The DOI matches its Crossref record; 43 of the 43 references it cites were found in a registry or an index.
Disulfiram’s anti-cancer activity reflects targeting NPL4, not inhibition of aldehyde dehydrogenase
Abstract
Aldehyde dehydrogenase (ALDH) is a proposed biomarker and possible target to eradicate cancer stem cells. ALDH inhibition as a treatment approach is supported by anti-cancer effects of the alcohol-abuse drug disulfiram (DSF, Antabuse). Given that metabolic products of DSF, rather than DSF itself inhibit ALDH in vivo, and that DSF's anti-cancer activity is potentiated by copper led us to investigate the relevance of ALDH as the suggested molecular cancer-relevant target of DSF. Here we show that DSF does not directly inhibit ALDH activity in diverse human cell types, while DSF's in vivo metabolite, S-methyl-N,N-diethylthiocarbamate-sulfoxide inhibits ALDH activity yet does not impair cancer cell viability. Our data indicate that the anti-cancer activity of DSF does not involve ALDH inhibition, and rather reflects the impact of DSF's copper-containing metabolite (CuET), that forms spontaneously in vivo and in cell culture media, and kills cells through aggregation of NPL4, a subunit of the p97/VCP segregase. We also show that the CuET-mediated, rather than any ALDH-inhibitory activity of DSF underlies the preferential cytotoxicity of DSF towards BRCA1- and BRCA2-deficient cells. These findings provide evidence clarifying the confusing literature about the anti-cancer mechanism of DSF, a drug currently tested in clinical trials for repositioning in oncology.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“DIS anticancer effects instead arise from its copper-containing metabolite, which forms spontaneously in vitro and in vivo, that induces nuclear protein localization 4 (NPL4) aggregation, disrupting the p97/valosin-containing protein (VCP) segregase.81”
From Off-label and repurposed use of disulfiram beyond alcohol dependence: A systematic review of clinical and preclinical evidence (2026) · cites this paper as [81]
Citations
Cites
Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy
Farmer, H., McCabe, N., Lord, C. J., Tutt, A. N. J., Johnson, D. A., Richardson, T. B., Santarosa, M., Dillon, K. J., Hickson, I., Knights, C., et al. (2005) · Nature · doi:10.1038/nature03445 · Cited by 6,683
Ginestier, C., Hur, M. H., Charafe‐Jauffret, E., Monville, F., Dutcher, J. A., Brown, M., Jacquemier, J. D., Viens, P., Kleer, C. G., Liu, S., et al. (2007) · Cell stem cell · doi:10.1016/j.stem.2007.08.014 · Cited by 4,093
Batlle, E., & Clevers, H. (2017) · Nature Medicine · doi:10.1038/nm.4409 · Cited by 2,769
Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4
Skrott, Z., Mistrik, M., Andersen, K. K., Friis, S., Majera, D., Gursky, J., Ozdian, T., Bartkova, J., Turi, Z., Moudry, P., et al. (2017) · Nature · doi:10.1038/nature25016 · Cited by 807
Self-citationNon-P450 aldehyde oxidizing enzymes: the aldehyde dehydrogenase superfamily
Marchitti, S. A., Brocker, C. N., Stagos, D., & Vasiliou, V. (2008) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425255.4.6.697 · Cited by 806
Charafe-Jauffret, E., Ginestier, C., Iovino, F., Tarpin, C., Diebel, M., Esterni, B., Houvenaeghel, G., Extra, J.-M., Bertucci, F., Jacquemier, J., et al. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-1630 · Cited by 732
Chen, D., Cui, Q. C., Yang, H., & Dou, Q. P. (2006) · Cancer Research · doi:10.1158/0008-5472.can-06-2126 · Cited by 683
Koppaka, V., Thompson, D. C., Chen, Y., Ellermann, M., Nicolaou, K. C., Juvonen, R. O., Petersen, D. R., Deitrich, R. A., Hurley, T. D., & Vasiliou, V. (2012) · Pharmacological Reviews · doi:10.1124/pr.111.005538 · Cited by 561
Yip, N. C., Fombon, I. S., Liu, P., Brown, S., Kannappan, V., Armesilla, A. L., Xu, B., Cassidy, J., Darling, J. L., & Wang, W. (2011) · British Journal of Cancer · doi:10.1038/bjc.2011.126 · Cited by 426
van den Hoogen, C., van der Horst, G., Cheung, H., Buijs, J. T., Down, J. M., Guzmán‐Ramírez, N., Hamdy, F. C., Eaton, C. L., Thalmann, G. N., Cecchini, M. G., et al. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-3806 · Cited by 403
Cited by
Sorted by citations
Cuproptosis: mechanisms and links with cancers
Xie, J., Yang, Y., Gao, Y., & He, J. (2023) · Molecular Cancer · doi:10.1186/s12943-023-01732-y · Cited by 843
Mitochondrial adaptation in cancer drug resistance: prevalence, mechanisms, and management
Jin, P., Jiang, J., Zhou, L., Huang, Z., Nice, E. C., Huang, C., & Fu, L. (2022) · Journal of Hematology & Oncology · doi:10.1186/s13045-022-01313-4 · Cited by 299
Photothermally Triggered Copper Payload Release for Cuproptosis‐Promoted Cancer Synergistic Therapy
Zhou, J., Yu, Q., Song, J., Li, S., Li, X., Kang, B., Chen, H., & Xu, J. (2022) · Angewandte Chemie International Edition · doi:10.1002/anie.202213922 · Cited by 242
The molecular mechanism and therapeutic landscape of copper and cuproptosis in cancer
Guo, Z., Chen, D., Yao, L., Sun, Y., Li, D., Le, J., Dian, Y., Zeng, F., Chen, X., & Deng, G. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02192-0 · Cited by 221
Disulfiram: a novel repurposed drug for cancer therapy
Chen, L., Li, X., Ren, Y., & Zhang, X. (2021) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-020-04216-8 · Cited by 159
Metadata
- Authors
- Skrott, Z., Majera, D., Gursky, J., Buchtova, T., Hajduch, M., Mistrik, M., & Bartek, J.
- Venue
- Oncogene
- Published
- 2019-08-07
- Volume
- 38
- Issue
- 40
- Pages
- 6711-6722
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2965238366
- Cited by
- 115
- References
- 43
- Citations by year
- 2026: 7 · 2025: 18 · 2024: 18 · 2023: 17 · 2022: 23 · 2021: 16 · 2020: 13 · 2019: 2
- FWCI
- 10.18
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Novo Nordisk Fonden (NNF15OC0016584)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- disulfiram, aldehyde dehydrogenase, Npl4, cancer stem cells, BRCA1 deficiency, BRCA2 deficiency, drug repurposing, anticancer mechanism, protein aggregation
- MeSH terms
- A549 Cells, Aldehyde Dehydrogenase, Antineoplastic Agents, Culture Media, Disulfiram, Humans, Nuclear Proteins, K562 Cells, Acetaldehyde Dehydrogenase Inhibitors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
