Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Comment
. 2018 Apr;7(Suppl 4):S495-S499.
doi: 10.21037/tcr.2018.03.33.

Disulfiram combats cancer via crippling valosin-containing protein/p97 segregase adaptor NPL4

Nan Ding  1   2 , Qianzheng Zhu  2   3
Affiliations
Comment

Disulfiram combats cancer via crippling valosin-containing protein/p97 segregase adaptor NPL4

Nan Ding et al. Transl Cancer Res. 2018 Apr.
No abstract available

PubMed Disclaimer

Conflict of interest statement

Conflicts of Interest: The authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
The actions of disulfiram on NPL4 component of VCP/p97 segregase complex in the ubiquitin-proteasome system, the cellular consequences and their implications. The targeted protein substrates are labeled with ubiquitin moieties through an E1-E2-E3 cascade of enzymatic ubiquitination reaction. In VCP/p97-mediated proteolysis, the poly-ubiquitinated substrates are segregated from their binding partners by VCP/p97 segregase and presented to proteasome for proteolysis. Alternatively, the VCP/p97-mediated substrate segregation is followed by non-proteolytic processing and ubiquitin removal by deubiquitinating enzymes (DUBs). Disulfiram acts on NPL4, causes NPL4 clustering/aggregation, and leads to diverse phenotypic features, including heat-stock response, ER stress, ubiquitin stress and accumulation of ubiquitin conjugates, etc. As a result, many cellular functions, such as cell death, DNA replication and DNA repair pathways, may be affected. The mechanism of disulfiram’s action has implications in future studies toward repurposing disulfiram as an anticancer drug, including but not limited to the use of disulfiram as radio-sensitizer, in synergy with DNA-damaging therapeutics, proteasome and VCP/p97 inhibitors, deubiquitinating enzyme inhibitors, or to overcome drug-resistance of cancer cells to proteasome inhibitors. VCP, valosin-containing protein; DUB, deubiquitinating enzyme; ER, endoplasmic reticulum.
See this image and copyright information in PMC

Comment on

  • Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4.
    Skrott Z, Mistrik M, Andersen KK, Friis S, Majera D, Gursky J, Ozdian T, Bartkova J, Turi Z, Moudry P, Kraus M, Michalova M, Vaclavkova J, Dzubak P, Vrobel I, Pouckova P, Sedlacek J, Miklovicova A, Kutt A, Li J, Mattova J, Driessen C, Dou QP, Olsen J, Hajduch M, Cvek B, Deshaies RJ, Bartek J. Skrott Z, et al. Nature. 2017 Dec 14;552(7684):194-199. doi: 10.1038/nature25016. Epub 2017 Dec 6. Nature. 2017. PMID: 29211715 Free PMC article.

References

    1. Hald J, Jacobsen E. A drug sensitizing the organism to ethyl alcohol. Lancet. 1948;2:1001–4. - PubMed
    1. Johansson B. A review of the pharmacokinetics and pharmacodynamics of disulfiram and its metabolites. Acta Psychiatr Scand Suppl. 1992;369:15–26. - PubMed
    1. Dufour P, Lang JM, Giron C, et al. Sodium dithiocarb as adjuvant immunotherapy for high risk breast cancer: a randomized study. Biotherapy. 1993;6:9–12. - PubMed
    1. Valeriote F, Grates HE. Potentiation of nitrogen mustard cytotoxicity by disulfiram, diethyldithiocarbamic acid, and diethylamine in mice. Cancer Res. 1989;49:6658–61. - PubMed
    1. Brar SS, Grigg C, Wilson KS, et al. Disulfiram inhibits activating transcription factor/cyclic AMP-responsive element binding protein and human melanoma growth in a metal-dependent manner in vitro, in mice and in a patient with metastatic disease. Mol Cancer Ther. 2004;3:1049–60. - PubMed

LinkOut - more resources