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

Abstract

Cancer incidence is rising and this global challenge is further exacerbated by tumour resistance to available medicines. A promising approach to such unmet need for improved cancer treatment is drug repurposing. Here we highlight the potential for repurposing disulfiram (Antabuse), an old alcohol-aversion drug 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 ditiocarb-copper complex as the metabolite of disulfiram responsible for anticancer effects, and provide methods to detect its preferential accumulation in tumours and candidate biomarkers for impact in cells and tissues. Finally, our functional and biophysical analyses reveal the long-sought molecular target of disulfiram’s tumour suppressing effects as NPL4, an adapter of p97/VCP segregase essential for protein turnover involved in multiple regulatory and stress-response cellular pathways.