Disulfiram's anti-cancer activity reflects targeting NPL4, not inhibition of aldehyde dehydrogenase

Oncogene
Zdenek SkrottJiri Bartek

Abstract

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 conf...Continue Reading

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Citations

Aug 25, 2019·Cancers·Silvia SchmidtovaLucia Kucerova
Jul 3, 2020·Chemical & Pharmaceutical Bulletin·Shintaro Fumoto, Koyo Nishida
May 18, 2020·Cells·Eleni Sertedaki, Athanassios Kotsinas
Feb 6, 2020·Chemical Communications : Chem Comm·Cheng ChenLe-Yun Sun
Dec 17, 2020·International Journal of Molecular Sciences·Dusana Majera, Martin Mistrik
Jan 12, 2021·Cancer Chemotherapy and Pharmacology·Chen LuXiao Zhang
Jun 29, 2021·Biochimica Et Biophysica Acta. Molecular Cell Research·Ali NasrollahzadehSeyed H Ghaffari
Jul 3, 2021·Current Oncology·Denisa Weiser Drozdkova, Katerina Smesny Trtkova
Aug 10, 2021·International Journal of Pharmaceutics·Qing-Hua LanQing Yao
Sep 21, 2021·Proteomics. Clinical Applications·Peng ZhengTongcun Zhang

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Methods Mentioned

BETA
flow cytometry

Software Mentioned

ScanR Acquisition
ScanR Analysis
STATISTICA

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