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.

Danish Cancer Society Research Center Copenhagen Denmark

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

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

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Biochem Pharmacol. 1993 Dec 14;46(12):2285-90 PubMed

FASEB J. 2013 Jan;27(1):13-24 PubMed

Oncotarget. 2016 Sep 6;7(36):58516-58530 PubMed

Sci Rep. 2019 Jan 18;9(1):236 PubMed

Nature. 2005 Apr 14;434(7035):917-21 PubMed

Biosci Rep. 2011 Jun;31(3):199-210 PubMed

Cancer Res. 2014 Jul 1;74(13):3579-90 PubMed

Br J Cancer. 2012 Oct 23;107(9):1488-97 PubMed

Prostate. 2019 Mar;79(4):352-362 PubMed

J Clin Psychopharmacol. 2006 Jun;26(3):290-302 PubMed

Leuk Res. 2010 Jun;34(6):757-62 PubMed

J Med Chem. 2018 Oct 11;61(19):8754-8773 PubMed

Biochemistry. 1997 Nov 4;36(44):13748-54 PubMed

Clin Cancer Res. 2010 Jan 1;16(1):45-55 PubMed

Drug Discov Today. 2014 Dec;19(12):1953-63 PubMed

Neuro Oncol. 2015 Jun;17(6):810-21 PubMed

Alcohol Clin Exp Res. 2014 Jan;38(1):44-50 PubMed

J Exp Clin Cancer Res. 2017 Feb 1;36(1):22 PubMed

EMBO Mol Med. 2017 Oct;9(10):1398-1414 PubMed

ACS Appl Mater Interfaces. 2018 Dec 5;10(48):41118-41128 PubMed

Int J Cancer. 2016 Sep 1;139(5):965-75 PubMed

Pharmacol Rev. 2012 Jul;64(3):520-39 PubMed

Alcohol. 2005 Apr;35(3):187-93 PubMed

Mol Oncol. 2015 Jun;9(6):1155-68 PubMed

Nat Med. 2017 Oct 6;23(10):1124-1134 PubMed

Biochem Pharmacol. 1991 Sep 12;42(7):1361-6 PubMed

J Cell Biochem. 2018 Aug;119(8):6882-6893 PubMed

Nature. 2017 Dec 14;552(7684):194-199 PubMed

Oncotarget. 2017 Aug 3;8(42):72544-72563 PubMed

Biomacromolecules. 2019 Jun 10;20(6):2372-2383 PubMed

Cancer Res. 2006 Nov 1;66(21):10425-33 PubMed

Chem Biol Interact. 2001 Jan 30;130-132(1-3):93-102 PubMed

Cancer Res. 2010 Jun 15;70(12):5163-73 PubMed

Cell Stem Cell. 2007 Nov;1(5):555-67 PubMed

Exp Cell Res. 2018 Jan 1;362(1):72-82 PubMed

Br J Cancer. 2013 Oct 1;109(7):1876-85 PubMed

Biochem Pharmacol. 1995 Mar 1;49(5):693-700 PubMed

Cell Biol Toxicol. 2019 Apr;35(2):161-177 PubMed

Br J Cancer. 2011 May 10;104(10):1564-74 PubMed

Oncotarget. 2014 Sep 15;5(17):7471-85 PubMed

Expert Opin Drug Metab Toxicol. 2008 Jun;4(6):697-720 PubMed

Biochem Pharmacol. 2001 Mar 1;61(5):537-45 PubMed

J Biomed Sci. 2017 Mar 3;24(1):19 PubMed

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