Clinical and Translational Oncology

, Volume 8, Issue 5, pp 313–317 | Cite as

The proteasome: a novel target for anticancer therapy

Educational Series Green Series

Abstract

The proteasome is an ubiquituous enzyme complex that plays a critical role in the degradation of many proteins involved in cell cycle regulation, apoptosis and angiogenesis. Since these pathways are fundamental for cell survival and proliferation, particularly in cancer cells, the inhibition of proteasome is an attractive potential anticancer therapy. Bortezomib (Velcade, formerly PS-341) is an extremely potent and selective proteasome inhibitor that shows strong activity inin vitro andin vivo laboratory studies against many solid and hematologic tumor types. Moreover, bortezomib, mainly by inhibition of the NF-κB pathway, has a chemosensitizing effect when administered together with other antitumoral drugs. Clinical phase I trials, showed good tolerance of bortezomib at doses that achieved a desired degree of proteasome inhibition. Phase II studies showed high response rates in refractory multiple myeloma patients, which led to the accelerated approval of bortezomib by the Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) for this indication. A phase III trial comparing bortezomib to dexamethasone in refractory/relapsed multiple myeloma patients had to be halted due to a survival advantage in the bortezomib arm. Additional studies are focusing in the potential benefit of bortezomib in newly diagnosed multiple myeloma patients. In other solid and hematological malignancies, phase II studies with bortezomib alone or in combination are ongoing with encouraging results, particularly in lung cancer and lymphoma.

