Recent efforts to repurpose disulfiram, a drug used in alcohol-aversion therapy for decades, for other diseases suggest the molecule is almost an in vitro panacea: it seems to be effective against various cancers (by multiple mechanisms of action), Alzheimer's disease, obesity and metabolic syndrome, pythiosis, lyme borreliosis, COVID-19, and sepsis. The problem is that the molecule almost does not exist in the body after ingestion and, most importantly, is not the pharmacologically active entity in alcoholic patients, being rather a prodrug. This prodrug is widely and misleadingly used in many in vitro and in vivo experiments regardless of its physiologically reachable concentration or its metabolism in vivo.

• Publikační typ
• časopisecké články MeSH

The current Coronavirus 2019 (COVID-19) pandemic has shown us that the pharmaceutical research community can organize and administer large nonprofit clinical trials (RECOVERY and SOLIDARITY) and achieve the swift development of common, unpatentable drugs for a new indication: in this case an old, inexpensive drug, dexamethasone, for COVID-19. Why is it that such nonprofit efforts are so rare and are not organized as a systemic, routine part of drug development in the public interest? Based on my own experience with repurposing the alcohol-abuse drug disulfiram (Antabuse) for cancer, I identify at least four serious deadlocks to development of nonprofit drugs. All of these obstacles should be addressed to leverage the potential of the COVID-19 pandemic for better future healthcare systems in all countries around the world.

• Klíčová slova
• Biomedicine, COVID-19, Clinical trials, Dexamethasone, Disulfiram, Nonprofit drugs,
• MeSH
• COVID-19 * MeSH
• disulfiram MeSH
• lidé MeSH
• neziskové organizace MeSH
• pandemie * MeSH
• poskytování zdravotní péče MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• disulfiram MeSH

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.

• MeSH
• alkoholismus farmakoterapie   epidemiologie   MeSH
• cílená molekulární terapie MeSH
• disulfiram chemie   farmakologie   terapeutické užití   MeSH
• dospělí MeSH
• jaderné proteiny chemie   metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• měď chemie   MeSH
• myši MeSH
• nádory farmakoterapie   metabolismus   mortalita   patologie   MeSH
• odvykací prostředky alkoholu * farmakologie   terapeutické užití   MeSH
• přehodnocení terapeutických indikací léčivého přípravku * MeSH
• proteinové agregáty MeSH
• proteolýza účinky léků   MeSH
• protinádorové látky * farmakologie   terapeutické užití   MeSH
• reakce na tepelný šok účinky léků   MeSH
• vazba proteinů účinky léků   MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Dánsko epidemiologie   MeSH
• Názvy látek
• disulfiram MeSH
• jaderné proteiny MeSH
• měď MeSH
• NPLOC4 protein, human MeSH Prohlížeč
• odvykací prostředky alkoholu * MeSH
• proteinové agregáty MeSH
• protinádorové látky * MeSH