Cancer incidence is rising and this global challenge is further exacerbated by tumour resistance to available medicines. A promising approach to meet the need for improved cancer treatment is drug repurposing. Here we highlight the potential for repurposing disulfiram (also known by the trade name Antabuse), an old alcohol-aversion drug that has been shown to be effective against diverse cancer types in preclinical studies. Our nationwide epidemiological study reveals that patients who continuously used disulfiram have a lower risk of death from cancer compared to those who stopped using the drug at their diagnosis. Moreover, we identify the ditiocarb–copper complex as the metabolite of disulfiram that is responsible for its anti-cancer effects, and provide methods to detect preferential accumulation of the complex in tumours and candidate biomarkers to analyse its effect on cells and tissues. Finally, our functional and biophysical analyses reveal the molecular target of disulfiram’s tumour-suppressing effects as NPL4, an adaptor of p97 (also known as VCP) segregase, which is essential for the turnover of proteins involved in multiple regulatory and stress-response pathways in cells.

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  1. 1.

    Mining for therapeutic gold. Nat. Rev. Drug Discov. 10, 397 (2011)

  2. 2.

    et al. The repurposing drugs in oncology (ReDO) project. Ecancermedicalscience 8, 442 (2014)

  3. 3.

    et al. High-throughput cell-based screening of 4910 known drugs and drug-like small molecules identifies disulfiram as an inhibitor of prostate cancer cell growth. Clin. Cancer Res. 15, 6070–6078 (2009)

  4. 4.

    Nonprofit drugs as the salvation of the world’s healthcare systems: the case of Antabuse (disulfiram). Drug Discov. Today 17, 409–412 (2012)

  5. 5.

    , , , & Determination of in vivo adducts of disulfiram with mitochondrial aldehyde dehydrogenase. Biochem. Pharmacol. 61, 537–545 (2001)

  6. 6.

    , , & Disulfiram, a clinically used anti-alcoholism drug and copper-binding agent, induces apoptotic cell death in breast cancer cultures and xenografts via inhibition of the proteasome activity. Cancer Res. 66, 10425–10433 (2006)

  7. 7.

    et al. Disulfiram targeting lymphoid malignant cell lines via ROS–JNK activation as well as Nrf2 and NF-κB pathway inhibition. J. Transl. Med. 12, 163 (2014)

  8. 8.

    et al. Copper signaling axis as a target for prostate cancer therapeutics. Cancer Res. 74, 5819–5831 (2014)

  9. 9.

    et al. Liposome encapsulated disulfiram inhibits NFκB pathway and targets breast cancer stem cells in vitro and in vivo. Oncotarget 5, 7471–7485 (2014)

  10. 10.

    et al. Sodium dithiocarb as adjuvant immunotherapy for high risk breast cancer: a randomized study. Biotherapy 6, 9–12 (1993)

  11. 11.

    et al. Disulfiram modulated ROS–MAPK and NFκB pathways and targeted breast cancer cells with cancer stem cell-like properties. Br. J. Cancer 104, 1564–1574 (2011)

  12. 12.

    et al. Inhibition of proteasome activity, nuclear factor-κB translocation and cell survival by the antialcoholism drug disulfiram. Int. J. Cancer 118, 1577–1580 (2006)

  13. 13.

    et al. Disulfiram (DSF) acts as a copper ionophore to induce copper-dependent oxidative stress and mediate anti-tumor efficacy in inflammatory breast cancer. Mol. Oncol. 9, 1155–1168 (2015)

  14. 14.

    et al. A phase IIb trial assessing the addition of disulfiram to chemotherapy for the treatment of metastatic non-small cell lung cancer. Oncologist 20, 366–367 (2015)

  15. 15.

    et al. Alcohol drinking and all cancer mortality: a meta-analysis. Ann. Oncol. 24, 807–816 (2013)

  16. 16.

    et al. Copper improves the anti-angiogenic activity of disulfiram through the EGFR/Src/VEGF pathway in gliomas. Cancer Lett. 369, 86–96 (2015)

  17. 17.

    et al. The origin of an EPR signal observed in dithiocarbamate-loaded tissues. Copper(ii)-dithiocarbamate complexes account for the narrow hyperfine lines. Biochim. Biophys. Acta 1335, 242–245 (1997)

  18. 18.

    , , , & Cell death assays for drug discovery. Nat. Rev. Drug Discov. 10, 221–237 (2011)

  19. 19.

    et al. RNF168 binds and amplifies ubiquitin conjugates on damaged chromosomes to allow accumulation of repair proteins. Cell 136, 435–446 (2009)

  20. 20.

    , , , & The p97–UFD1L–NPL4 protein complex mediates cytokine-induced IκBα proteolysis. Mol. Cell. Biol. 34, 335–347 (2014)

  21. 21.

    & Quantitative cell-based protein degradation assays to identify and classify drugs that target the ubiquitin–proteasome system. J. Biol. Chem. 286, 16546–16554 (2011)

  22. 22.

    & Monitoring activity and inhibition of 26S proteasomes with fluorogenic peptide substrates. Methods Enzymol. 398, 364–378 (2005)

  23. 23.