Key words

bortezomib NF-kappaB myeloma proteasome 

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References

  1. 1.
    Shah SA, Potter MW, McDade TP, et al. 26S proteasome inhibition induces apoptosis and limits growth of human pancreatic cancer. J Cell Biochem. 2001;82:110–22.PubMedCrossRefGoogle Scholar
  2. 2.
    Wu Y, Luo H, Kanaan N, et al. The proteasome controls the expression of a proliferation-associated nuclear antigen Ki-67, J Cell Biochem, 2000;76:596–604.PubMedCrossRefGoogle Scholar
  3. 3.
    Naujokat C, Sezer O, Zinke H, et al. Proteasome inhibitors induced caspase-dependent apoptosis and accumulation of p21 WAF1/Cipl in human immature leukemic cells. Eur J Haematol. 2000;65:221–56.PubMedCrossRefGoogle Scholar
  4. 4.
    Maki CG, Huibregtse JM, Howley PM.In vivo ubiquitination and proteasome-mediated degradation of p53(1). Cancer Res, 1996;56:2649–54.PubMedGoogle Scholar
  5. 5.
    An WG, Hwang SG, Trepel JB, et al. Protease inhibitor-induced apoptosis: accumulation of wt p53, p21WAF1/CIP1, and induction of apoptosis are independent markers of proteasome inhibition. Leukemia. 2000;14:1276–83.PubMedCrossRefGoogle Scholar
  6. 6.
    Ciechanover A. The ubiquitin-proteasome pathway: on protein death and cell life, Embo J. 1998;17:7151–60.PubMedCrossRefGoogle Scholar
  7. 7.
    Pickart CM. Mechanisms underlying ubiquitination. Annu Rev Biochem 2001;70:503–53.PubMedCrossRefGoogle Scholar
  8. 8.
    Brooks P, Fuertes G, Murray RZ, et al. Subcellular localization of proteasomes and their regulatory complexes in mammalian cells. Biochem J. 2000;346 Pt 1: 155–61.PubMedCrossRefGoogle Scholar
  9. 9.
    Glickman MH, Rubin DM, Coux O, et al. A subcomplex of the proteasome regulatory particle required for ubiquitin-conjugate degradation and related to the COP9-signalosome and eIF3. Cell. 1998;94:615–23.PubMedCrossRefGoogle Scholar
  10. 10.
    Thrower JS, Hoffman L, Rechsteiner M, et al. Recognition of the polyubiquitin proteolytic signal. Embo J. 2000;19:94–102.PubMedCrossRefGoogle Scholar
  11. 11.
    Nussbaum AK, Dick TP, Keilholz W, et al. Cleavage motifs of the yeast 20S proteasome beta subunits deduced from digests of enolase 1. Proc Natl Acad Sci U S A. 1998;95:12504–9.PubMedCrossRefGoogle Scholar
  12. 12.
    DeMartino GN, Slaughter CA. The proteasome, a novel protease regulated by multiple mechanisms. J Biol Chem. 1999;274: 22123–6.PubMedCrossRefGoogle Scholar
  13. 13.
    Zwickl P, Voges D, Baumeister W. The proteasome: a macromolecular assembly designed for controlled proteolysis. Philos Trans R Soc Lond B Biol Sci. 1999;354: 1501–11.PubMedCrossRefGoogle Scholar
  14. 14.
    Adams J. Proteasome inhibitors as new anticancer drugs. Curr Opin Oncol. 2002;14: 628–34.PubMedCrossRefGoogle Scholar
  15. 15.
    Gerards WL, de Jong WW, Boelens W, et al. Structure and assembly of the 20S proteasome. Cell Mol Life Sci. 1998;54:253–62.PubMedCrossRefGoogle Scholar
  16. 16.
    Arrigo AP, Tanaka K, Goldberg AL, et al. Identity of the 19S «prosome» particle with the large multifunctional protease complex of mammalian cells (the proteasome). Nature. 1988;531:192–4.CrossRefGoogle Scholar
  17. 17.
    Tan C, Waldmann TA. Proteasome inhibitor PS-541, a potential therapeutic agent for adult T-cell leukemia. Cancer Res. 2002;62:1085–6.Google Scholar
  18. 18.
    Adams J, Palombella VJ, Sausville EA, et al. Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res. 1999;59:2615–22.PubMedGoogle Scholar
  19. 19.
    Montagut C, Rovira A, Mellado B, et al. Preclinical and clinical development of the proteasome inhibitor bortezomib in cancer treatment. Drugs Today (Barc). 2005; 41:299–315.CrossRefGoogle Scholar
  20. 20.
    Albanell J, Adams J. Bortezomib, a proteasome inhibitor for cancer therapy: from concept to clinic. Drugs of the Future. 2002;27:1–14.CrossRefGoogle Scholar
  21. 21.
    Delic J, Masdehors P, Omura S, et al. The proteasome inhibitor lactacystin induces apoptosis and sensitizes chemo- and radioresistant human chronic lymphocytic leukaemia lymphocytes to TNF-alpha-initiated apoptosis. Br J Cancer. 1998;77:1103–7.PubMedGoogle Scholar
  22. 22.
    Kudo Y, Takata T, Ogawa I, et al. p27Kip1 accumulation by inhibition of proteasome function induces apoptosis in oral squamous cell carcinoma cells. Clin Cancer Res. 2000;6:916–23.PubMedGoogle Scholar
  23. 23.
