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The ubiquitin–proteasome system as a molecular target in solid tumors: an update on bortezomib

By A Milano, F Perri and F Caponigro


The ubiquitin–proteasome system has become a promising molecular target in cancer therapy due to its critical role in cellular protein degradation, interaction with cell cycle and apoptosis regulation, and unique mechanism of action. Bortezomib (PS-341) is a potent and specific reversible proteasome inhibitor, which has shown strong in vitro antitumor activity as single agent and in combination with other cytotoxic drugs in a broad spectrum of hematological and solid malignancies. In preclinical studies, bortezomib induced apoptosis of malignant cells through the inhibition of NF-|B and stabilization of pro-apoptotic proteins. Bortezomib also promotes chemo- and radiosensitization of malignant cells in vitro and inhibits tumor growth in murine xenograft models. The proteasome has been established as a relevant target in hematologic malignancies and bortezomib has been approved for the treatment of multiple myeloma. This review summarizes recent data from clinical trials in solid tumors

Topics: Review
Publisher: Dove Medical Press
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Provided by: PubMed Central

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  1. 26S proteasome inhibition induces apoptosis and limits growth of human pancreatic cancer.
  2. A Multicenter phase II study of bortezomib in recurrent or metastatic sarcomas.
  3. A phase 2 study of bortezomib in relapsed, refractory myeloma.
  4. A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma.
  5. A phase I and pharmacologic trial of two schedules of the proteasome inhibitor, PS-341 (Bortezomib, Velcade), in patients with advanced cancer. Clin Cancer Res.
  6. A phase I study of bortezomib plus irinotecan in patients with advanced solid tumors.
  7. A phase II study of bortezomib in the treatment of metastatic malignant melanoma.
  8. (2004). A phase II study of the proteasome inhibitor PS-341 in patients (pts) with metastatic breast cancer (MBC). J Clin Oncol.
  9. (2004). A phase II trial of the proteasome inhibitor PS-341 in patients with metastatic colorectal cancer. J Clin Oncol.
  10. An EORTC phase I study of Bortezomib in combination with oxaliplatin, leucovorin and 5-fluorouracil in patients with advanced colorectal cancer.
  11. Back to the future with ubiquitin.
  12. Bortezomib (VELCADE) in metastatic breast cancer: pharmacodynamics, biological effects, and prediction of clinical benefits.
  13. (2007). Bortezomib for the treatment of mantle cell lymphoma. Clin Cancer Res.
  14. Bortezomib or highdose dexamethasone for relapsed multiple myeloma.
  15. (2006). Can NF-κB be a target for novel and efficient anti-cancer agents? Biochem Pharmacol.
  16. (2001). Chemosensitization of pancreatic caner by inhibition of the 26S proteasome. J Surg Res.
  17. (1999). Decreased resistance to gemcitabine (2’,2’-difluorodeoxycytidine) of cytosinearabinosideresistant myeloblastic murine and rat leukaemia cell lines: role of altered activity and substrate specificity of deoxycytidine kinase. Biochem Pharmaco.
  18. (2003). Differential effects of the proteasome inhibitor bortezomib on apoptosis and angiogenesis in human prostate tumor xenografts. Mol Cancer Ther.
  19. Enhanced chemosensitivity to CPT-11 with proteasome inhibitor PS-341: implications for systemic nuclear factor-kappaB inhibition. Cancer Res.
  20. Enhancement of radiosensitivity by proteasome inhibition; implications for a role of NF-kappaB.
  21. (2007). Epidermal growth factor receptor inhibition sensitizes renal cell carcinoma cells to the cytotoxic effects of bortezomib. Mol Cancer Ther.
  22. (2002). Ethanol withdrawal induced CYP2E1 degradation in vivo, blocked by proteasomal inhibitor PS-341. Free Radic Biol Med.
  23. (2002). NF-kappaB in cancer: from innocent bystander to major culprit. Nat Rev Cancer.
  24. Phase I clinical trial of bortezomib in combination with gemcitabine in patients with advanced solid tumors.
