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Cited by 9Neuroblastoma Research and TreatmentsNeurofibromatosis and Schwannoma CasesGlioma Diagnosis and Treatment

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

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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.·2023·Scientific Reports
DOI 10.1038/s41598-023-43219-2PMC PMC10543387
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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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Metadata

Authors
Beaudry, A., Jacques-Ricard, S., Darracq, A., Sgarioto, N., Garcia, A., García, T. R., Lemieux, W., Béland, K., Haddad, E., Cordeiro, P., Duval, M., McGraw, S., Richer, C., Caron, M., Marois, F., St-Onge, P., Sinnett, D., Banquy, X., & Raynal, N. J.-M.
Affiliations
  • Centre Hospitalier Universitaire Sainte-Justine (CA)
  • Université de Montréal (CA)
Corresponding author
Raynal, Noël J.-M.
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2023-09-30
Volume
13
Issue
1
Pages
16443-16443
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-023-43219-2
PMC
PMC10543387
OpenAlex
W4387212726
Cited by
9
References
50
Citations by year
2026: 3 · 2025: 1 · 2024: 4 · 2023: 1
FWCI
1.53
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Canadian Institutes of Health Research
  • Cancer Research Society
  • Fonds de Recherche du Québec - Santé
Topics
  • Health Sciences › Medicine › Oncology › Neuroblastoma Research and Treatments
  • Health Sciences › Medicine › Clinical Neurology › Neurofibromatosis and Schwannoma Cases
  • Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
Keywords
disulfiram, drug repurposing, neuroblastoma, GCN5, histone H3 acetylation, epigenetics, MYCN, neuronal differentiation, cell cycle arrest, water-oil emulsions, lipophilic drug delivery, childhood cancer, anticancer activity
MeSH terms
p300-CBP-Associated Factor, Alcohol Deterrents, Animals, Child, Disulfiram, Emulsions, Humans, Neuroblastoma, Down-Regulation, Cell Line, Tumor, Mice, Histone Acetyltransferases, Drug Repositioning

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