Article

Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4

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Abstract

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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Acknowledgements

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.

Affiliations

  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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Contributions

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.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Figure 1

    This file contains the uncropped gels and gating strategy example.

  2. 2.

    Life Sciences Reporting Summary

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