Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Paper
  • Published:

Proteasome inhibitors and their combination with antiandrogens: effects on apoptosis, cellular proliferation and viability of prostatic adenocarcinoma cell cultures

Prostate Cancer and Prostatic Diseases volume 7, pages 138–143 (2004)Cite this article

Abstract

The 26S proteasome is a ubiquitin-dependent proteolytic system that has been implicated in the regulation of cell cycle progression and apoptosis. We investigated the effects of the proteasome inhibitors MG115 and PSI alone or in combination with different concentrations of the antiandrogen hydroxyflutamide on the cellular proliferation, apoptosis and viability of 10 prostatic adenocarcinoma cell cultures. Treatment with both proteasome inhibitors resulted in apoptosis induction, whereas the combinations with hydroxyflutamide generally did not, with the exception of MG115 combined with 10−7 M hydroxyflutamide. MG115 caused a significant decrease in cellular proliferation, as did the combinations of both proteasome inhibitors with hydroxyflutamide, whereas hydroxyflutamide alone was only effective at a concentration of 10−5 M. Cellular viability was significantly reduced when both proteasome inhibitors were combined with 10−5 M hydroxyflutamide. Although the results varied among different cell lines, we conclude that proteasome inhibitors are able to induce apoptosis and reduce cellular proliferation. They might prove effective as antineoplastic substances in prostatic adenocarcinoma alone or in combination with antiandrogens.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Ciechanover A . The ubiquitin–proteasome proteolytic pathway. Cell 79; 1994: 13–21.

    Google Scholar 

  2. Spataro V, Norbury C, Harris AL . The ubiquitin–proteasome pathway in cancer. Br J Cancer 77; 1998: 448–455.

    Google Scholar 

  3. Williams SA, McConkey DJ . The proteasome inhibitor bortezomib stabilizes a novel active form of p53 in human LNCaP-Pro5 prostate cancer cell. Cancer Res 2003; 63: 7338–7344.

    PubMed  CAS  Google Scholar 

  4. Maki CG, Huibregtse JM, Howley PM . In vivo ubiquitination and proteasome-mediated degradation of p53. Cancer Res 1996; 56: 2649–2654.

    PubMed  CAS  Google Scholar 

  5. Pagano M et al. Role of the ubiquitin–proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. Science 1995; 269: 682–685.

    Article  CAS  PubMed  Google Scholar 

  6. Glotzer M, Murray AW, Kirschner MW . Cyclin is degraded by the ubiquitin pathway. Nature 1991; 349: 132–138.

    Article  CAS  PubMed  Google Scholar 

  7. Grimm LM, Osborne BA . Apoptosis and the proteasome. Results Probl Cell Differ 1999; 23: 209–228.

    Article  CAS  PubMed  Google Scholar 

  8. Lopes UG, Erhardt P, Yao R, Cooper GM . p53-dependent induction of apoptosis by proteasome inhibitors. J Biol Chem 1997; 272: 12893–12896.

    Article  CAS  PubMed  Google Scholar 

  9. McDade TP, Perugini RA, Vittimberga FJ, Callery MP . Ubiquitin–proteasome inhibition enhances apoptosis of human pancreatic cancer cells. Surgery 1999; 126: 371–377.

    Article  CAS  PubMed  Google Scholar 

  10. Chandra J et al. Proteasome inhibitors induce apoptosis in glucocorticoid-resistant chronic lymphocytic leukemic lymphocytes. Blood 1998; 92: 4220–4229.

    PubMed  CAS  Google Scholar 

  11. Herrmann JL et al. Prostate carcinoma cell death resulting from inhibition of proteasome activity is independent of functional bcl-2 and p53. Oncogene 1998; 17: 2889–2899.

    Article  CAS  PubMed  Google Scholar 

  12. Frankel A et al. Lack of multicellular drug resistance observed in human ovarian and prostate carcinoma treated with the proteasome inhibitor PS-341. Clin Cancer Res 2000; 6: 3719–3728.

