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Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4
Zdenek Skrott1, Martin Mistrik1, Klaus Kaae Andersen2
1Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.
Abstract:
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.
Insights
Repurposing the alcohol-aversion drug disulfiram shows promise for cancer treatment. Continuous use in patients correlated with a lower risk of cancer death, identifying a key metabolite and its molecular target.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Rising cancer incidence and drug resistance necessitate novel therapeutic strategies.
- Drug repurposing offers a viable approach to discover new cancer treatments.
- Disulfiram (Antabuse), an alcohol-aversion medication, has demonstrated preclinical anti-cancer activity.
Purpose of the Study:
- To investigate the efficacy of disulfiram repurposing for cancer treatment.
- To identify the active metabolite of disulfiram responsible for anti-cancer effects.
- To elucidate the molecular mechanisms underlying disulfiram's anti-cancer activity.
Main Methods:
- Nationwide epidemiological study analyzing patient drug use and cancer mortality.
- Metabolomic analysis to identify disulfiram's active compound.
- Functional and biophysical assays to determine molecular targets.
Main Results:
- Continuous disulfiram use was associated with a reduced risk of cancer-related death.
- The ditiocarb-copper complex was identified as the anti-cancer metabolite of disulfiram.
- Disulfiram targets NPL4, a p97 (VCP) segregase adaptor, crucial for cellular protein regulation.
Conclusions:
- Disulfiram is a promising repurposed drug for cancer therapy.
- The ditiocarb-copper complex mediates disulfiram's anti-cancer effects.
- Targeting NPL4 offers a new avenue for cancer treatment development.
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