    Masdehors P, Omura S, Merle-Beral H, et al. Increased sensitivity of CLL-derived lymphocytes to apoptotic death activation by the proteasome-specific inhibitor lactacystin. Br J Haematol. 1999;105:752–7.PubMedCrossRefGoogle Scholar
  24. 24.
    Soligo D, Servida F, Delia D, et al. The apoptogenic response of human myeloid leukaemia cell lines and of normal and malignant haematopoietic progenitor cells to the proteasome inhibitor PSI. Br J Haematol. 2001;115:126–35.CrossRefGoogle Scholar
  25. 25.
    Orlowski RZ, Eswara JR, Lafond-Walker A, et al. Tumor growth inhibition induced in a murine model of human Burkitt's lymphoma by a proteasome inhibitor. Cancer Res. 1998;58:4542–8.Google Scholar
  26. 26.
    Hideshima T, Richardson P, Chauhan D, et al. The proteasome inhibitor PS-541 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res. 2001;61:5071–6.Google Scholar
  27. 27.
    Masdehors P, Merle-Beral H, Maloum K, et al. Deregulation of the ubiquitin system and p55 proteolysis modify the apoptotic response in B-CLL lymphocytes. Blood. 2000;96:269–74.PubMedGoogle Scholar
  28. 28.
    Pérez-Soler R, Kemp B, Wu QP, et al. Response and determinants of sensitivity to paclitaxel in human non-small cell lung cancer tumors heterotransplanted in nude mice. Clin Cancer Res. 2000;6:4952–8.Google Scholar
  29. 29.
    Kanayama H, Tanaka K, Aki M, et al. Changes in expressions of proteasome and ubiquitin genes in human renal cancer cells. Cancer Res. 1991;51:6677–85.PubMedGoogle Scholar
  30. 30.
    Kumatori A, Tanaka K, Tamura T, et al. cDNA cloning and sequencing of component C9 of proteasomes from rat hepatoma cells. FEBS Lett. 1990;264:279–82.PubMedCrossRefGoogle Scholar
  31. 31.
    Oikawa T, Sasaki T, Nakamura M, et al. The proteasome is involved in angiogenesis. Biochem Biophys Res Commun. 1998; 246:243–8.PubMedCrossRefGoogle Scholar
  32. 32.
    Drexler HC, Risau W, Konerding MA. Inhibition of proteasome function induces programmed cell death in proliferating endothelial cells. Faseb J. 2000;14:65–77.PubMedGoogle Scholar
  33. 33.
    Berenson JR, Ma HM, Vescio R. The role of nuclear factor-kappaB in the biology and treatment of multiple myeloma. Semin Oncol. 2001;28:626–33.PubMedCrossRefGoogle Scholar
  34. 34.
    Guzmán ML, Neering SJ, Upchurch D, et al Nuclear factor-kappaB is constitutively activated in primitive human acute myelogenous leukemia cells. Blood. 2001;98: 2501–7.CrossRefGoogle Scholar
  35. 35.
    Biswas DK, Shi Q, Baily S, et al. NF-kappa B activation in human breast cancer specimens and its role in cell proliferation and apoptosis. Proc Natl Acad Sci U S A. 2004;101:10157–42.CrossRefGoogle Scholar
  36. 36.
    Domingo-Doménech J, Mellado B, Ferrer B, et al. Activation of nuclear factor-kappaB in human prostate carcinogensis and association to biochemical relapse. Br J Cancer. 2005;95:1285–94.CrossRefGoogle Scholar
  37. 37.
    Sunwoo JB, Chen Z, Dong G, et al. Novel proteasome inhibitor PS-541 inhibits activation of nuclear factor-kappa B, cell survival, tumor growth, and angiogenesis in squamous cell carcinoma. Clin Cancer Res. 2001;7:1419–28.PubMedGoogle Scholar
  38. 38.
    Cusack JC, Jr., Liu R, Houston M, et al. Enhanced chemosensitivity to CPT-11 with proteasome inhibitor PS-341: implications for systemic nuclear factor-kappaB inhibition. Cancer Res. 2001;61:3535–40.PubMedGoogle Scholar
  39. 39.
    Das KC, White CW. Activation of NF-kappaB by antineoplastic agents. Role of protein kinase C. J Biol Chem. 1997;272: 14914–20.PubMedCrossRefGoogle Scholar
  40. 40.
    Karin M, Cao Y, Greten FR, et al. NF-kappaB in cancer: from innocent bystander to major culprit. Nat Rev Cancer. 2002;2:501–10.CrossRefGoogle Scholar
  41. 41.
    Wang CY, Cusack JC Jr., Liu R, et al. Control of inducible chemoresistance: enhanced anti-tumor therapy through increased apoptosis by inhibition of NF-kappaB. Nat Med. 1999;5:412–7.PubMedCrossRefGoogle Scholar
  42. 42.
    Mitsiades N, Mitsiades CS, Richardson PG, et al. The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications. Blood. 2005;101:2577–80.Google Scholar
  43. 43.
    Bold RJ, Virudachalam S, McConkey DJ. Chemosensitization of pancreatic cancer by inhibition of the 26S proteasome. J Surg Res. 2001;100:11–7.PubMedCrossRefGoogle Scholar
  44. 44.
    Nawrocki ST, Sweeney-Gotsch B, Takamori R, et al. The proteasome inhibitor bortezomib enhances the activity of docetaxel in orthotopic human pancreatic tumor xenografts. Mol Cancer Ther. 2004;5: 59–70.Google Scholar
