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\begin{document}

\title{Why disulfiram is not a panacea?}



\author[1]{Boris Cvek}%
\affil[1]{Palacky University Olomouc}%


\vspace{-1em}



  
  \date{May 05, 2024}


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\begin{abstract}
It is well-known fact that some drugs and drug candidates are remarkably
``promiscuous'' molecules. That means they bind to many various targets.
Especially confusing is the case of disulfiram, an old drug used in
alcohol aversion therapy.%
\end{abstract}%



\sloppy


Why disulfiram is not a panacea?

It is well-known fact that some drugs and drug candidates are remarkably
``promiscuous'' molecules. That means they bind to many various targets.
Especially confusing is the case of disulfiram, an old drug used in
alcohol aversion therapy.

Disulfiram is a highly reactive molecule which almost does not exist in
the body after ingestion (and is metabolized after a few minutes in the
blood). The therapeutic effect of the drug in alcoholics is caused by
its metabolites which inhibit aldehyde dehydrogenase in human organism.
Disulfiram easily creates S-S bonds with thiols and chelates metals
(Eneanya, Bianchine, Duran, Andresen, 1981).

A lot of scientific literature has been published describing disulfiram
ability to target various proteins in cancer (Cvek, 2011). For example,
according to widely held assumption disulfiram can suppress cancer via
inhibition of aldehyde dehydrogenase in cancer cells, although its
metabolite while inhibiting the enzyme in cancer cells is not able -- in
contrast to disulfiram in copper containing medium -- to kill the cells
(Skrott et al., 2019).

Judging according to published scientific literature, disulfiram seems
to be promising treatment for conditions as distinct as Alzheimer's
disease (Reinhardt et al., 2018), obesity (Bernier et al., 2020),
tuberculosis (Dalecki et al. 2015), lyme borreliosis (Potula et al.,
2020), and even for current pandemic. Indeed, two recent studies in
Nature and Nature Immunology suggest that disulfiram could treat
covid-19 (Jin et al., 2020) and sepsis (Hu et al., 2020), respectively.

The reactivity of the ``promiscuous'' drug pretends it is a panacea.
Obviously, it is not. Meaningful biomedical research focused on
disulfiram should identify the active compound, i.e. a disulfiram
metabolite, in vivo and demonstrate coherence of both in vitro (the
experiments with the disulfiram metabolite) and in vivo data (Skrott et
al., 2017). Almost all published work on disulfiram ability to treat
various maladies, including the two recent studies in Nature and Nature
Immunology, fail to do so.

Boris Cvek (cvekb@seznam.cz)

Olomouc University Social Health Instituce (OUSHI), Czech Republic

ORCID: http://orcid.org/0000-0001-8238-3890

References:

Bernier\emph{,} M.\emph{,} Mitchell\emph{,} S. J.\emph{,}
Wahl\emph{,}D.\emph{,} Diaz\emph{,} A.\emph{,} Singh\emph{,} A.\emph{,}
Seo\emph{,}W.\emph{,} \ldots{} de Cabo\emph{,} R. (2020) Disulfiram
treatment normalizes body weight in obese mice. \emph{Cell
Metabolism,}\textbf{32} (2)\emph{,} 203-214.

Cvek\emph{,} B. (2011) Targeting malignancies with disulfiram
(Antabuse): multidrug resistance, angiogenesis, and
proteasome.\emph{Current Cancer Drug Targets,} \textbf{11} (3)\emph{,}
332-337.

Dalecki\emph{,} A. G.\emph{,} Haeili\emph{,} M.\emph{,}
Shah\emph{,}S.\emph{,} Speer\emph{,} A.\emph{,} Niederweis\emph{,}
M.\emph{,}Kutsch\emph{,} O.\emph{,} Wolschendorf\emph{,} F. (2015)
Disulfiram and copper ions kill Mycobacterium tuberculosis in a
synergistic manner.\emph{Antimicrobial Agents and Chemotherapy,}
\textbf{59} (8)\emph{,}4835-4844.

Eneanya\emph{,} D. I.\emph{,} Bianchine\emph{,} J.
R.\emph{,}Duran\emph{,} D. O.\emph{,} Andresen\emph{,} B. D. (1981). The
actions of metabolic fate of disulfiram. \emph{Annual Review of
Pharmacology and Toxicology,} \textbf{21} \emph{,} 575-596.

Hu\emph{,} J. J.\emph{,} Liu, X.\emph{,} Xia\emph{,}
S.\emph{,}Zhang\emph{,} Z.\emph{,} Zhang\emph{,} Y.\emph{,}
Zhao\emph{,}J.\emph{,} \ldots{} Wu\emph{,} H. (2020) FDA-approved
disulfiram inhibits pyroptosis by blocking gasdermin D pore
formation.~\emph{Nature Immunology} \textbf{21} (7), 736-745.

Jin\emph{,} Z.\emph{,} Du\emph{,} X.\emph{,} Xu\emph{,}
Y.\emph{,}Deng\emph{,} Y.\emph{,} Liu\emph{,} M.\emph{,} Zhao\emph{,}
Y.\emph{,}\ldots{} Yang\emph{,} H. (2020) Structure of
M\textsuperscript{pro}~from COVID-19 virus and discovery of its
inhibitors.\emph{~Nature,}\textbf{582} (7811), 289-293.

Potula\emph{,} H.-H. S. K.\emph{,} Shahryari\emph{,}
J.\emph{,}Inayathullah\emph{,} M.\emph{,} Malkovskiy\emph{,} A.
V.\emph{,}Kim\emph{,} K.-M.\emph{,} Rajadas\emph{,} J. (2020)
Repurposing disulfiram (tetraethylthiuram disulfide) as a potential drug
candidate against Borrelia burgdorferi in vitro and in vivo.
\emph{Antibiotics (Basel),} \textbf{9} (9)\emph{,} 633.

Reinhardt\emph{,} S.\emph{,} Stoye\emph{,} N.\emph{,}
Luderer\emph{,}M.\emph{,} Kiefer\emph{,} F.\emph{,} Schmitt\emph{,}
U.\emph{,}Lieb\emph{,} K.\emph{,} Endres\emph{,} K. (2018)
Identification of disulfiram as a secretase-modulating compound with
beneficial effects on Alzheimer's disease hallmarks. \emph{Scientific
Reports,}\textbf{8} (1)\emph{,} 1329.

Skrott\emph{,} Z.\emph{,} Majera\emph{,} D.\emph{,}
Gursky\emph{,}J.\emph{,} Buchtova\emph{,} T.\emph{,} Hajduch\emph{,}
M.\emph{,}Mistrik\emph{,} M.\emph{,} Bartek J. (2019) Disulfiram's
anti-cancer activity reflects targeting NPL4, not inhibition of aldehyde
dehydrogenase. \emph{Oncogene,} \textbf{38} (40)\emph{,} 6711-6722.

Skrott\emph{,} Z.\emph{,} Mistrik\emph{,} M.\emph{,} Andersen\emph{,} K.
K.\emph{,} Friis\emph{,} S.\emph{,} Majera\emph{,}
D.\emph{,}Gursky\emph{,} J.\emph{,} \ldots{} Bartek\emph{,} J. (2017)
Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor
NPL4. \emph{Nature,} \textbf{552} (7684)\emph{,} 194-199.

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