Cited by 116Bioactive Compounds and Antitumor AgentsCancer Cells and MetastasisCancer-related Molecular Pathways

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Disulfiram’s anti-cancer activity reflects targeting NPL4, not inhibition of aldehyde dehydrogenase

Skrott, Zdenek, Majera, Dusana, Gursky, Jan, Buchtova, Tereza, Hajduch, Marian, Mistrik, Martin, Bartek, Jiri·2019·Oncogene

DOI 10.1038/s41388-019-0915-2

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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.

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Authors: Skrott, Z., Majera, D., Gursky, J., Buchtova, T., Hajduch, M., Mistrik, M., & Bartek, J.
ORCID: Gursky, Jan
Hajduch, Marian
Venue: Oncogene
Publisher: Springer Science and Business Media LLC
Published: 2019-08-07
Volume: 38
Issue: 40
Pages: 6711-6722
ISSN: 0950-9232 (ISSN-L)
1476-5594
DOI: 10.1038/s41388-019-0915-2
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
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
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

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Disulfiram’s anti-cancer activity reflects targeting NPL4, not inhibition of aldehyde dehydrogenase

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