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Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4

2017; Nature Portfolio; Volume: 552; Issue: 7684 Linguagem: Inglês

10.1038/nature25016

1476-4687

Zdeněk Škrott, Martin Mistrík, Klaus Kaae Andersen, Søren Friis, Dušana Majera, Ján Gurský, Tomáš Oždian, Jiřina Bártková, Zsofia Turi, Pavel Moudrý, Marianne Kraus, Martina Michalova, Jana Václavková, Petr Džubák, Ivo Vrobel, P Poučková, Jindřich Sedláček, Andrea Miklovicova, Anne Kutt, Jing Li, Jana Mattová, Christoph Driessen, Q. Ping Dou, Jørgen H. Olsen, Marián Hajdúch, Boris Cvek, Raymond J. Deshaies, Jiří Bártek,

Alcohol Consumption and Health Effects

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. Disulfiram is metabolized into copper–diethyldithiocarbamate, which binds to NPL4 and induces its aggregation in cells, leading to blockade of the p97–NPL4–UFD1 pathway and induction of a complex cellular phenotype that results in cell death. Disulfiram (trade names Antabuse and Antabus) has been used to treat alcohol dependence for several decades. Jiri Bartek and colleagues report epidemiological data from Danish nationwide registries showing that individuals who continued to take disulfiram after a cancer diagnosis had lower cancer-related mortality than individuals who stopped taking the drug. The authors show that disulfiram has anti-cancer effects in vitro and in vivo and identify the NPL4 protein as a drug target. NPL4 is involved in protein turnover, including stress-response pathways that promote tumorigenesis. These findings suggest that re-purposing disulfiram as an anti-cancer drug is a potential future therapeutic strategy.