Cited by 812Ubiquitin and proteasome pathwaysCancer-related Molecular PathwaysMetabolism, Diabetes, and Cancer

Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4

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Skrott, Zdenek, Mistrik, Martin, Andersen, Klaus Kaae, Friis, Søren, Majera, Dusana, Gursky, Jan, Ozdian, Tomas, Bartkova, Jirina +20 more·2017·Nature

Abstract

Cancer incidence is rising and this global challenge is further exacerbated by tumour resistance to available medicines. A promising approach to meet the need for improved cancer treatment is drug repurposing. Here we highlight the potential for repurposing disulfiram (also known by the trade name Antabuse), an old alcohol-aversion drug that has been shown to be effective against diverse cancer types in preclinical studies. Our nationwide epidemiological study reveals that patients who continuously used disulfiram have a lower risk of death from cancer compared to those who stopped using the drug at their diagnosis. Moreover, we identify the ditiocarb-copper complex as the metabolite of disulfiram that is responsible for its anti-cancer effects, and provide methods to detect preferential accumulation of the complex in tumours and candidate biomarkers to analyse its effect on cells and tissues. Finally, our functional and biophysical analyses reveal the molecular target of disulfiram's tumour-suppressing effects as NPL4, an adaptor of p97 (also known as VCP) segregase, which is essential for the turnover of proteins involved in multiple regulatory and stress-response pathways in cells.

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Authors
Skrott, Z., Mistrik, M., Andersen, K. K., Friis, S., Majera, D., Gursky, J., Ozdian, T., Bartkova, J., Turi, Z., Moudry, P., Kraus, M., Michalova, M., Vaclavkova, J., Dzubak, P., Vrobel, I., Pouckova, P., Sedlacek, J., Miklovicova, A., Kutt, A., Li, J., Mattova, J., Driessen, C., Dou, Q. P., Olsen, J., Hajduch, M., Cvek, B., Deshaies, R. J., & Bartek, J.
Affiliations
  • Danish Cancer Society (DK)
  • Institute of Molecular and Translational Medicine (CZ)
  • Kantonsspital St. Gallen (CH)
  • Charles University (CZ)
  • Nemocnice Šternberk (CZ)
  • California Institute of Technology (US)
  • Wayne State University (US)
  • Palacký University Olomouc (CZ)
Corresponding author
  • Cvek, Boris
  • Deshaies, Raymond J.
Venue
Nature
Published
2017-12
Volume
552
Issue
7684
Pages
194-199
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
OpenAlex
W2772508026
Cited by
807
References
53
Citations by year
2026: 76 · 2025: 108 · 2024: 120 · 2023: 108 · 2022: 112 · 2021: 81 · 2020: 92 · 2019: 60 · 2018: 50
FWCI
22.68
Type
journal article
Language
en
Open access
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • CaltechAUTHORS (California Institute of Technology) (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • Howard Hughes Medical Institute
  • Lundbeckfonden (R93-2011-8990)
  • National Cancer Institute (R01CA164803)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
disulfiram, drug repurposing, cancer, Npl4, VCP, diethyldithiocarbamate, cancer mortality, tumor suppression, protein turnover, stress response, biomarkers, cell death
MeSH terms
Adult, Alcohol Deterrents, Alcoholism, Animals, Antineoplastic Agents, Copper, Denmark, Disulfiram, Female, Humans, Male, Middle Aged, Neoplasms, Nuclear Proteins, Protein Binding, Heat-Shock Response, Mice, Drug Repositioning, Molecular Targeted Therapy, Proteolysis, Protein Aggregates

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