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

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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, Turi, Zsofia, Moudry, Pavel, Kraus, Marianne, Michalova, Martina, Vaclavkova, Jana, Dzubak, Petr, Vrobel, Ivo, Pouckova, Pavla, Sedlacek, Jindrich, Miklovicova, Andrea, Kutt, Anne, Li, Jing, Mattova, Jana, Driessen, Christoph, Dou, Q. Ping, Olsen, Jørgen, Hajduch, Marian, Cvek, Boris, Deshaies, Raymond J., Bartek, Jiri·2017·Nature

DOI 10.1038/nature25016PMC PMC5730499

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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.
ORCID: Andersen, Klaus Kaae
Kraus, Marianne
Vrobel, Ivo
Pouckova, Pavla
Li, Jing
Driessen, Christoph
Dou, Q. Ping
Olsen, Jørgen
Cvek, Boris
Deshaies, Raymond J.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2017-12
Volume: 552
Issue: 7684
Pages: 194-199
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature25016
PMC: PMC5730499
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: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
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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Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4

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