    ., ., ., & Regulation of p53 stability and p53-dependent apoptosis by NADH quinone oxidoreductase 1. Proc. Natl Acad. Sci. USA 98, 1188–1193 (2001)

  24. 24.

    ., ., & A mechanism of ubiquitin-independent proteasomal degradation of the tumor suppressors p53 and p73. Genes Dev. 19, 316–321 (2005)

  25. 25.

    et al. Role of Rpn11 metalloprotease in deubiquitination and degradation by the 26S proteasome. Science 298, 611–615 (2002)

  26. 26.

    & Valosin-containing protein is a multi-ubiquitin chain-targeting factor required in ubiquitin–proteasome degradation. Nat. Cell Biol. 3, 740–744 (2001)

  27. 27.

    . et al. UBXD7 binds multiple ubiquitin ligases and implicates p97 in HIF1α turnover. Cell 134, 804–816 (2008)

  28. 28.

    et al. Reversible inhibitor of p97, DBeQ, impairs both ubiquitin-dependent and autophagic protein clearance pathways. Proc. Natl Acad. Sci. USA 108, 4834–4839 (2011)

  29. 29.

    et al. The p97–Ufd1–Npl4 ATPase complex ensures robustness of the G2/M checkpoint by facilitating CDC25A degradation. Cell Cycle 13, 919–927 (2014)

  30. 30.

    , & p97-dependent retrotranslocation and proteolytic processing govern formation of active Nrf1 upon proteasome inhibition. eLife 3, e01856 (2014)

  31. 31.

    , & Emerging functions of the VCP/p97 AAA-ATPase in the ubiquitin system. Nat. Cell Biol. 14, 117–123 (2012)

  32. 32.

    et al. Covalent and allosteric inhibitors of the ATPase VCP/p97 induce cancer cell death. Nat. Chem. Biol. 9, 548–556 (2013)

  33. 33.

    , , & Methods for monitoring endoplasmic reticulum stress and the unfolded protein response. Int. J. Cell Biol. 2010, 830307 (2010)

  34. 34.

    et al. Combined inhibition of p97 and the proteasome causes lethal disruption of the secretory apparatus in multiple myeloma cells. PLoS ONE 8, e74415 (2013)

  35. 35.

    et al. Proteasome inhibitor-adapted myeloma cells are largely independent from proteasome activity and show complex proteomic changes, in particular in redox and energy metabolism. Leukemia 30, 2198–2207 (2016)

  36. 36.

    , , , & Analysis of Npl4 deletion mutants in mammalian cells unravels new Ufd1-interacting motifs and suggests a regulatory role of Npl4 in ERAD. Exp. Cell Res. 314, 2715–2723 (2008)

  37. 37.

    , , , & Purification of proteins containing zinc finger domains using immobilized metal ion affinity chromatography. Protein Expr. Purif. 79, 88–95 (2011)

  38. 38.

    et al. Biophysical methods in drug discovery from small molecule to pharmaceutical. Methods Mol. Biol. 1008, 327–355 (2013)

  39. 39.

    et al. Target identification using drug affinity responsive target stability (DARTS). Proc. Natl Acad. Sci. USA 106, 21984–21989 (2009)

  40. 40.

    et al. Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice. Nature 544, 367–371 (2017)

  41. 41.

    et al. A cellular system that degrades misfolded proteins and protects against neurodegeneration. Mol. Cell 55, 15–30 (2014)

  42. 42.

    , , , & Molecular chaperone functions in protein folding and proteostasis. Annu. Rev. Biochem. 82, 323–355 (2013)

  43. 43.

    & HSF1: guardian of proteostasis in cancer. Trends Cell Biol. 26, 17–28 (2016)

  44. 44.

    Targeting malignancies with disulfiram (Antabuse): multidrug resistance, angiogenesis, and proteasome. Curr. Cancer Drug Targets 11, 332–337 (2011)

  45. 45.

    Proteotoxic crisis, the ubiquitin–proteasome system, and cancer therapy. BMC Biol. 12, 94 (2014)

  46. 46.

    . et al. Targeting the AAA ATPase p97 as an approach to treat cancer through disruption of protein homeostasis. Cancer Cell 28, 653–665 (2015)

  47. 47.

    et al. High expression of valosin-containing protein predicts poor prognosis in patients with breast carcinoma. Tumour Biol. 36, 9919–9927 (2015)

  48. 48.

    et al. Expression of valosin-containing protein in colorectal carcinomas as a predictor for disease recurrence and prognosis. Clin. Cancer Res. 10, 651–657 (2004)

  49. 49.

    et al. Elevated expression of valosin-containing protein (p97) is associated with poor prognosis of prostate cancer. Clin. Cancer Res. 10, 3007–3012 (2004)

  50. 50.

    , , & Introduction to Danish (nationwide) registers on health and social issues: structure, access, legislation, and archiving. Scand. J. Public Health 39 (Suppl), 12–16 (2011)

  51. 51.

    & The central role of the propensity score in observational studies for causal effects. Biometrika 70, 41–55 (1983)

  52. 52.

