期刊
ONCOGENE
卷 38, 期 40, 页码 6711-6722出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41388-019-0915-2
关键词
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资金
- Grant agency of Czech Rep. GACR [17-25976 S]
- MEYS CR [LM2015062, 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 [LM2015064, CZ.02.1.01/0.0/0.0/16_019/0000868]
- Novo Nordisk Foundation [16854]
- Danish National Research Foundation [DNRF125]
- Danish Cancer Society [R204-A12617]
- Swedish Research Council [VR-MH 2014-46602-117891-30]
- Swedish Cancer Society [170176]
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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