro, Paulo; Duval, Michel; McGraw, Serge; Richer, Chantal; Caron, Maxime; Marois, François; St-Onge, Pascal; Sinnett, Daniel; Banquy, Xavier; Raynal, Noël J.-M.
Scientific reports, 09/2023, Volume: 13, Issue: 1Journal Article
Abstract 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.
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