    PubMed  CAS  Google Scholar 

  13. Zwergel T et al. A new serial transfer explant cell culture system for human prostatic cancer tissues preventing selection toward diploid cells. Cancer Genet Cytogenet 1998; 101: 16–23.

    Article  CAS  PubMed  Google Scholar 

  14. Adams J et al. Proteasome inhibitors:a novel class of potent and effective antitumor agents. Cancer Res 1999; 59: 2615–2622.

    PubMed  CAS  Google Scholar 

  15. Grimm LM et al. Proteasomes play an essential role in thymocyte apoptosis. EMBO J 1996; 15: 3835–3844.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Sadoul R et al. Involvement of the proteasome in the programmed cell death of NGF-deprived sympathetic neurons. EMBO J 1996; 15: 3845–3852.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Tonomura N et al. Glucocorticoid-induced apoptosis of thymocytes: requirement of proteasome-dependent mitochondrial activity. J Immunol. 2003; 170: 2469–2478.

    Article  CAS  PubMed  Google Scholar 

  18. Shinohara K et al. Apoptosis induction resulting from proteasome inhibition. Biochem J 1996; 317: 385–388.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wilding G, Chen M, Gelmann EP . Aberrant response in vitro of hormone-responsive prostate cancer cells to antiandrogens. Prostate 1989; 14: 103–115.

    Article  CAS  PubMed  Google Scholar 

  20. Veldscholte J, Berrevoets CA, Mulder E . Studies on the human prostatic cancer cell line LNCaP. J Steroid Biochem Mol Biol 1994; 49: 341–346.

    Article  CAS  PubMed  Google Scholar 

  21. Veldscholte J, Berrevoets CA, Mulder E . Studies on the human prostatic cancer cell line LNCaP. J Steroid Biochem Mol Biol 1994; 49: 341–346.

    Article  CAS  PubMed  Google Scholar 

  22. An J, Sun YP, Adams J, Fisher M, Belldegrun A, Rettig MB . Drug interactions between the proteasome inhibitor bortezomib and cytotoxic chemotherapy, tumor necrosis factor (TNF) alpha and TNF-realted apoptosis-inducing ligand in prostate cancer. Clin Res 2003; 9: 4537–4545.

    CAS  Google Scholar 

  23. Adams J . Development of the proteasome inhibitor PS-341. Oncologist 2002; 7: 9–16.

    Article  CAS  PubMed  Google Scholar 

  24. Ficazzola MA et al. Antiproliferative B cell translocation gene 2 protein is down-regulated post-transcriptionally as an early event in prostate carcinogenesis. Carcinogenesis 2001; 22: 1271–1279.

    Article  CAS  PubMed  Google Scholar 

  25. Lin R, Wang TT, Miller Jr WH, White JH . Inhibition of F-Box protein p45(SKP2) expression and stabilization of cyclin-dependent kinase inhibitor p27(KIP1) in vitamin D analog-treated cancer cells. Endocrinology 2003; 144: 749–753.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the Else Kröner Foundation, Germany (Zw – 2001).

Author information

Authors and Affiliations

  1. Clinic and Department of Urology and Pediatric Urology, University of the Saarland, Germany

    T Zwergel, A Tahmatzopoulos, B Wullich, U Zwergel, M Stöckle & G Unteregger

Authors
  1. T Zwergel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A Tahmatzopoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. B Wullich
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. U Zwergel
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M Stöckle
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. G Unteregger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T Zwergel.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zwergel, T., Tahmatzopoulos, A., Wullich, B. et al. Proteasome inhibitors and their combination with antiandrogens: effects on apoptosis, cellular proliferation and viability of prostatic adenocarcinoma cell cultures. Prostate Cancer Prostatic Dis 7, 138–143 (2004). https://doi.org/10.1038/sj.pcan.4500709

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.pcan.4500709

Keywords

This article is cited by

Search

Advanced search

Quick links