Disulfiram's anti-cancer activity reflects targeting NPL4, not inhibition of aldehyde dehydrogenase
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15110%2F19%3A73595409" target="_blank" >RIV/61989592:15110/19:73595409 - isvavai.cz</a>
Result on the web
<a href="https://www.nature.com/articles/s41388-019-0915-2" target="_blank" >https://www.nature.com/articles/s41388-019-0915-2</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1038/s41388-019-0915-2" target="_blank" >10.1038/s41388-019-0915-2</a>
Alternative languages
Result language
angličtina
Original language name
Disulfiram's anti-cancer activity reflects targeting NPL4, not inhibition of aldehyde dehydrogenase
Original language description
Aldehyde dehydrogenase (ALDH) is a proposed biomarker and possible target to eradicate cancer stem cells. ALDH inhibition as a treatment approach is supported by anti-cancer effects of the alcohol-abuse drug disulfiram (DSF, Antabuse). Given that metabolic products of DSF, rather than DSF itself inhibit ALDH in vivo, and that DSF's anti-cancer activity is potentiated by copper led us to investigate the relevance of ALDH as the suggested molecular cancer-relevant target of DSF. Here we show that DSF does not directly inhibit ALDH activity in diverse human cell types, while DSF's in vivo metabolite, S-methyl-N, N-diethylthiocarbamate-sulfoxide inhibits ALDH activity yet does not impair cancer cell viability. Our data indicate that the anti-cancer activity of DSF does not involve ALDH inhibition, and rather reflects the impact of DSF's copper-containing metabolite (CuET), that forms spontaneously in vivo and in cell culture media, and kills cells through aggregation of NPL4, a subunit of the p97/VCP segregase. We also show that the CuET-mediated, rather than any ALDH-inhibitory activity of DSF underlies the preferential cytotoxicity of DSF towards BRCA1-and BRCA2-deficient cells. These findings provide evidence clarifying the confusing literature about the anti-cancer mechanism of DSF, a drug currently tested in clinical trials for repositioning in oncology.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10608 - Biochemistry and molecular biology
Result continuities
Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2019
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
ONCOGENE
ISSN
0950-9232
e-ISSN
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Volume of the periodical
38
Issue of the periodical within the volume
40
Country of publishing house
GB - UNITED KINGDOM
Number of pages
12
Pages from-to
6711-6722
UT code for WoS article
000488953500005
EID of the result in the Scopus database
2-s2.0-85070250842