  25. (2008). Phase I of fixed-dose-rate gemcitabine in combination with bortezomib in patients with advanced solid tumors. J Clin Oncol.
  26. (2004). Phase I study of PS-341 (bortezomib) with 5-fluorouracil/leucovorin (5-FU/LV) in advanced solid tumors: A California Cancer Consortium study. J Clin Oncol.
  27. (2005). Phase I trial of bortezomib (Velcade) in combination with paclitaxel in advanced solid tumor patients (pts). J Clin Oncol.
  28. (2008). Phase I trial of bortezomib (velcade), cisplatin and radiotherapy for advanced head and neck cancer. J Clin Oncol.
  29. (2006). Phase I trial of bortezomib in combination with docetaxel in patienrts with advanced solid tumors. Clin Cancer Res.
  30. Phase I trial of the proteasome inhibitor bortezomib in patients with advanced solid tumors with observation in androgen-independent prostate cancer.
  31. (2004). Phase I/II trial of bortezomib in patients with unresectable hepatocellular carcinoma (HCC). J Clin Oncol.
  32. (2004). Phase II Study of the proteasome inhibitor bortezomib (PS-341) in patients with metastatic neuroendocrine tumors. Clin Cancer Res.
  33. Phase II trial of bortezomib for patients with advanced renal cell carcinoma.
  34. Phase II trial of PS-341 in patients with renal cell cancer: A University of Chicago phase II Consortium Study.
  35. Protease inhibitor-induced apoptosis: Accumulation of wt p53, p21WAF1/CIP1, and induction of apoptosis are independent markers of proteasome inhibition.
  36. (2008). Proteasome inhibition activates epidermal growth factor receptor (EGFR) and EGFR-independent mitogenic kinase signaling pathways in pancreatic cancer cells. Clin Cancer Res.
  37. Proteasome inhibition and its clinical prospects in the treatment of hematologic and solid malignancies.
  38. Proteasome inhibitors as therapeutic agents: current and future strategies. Curr Med Chem.
  39. (1999). Proteolytic degradation of heme-modified hepatic cytochromes P450: A role for phosphorylation, ubiquitination, and the 26S proteasome? Arch Biochem Biophys.
  40. (2005). PS-341 and gemcitabine in patients with metastatic pancreatic adenocarcinoma: a North Central Cancer Treatment Group (NCCTG) randomized phase II study. Ann Oncol.
  41. Putting the rap on Akt.
  42. Randomized phase II study of Bortezomib alone and bortezomib in combination with docetaxel in previously treated advanced non–small-cell lung cancer.
  43. (1998). Role of the proteasome and NF-kappaB in streptococcal cell wall-induced polyarthritis.
  44. (1995). Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation.
  45. (2000). The 26S proteasome is required for estrogen receptor-alpha and coactivator turnover and for efficient estrogen receptor-alpha transactivation. Mol Cell.
  46. (2006). The proteasome and proteasome inhibitors in cancer therapy Annu Rev Pharmacol Toxicol.
  47. (2003). The proteasome inhibitor PS-341 markedly enhances sensitivity of multiple myeloma tumor cells to chemotherapeutic agents. Clin Cancer Res.
  48. (2004). The proteasome inhibitor, bortezomib, in combination with gemcitabine (Gem) and carboplatin (Carbo) in advanced non-small cell lung cancer (NSCLC): Final results of a phase I California Cancer Consortium study. J Clin Oncol.
  49. (1998). The proteasome is involved in angiogenesis. Biochem Biophys Res Commun.
  50. (2003). The proteasome structure, function, and role in the cell. Cancer Treat Rev.
  51. The proteasome: a worthwhile target for the treatment of solid tumor?
  52. The proteasome: structure, function, and role in the cell.
  53. The stabilization mechanism of mutant-type p53 by impaired ubiquitination:
  54. The Ubiquitin Proteasome Pathway from Bench to Bedside. Hematology Am Soc Hematol Educ Program.
  55. (1998). The ubiquitin-proteasome pathway: the complexity and myriad functions of proteins death.
  56. (2002). The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev.
  57. (1996). TNF- and cancer therapyinduced apoptosis: potentiation by inhibition of NFkappa B.