    . R: A language and environment for statistical computing. R Foundation for Statistical Computing R v.3.2.3 (2015-12-10) (R Foundation for Statistical Computing, 2016)

  53. 53.

    , , & Ni(ii), Cu(ii), and Zn(ii) diethyldithiocarbamate complexes show various activities against the proteasome in breast cancer cells. J. Med. Chem. 51, 6256–6258 (2008)

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We thank J. Škvor, M. Zadinová, J. Vecˇerka and D. Doležal for help with animal experiments, Jana Vrbkova for statistical analysis, D. Fridecky and T. Adam for help with HPLC, I. Protivankova and M. Grønvig Nielsen for technical assistance. This work was supported by grants from the Kellner Family Foundation, Czech National Program of Sustainability, Grant Agency of the Czech Republic, MEYS CR project Czech-BioImaging, the Czech Health Research Council, of the Danish Cancer Society, the Danish National Research Foundation (project CARD), the Danish Council for Independent Research, the Novo Nordisk Foundation, the Czech Cancer League, the Swedish Research Council, Cancerfonden of Sweden, the European Commission (EATRIS), the Czech Ministry of Education, youth and sports (OPVKCZ), Cancer Research Czech Republic and the Howard Hughes Medical Institute.

Author information

Author notes

    • Boris Cvek
    •  & Raymond J. Deshaies

    Present addresses: Olomouc University Social Health Institute, Palacky University, Olomouc, Czech Republic (B.C.); Amgen, Thousand Oaks, California 91320, USA (R.J.D.).

    • Zdenek Skrott
    •  & Martin Mistrik

    These authors contributed equally to this work.


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

    • Zdenek Skrott
    • , Martin Mistrik
    • , Dusana Majera
    • , Jan Gursky
    • , Tomas Ozdian
    • , Zsofia Turi
    • , Pavel Moudry
    • , Martina Michalova
    • , Jana Vaclavkova
    • , Petr Dzubak
    • , Ivo Vrobel
    •  & Marian Hajduch
  2. Danish Cancer Society Research Center, DK-2100 Copenhagen, Denmark

    • Klaus Kaae Andersen
    • , Søren Friis
    • , Jirina Bartkova
    • , Anne Kutt
    • , Jørgen Olsen
    •  & Jiri Bartek
  3. Science for Life Laboratory, Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden

    • Jirina Bartkova
    •  & Jiri Bartek
  4. Kantonsspital St Gallen, Department Oncology/Hematology, St Gallen, Switzerland

    • Marianne Kraus
    •  & Christoph Driessen
  5. Institute of Biophysics and Informatics, First Faculty of Medicine, Charles University, 120 00 Prague 2, Czech Republic

    • Pavla Pouckova
    •  & Jana Mattova
  6. Department of Cell Biology & Genetics, Palacky University, Olomouc, Czech Republic

    • Jindrich Sedlacek
    •  & Boris Cvek
  7. Psychiatric Hospital, 785 01 Šternberk, Czech Republic

    • Andrea Miklovicova
  8. Division of Biology and Biological Engineering, Caltech, Pasadena, California 91125, USA

    • Jing Li
    •  & Raymond J. Deshaies
  9. Barbara Ann Karmanos Cancer Institute and Department of Oncology, School of Medicine, Wayne State University, Detroit, Michigan, USA

    • Q. Ping Dou
  10. School of Basic Medical Sciences, Affiliated Tumor Hospital of Guangzhou Medical University, Guangzhou 511436, China

    • Q. Ping Dou
  11. Howard Hughes Medical Institute, Caltech, Pasadena, California 91125, USA

    • Raymond J. Deshaies


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Z.S., M.Mis., B.C., R.J.D. and J.Barte. conceived the study. Z.S. and M.Mis. performed most biochemical and microscopy experiments and wrote the manuscript. D.M. established the expression cell lines and performed most cytotoxicity tests. T.O., P.D. and I.V. performed the HPLC experiments. K.K.A., S.F. and J.O. performed the epidemiological analyses. J.Bartk. performed the immunohistochemical analyses. J.V. and P.D. performed DARTS experiments. P.M. performed cell death analyses. Z.T. performed cytotoxicity tests and heat-shock response analyses. A.K. performed cytotoxicity tests. A.M. designed and performed phlebotomies of patients treated with Antabuse. M.Mic. performed the ITC. J.G. performed FACS analyses, cell death assays and cell sorting. J.S. performed 20S proteasome assays. J.L. performed 26S proteasome assays. M.K. and C.D. performed the cytotoxicity experiments on myeloid- and patient-derived cell lines. P.P., J.M. and M.H. performed mouse experiments. J.Barte., B.C., Q.P.D. and R.J.D. helped to design the experiments, interpreted the data and wrote/edited the manuscript. All authors approved the manuscript.

Competing interests

R.J.D. is a founder of and consultant for Cleave Biosciences. The other authors declare no competing financial interests.

Corresponding authors

Correspondence to Boris Cvek or Raymond J. Deshaies or Jiri Bartek.

Reviewer Information Nature thanks P. Brossart and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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