  45. 45.
    Adams J, Behnke M, Chen S, et al. Potent and selective inhibitors of the proteasome: dipeptidyl boronic acids. Bioorg Med Chem Lett. 1998;8:333–8.PubMedCrossRefGoogle Scholar
  46. 46.
    Bogyo M, Gaczynska M, Ploegh HL. Proteasome inhibitors and antigen presentation. Biopolymers. 1997;43:269–80.PubMedCrossRefGoogle Scholar
  47. 47.
    Groll M, Koguchi Y, Huber R, et al. Crystal structure of the 20 S proteasome: TMC-95A complex: a non-covalent proteasome inhibitor. J Mol Biol. 2001;511: 545–8.Google Scholar
  48. 48.
    Meng L, Kwok BH, Sin N, et al. Eponemycin exerts its antitumor effect through the inhibition of proteasome function. Cancer Res. 1999;59:2798–801.PubMedGoogle Scholar
  49. 49.
    Fenteany G, Standaert RF, Lane WS, et al. Inhibition of proteasome activities and subunit-specific amino-terminal threonine modification by lactacystin. Science. 1995;268:726–31.PubMedCrossRefGoogle Scholar
  50. 50.
    Kozlowski L, Stoklosa T, Omura S, et al. Lactacystin inhibits cathepsin A activity in melanoma cell lines. Tumour Biol. 2001; 22:211–5.PubMedCrossRefGoogle Scholar
  51. 51.
    Kisselev AF, Goldberg AL. Proteasome inhibitors: from research tools to drug candidates. Chem Biol. 2001;8:739–58.PubMedCrossRefGoogle Scholar
  52. 52.
    Aghajanian C, Soignet S, Dizon DS, et al. A phase 1 trial of the novel proteasome inhibitor PS341 in advanced solid tumor malignancies. Clin Cancer Res. 2002;8:2505–11.PubMedGoogle Scholar
  53. 53.
    Papandreou CN, Daliani DD, Nix D, et al. Phase I trial of the proleasome inhibitor bortezomib in patients with advanced solid tumors with observations in androgen-independent prostate cancer. J Clin Oncol. 2004;22:2108–21.PubMedCrossRefGoogle Scholar
  54. 54.
    Orlowski RZ, Stinchcombe TE, Mitchell BS, et al. Phase 1 trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin Oncol. 2002;20:4420–7.PubMedCrossRefGoogle Scholar
  55. 55.
    Cortes J, Thomas D, Koller C, et al. Phase I study of bortezomib in refractory or relapsed acute leukemias. Clin Cancer Res. 2004;348:2609–17.Google Scholar
  56. 57.
    Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myetoma. N Engl J Med. 2005;352:2487–98.PubMedCrossRefGoogle Scholar
  57. 58.
    Oakervee HE, Popat R, Curry N, et al. PAD combination therapy (PS-341/bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myeloma. Br J Haematol. 2005;129: 755–62.PubMedCrossRefGoogle Scholar
  58. 59.
    Jagannath S, Durie BG, Wolf J, et al. Bortezomib therapy alone and in combination with dexamethasone for previously untreated symptomatic multiple myeloma. Br J Haematol. 2005;129:776–85.PubMedCrossRefGoogle Scholar
  59. 60.
    Goy A, Younes A, McLaughlin P, et al. Phase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin's lymphoma. J Clin Oncol. 2005;25:667–75.CrossRefGoogle Scholar
  60. 61.
    O'Connor OA. Marked clinical activity of the proteasome inhibitor bortezomib in patients with follicular and mantle-cell lymphoma. Clin Lymphoma Myeloma. 2005; 6:191–9.PubMedCrossRefGoogle Scholar
  61. 62.
    Davis NB, Taber DA, Ansari RH, et al. Phase II trial of PS-541 in patients with renal cell cancer: a University of Chicago phase II consortium study. J Clin Oncol. 2004;22:115–9.PubMedCrossRefGoogle Scholar
  62. 63.
    Kondagunta GV, Drucker B, Schwartz L, et al. Phase II trial of bortezomib for patients with advanced renal cell carcinoma. J Clin Oncol. 2004;22:3720–5.PubMedCrossRefGoogle Scholar
  63. 64.
    Stevenson JP, Nho CW, Johnson SW, et al. Effects of bortezomib (PS-541) of NF-κB activation in peripheral blood mononuclear cells (PBMCs) of advanced nonsmall lung cancer (NSCLC) patients: A phase II/pharmacodynamic trial. Proc Am Soc Clin Oncol. 2004; abstr. 7145.Google Scholar
  64. 65.
    Albanell J, Baselga J, Guix M, et al. Phase I study of bortezomib in combination with docetaxel in anthracycline-pretreated advanced breast cancer. Proc Am Soc Clin Oncol. 2003; abstr. 63.Google Scholar
  65. 66.
    Codony-Servat J, Tapia MA, Bosch M, et al. Differential cellular and molecular effects of bortezomib, a proteasome inhibitor, in human breast cancer cells. Mol Cancer Ther. 2006;5:665–75.PubMedCrossRefGoogle Scholar

Copyright information

© FESEO 2006

Authors and Affiliations

  1. 1.Medical Oncology Department & Experimental Cancer Therapeutics Unit (URTEC)Hospital del MarBarcelonaSpain

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