Proteasome inhibition in cancer: development of PS-341

Semin Oncol. 2001 Dec;28(6):613-9. doi: 10.1016/s0093-7754(01)90034-x.


The 26S proteasome regulates protein turnover in eukaryotic cells. This is relevant in human cancer because the cell cycle, tumor growth, and survival are governed by a large repertoire of intracellular proteins that are regulated by the ubiquitin-mediated proteasome degradative pathway. In the development of new antitumor agents whose mechanisms are distinct from currently available therapies, we have discovered a potent, selective inhibitor of the proteasome: PS-341, a dipeptide boronic acid. Compared with normal cells, cancer cells--and specifically myeloma--treated with PS-341 are differentially sensitive to proteasome inhibition and apoptosis. A unique feature of PS-341 involves the inhibition of nuclear factor (NF)-kappaB activation through stabilization of the inhibitor protein IkappaB. Myeloma cells depend on NF-kappaB-mediated transcription of cytokine growth factor interleukin-6, angiogenesis through vascular endothelial growth factor, and the cell adhesion molecule VCAM-1 for adherence of the plasma cells to the stromal tissue in bone marrow. At low nanomolar concentrations, PS-341 is highly effective in abrogating the transcription of these genes, which are under the direct regulation of NF-kappaB. Moreover, PS-341 appears to synergize with dexamethasone in myeloma cell culture, which may prove to be of additional benefit clinically. The safety profile in phase I trials of PS-341 in patients with cancer appears encouraging. Because proteasome inhibition with PS-341 results in potent antitumor activity in vitro, PS-341 may offer a promising new approach to treating otherwise fatal malignancy.

Publication types

  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Boronic Acids / pharmacology*
  • Boronic Acids / therapeutic use
  • Bortezomib
  • Cell Cycle / drug effects
  • Clinical Trials as Topic
  • Cysteine Endopeptidases
  • Drug Screening Assays, Antitumor
  • Hematologic Neoplasms / drug therapy*
  • Humans
  • Multienzyme Complexes / antagonists & inhibitors
  • Multiple Myeloma / drug therapy*
  • Peptide Hydrolases
  • Protease Inhibitors / pharmacology*
  • Protease Inhibitors / therapeutic use
  • Proteasome Endopeptidase Complex
  • Pyrazines / pharmacology*
  • Pyrazines / therapeutic use
  • Structure-Activity Relationship


  • Antineoplastic Agents
  • Boronic Acids
  • Multienzyme Complexes
  • Protease Inhibitors
  • Pyrazines
  • Bortezomib
  • Peptide Hydrolases
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex
  • ATP dependent 26S protease