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

• Published in: Oncogene Vol. 38; no. 40; pp. 6711 - 6722
• Main Authors: Skrott, Zdenek, Majera, Dusana, Gursky, Jan, Buchtova, Tereza, Hajduch, Marian, Mistrik, Martin, Bartek, Jiri
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03-10-2019; Nature Publishing Group
• Subjects: 13; 13/106; 13/31; 14; 14/19; 631/154/556; 631/67/1059/153; A549 Cells; Acetaldehyde Dehydrogenase Inhibitors - metabolism; Acetaldehyde Dehydrogenase Inhibitors - pharmacology; Alcohol abuse; Aldehyde dehydrogenase; Aldehyde Dehydrogenase - antagonists & inhibitors; Aldehydes; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Apoptosis; BRCA1 protein; BRCA2 protein; Cancer; Cancer och onkologi; Cell Biology; Cell culture; Cell viability; Cell- och molekylärbiologi; Clinical trials; Copper; Culture Media; Cytotoxicity; Dehydrogenases; Disulfiram; Disulfiram - metabolism; Disulfiram - pharmacology; Drug abuse; Drug therapy; Genetic aspects; Human Genetics; Humans; Internal Medicine; K562 Cells; Klinisk medicin; Medicin och hälsovetenskap; Medicine; Medicine & Public Health; Medicinska och farmaceutiska grundvetenskaper; Nuclear Proteins - metabolism; Oncology; Oxidoreductases; Stem cells
• ISSN: 0950-9232; 1476-5594; 1476-5594
• DOI: 10.1038/s41388-019-0915-2

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.