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Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4
Open accessAbstract
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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“DIS`s definitive antineoplastic mechanism of action, identified over the past decade, involves the molecular target NPL4, which is an adapter for the p97/VCP segregase and is essential for protein turnover, playing a role in several regulatory and stress-responsive cellular pathways.26”
From Off-label and repurposed use of disulfiram beyond alcohol dependence: A systematic review of clinical and preclinical evidence (2026) · cites this paper as [26]
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“a nationwide epidemiological study revealed that patients who continuously used DIS have a lower risk of death from cancer compared to those who stopped using the drug at their diagnosis.26”
From Off-label and repurposed use of disulfiram beyond alcohol dependence: A systematic review of clinical and preclinical evidence (2026) · cites this paper as [26]
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“This triggers a multifaceted cellular stress response culminating in cell death,26”
From Off-label and repurposed use of disulfiram beyond alcohol dependence: A systematic review of clinical and preclinical evidence (2026) · cites this paper as [26]
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“Intracellular Cu(DDC)2 binds NPL4, inducing aggregation that disrupts the essential p97-NPL4-UFD1 segregase pathway.”
From Off-label and repurposed use of disulfiram beyond alcohol dependence: A systematic review of clinical and preclinical evidence (2026) · cites this paper as [26]
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“DIS’s cytotoxic activity stems from its rapid metabolism to Cu(DDC)2, which preferentially accumulates in tumors.”
From Off-label and repurposed use of disulfiram beyond alcohol dependence: A systematic review of clinical and preclinical evidence (2026) · cites this paper as [26]
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“This initial observation has since been substantiated through extensive research, including analyses of Danish demographic and health registries that observed lower mortality rates for colon, prostate, and breast cancers among ongoing DSF users compared to former users.111”
From Drug repurposing for cancer therapy (2024) · cites this paper as [111]
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Metadata
- 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
- Venue
- Nature
- Published
- 2017-12
- Volume
- 552
- Issue
- 7684
- Pages
- 194-199
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- 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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