The Alcohol-Abuse Drug Disulfiram Targets NPL4 to Exert Antitumor Effects

The alcohol-aversion drug disulfiram, which is FDA approved for the treatment of alcohol dependence, has emerged as a potential candidate for drug repurposing for the treatment of cancer. Disulfiram has antitumor activity in preclinical models, but the mechanism by which it acts is unclear and the active metabolite has not been determined. Skrott, Mistrik, and colleagues used epidemiologic and experimental approaches to determine the feasibility of repurposing disulfiram for cancer therapy. Analysis of cancer-specific mortality data among patients who were prescribed disulfiram for alcohol dependency from the Danish nationwide demographic and health registries revealed that patients who continued to use disulfiram had a lower risk of cancer death than patients who stopped using disulfiram at cancer diagnosis, supporting further investigation of disulfiram as a potential anticancer agent. Disulfiram suppressed the growth of breast cancer xenografts, and its activity was further enhanced by the addition of copper gluconate (CuGlu), which is consistent with previous reports that the anticancer activity of disulfiram may be copper-dependent. The disulfiram reactive metabolite DTC forms complexes with copper, and the DTC–copper complex bis(diethyldithiocarbamate) (CuET) was detected by high-resolution high-performance LC/MS in tumor xenografts. CuET preferentially accumulated in tumor tissues and was determined to be the active anticancer metabolite of disulfiram, with demonstrated antitumor activity in breast cancer and myeloma xenograft models. Mechanistically, CuET bound to NPL4, an adaptor protein of the p97 segregase, inducing NPL4 aggregation and immobilization and thereby inhibiting p97-segregase–dependent protein degradation and triggering the cellular unfolded protein response. Further, CuET-induced NPL4 aggregation triggered a cellular heat-shock response. Altogether, these findings suggest a model in which disulfiram is rapidly converted into CuET, which accumulates in tumors and induces NPL4 clustering to inhibit p97 segregase and trigger stress responses that lead to tumor cell death. Additionally, these results support further investigation of disulfiram as an anticancer drug.

Skrott Z, Mistrik M, Andersen KK, Friis S, Majera D, Gursky J, et al. Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4. Nature 2017;552:194–9.

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