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

Oncogene volume 38, pages 6711–6722 (2019)Cite this article

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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 confusing literature about the anti-cancer mechanism of DSF, a drug currently tested in clinical trials for repositioning in oncology.

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Acknowledgements

We thank Dr. M. Tarsounas (Oxford, UK) for the human H1299 cell lines with regulatable expression of shBRCA1 and shBRCA2. The study was supported by grants from: Grant agency of Czech Rep. GACR 17–25976 S, MEYS CR (LM2015062 Czech‐BioImaging and DRO‐61989592), Internal grant of University of Palacky IGA_LF_2019_026, Cancer Research Czech Republic, Ministry of School, Education, Youth and Sports of the Czech Republic (EATRIS-CZ No. LM2015064 and ENOCH No. CZ.02.1.01/0.0/0.0/16_019/0000868), the Novo Nordisk Foundation (no. 16854), the Danish National Research Foundation (project CARD: no. DNRF125), the Danish Cancer Society (R204-A12617) the Swedish Research Council (VR-MH 2014–46602–117891–30), and the Swedish Cancer Society (no. 170176).

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  1. These authors contributed equally: Zdenek Skrott, Dusana Majera

Authors and Affiliations

  1. Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic

    Zdenek Skrott, Dusana Majera, Jan Gursky, Tereza Buchtova, Marian Hajduch, Martin Mistrik & Jiri Bartek

  2. Danish Cancer Society Research Center, Copenhagen, Denmark

    Jiri Bartek

  3. Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Science for Life Laboratory, Karolinska Institute, Stockholm, Sweden

    Jiri Bartek

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Skrott, Z., Majera, D., Gursky, J. et al. Disulfiram’s anti-cancer activity reflects targeting NPL4, not inhibition of aldehyde dehydrogenase. Oncogene 38, 6711–6722 (2019). https://doi.org/10.1038/s41388-019-0915-2

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