26S proteasome inhibition induces apoptosis and limits growth of human pancreatic cancer

J Cell Biochem. 2001 Apr 2-27;82(1):110-22. doi: 10.1002/jcb.1150.

Abstract

The 26S proteasome degrades proteins that regulate transcription factor activation, cell cycle progression, and apoptosis. In cancer, this may allow for uncontrolled cell division, promoting tumor growth, and spread. We examined whether selective inhibition of the 26S proteasome with PS-341, a dipeptide boronic acid analogue, would block proliferation and induce apoptosis in human pancreatic cancer. Proteasome inhibition significantly blocked mitogen (FCS) induced proliferation of BxPC3 human pancreatic cancer cells in vitro, while arresting cell cycle progression and inducing apoptosis by 24 h. Accumulation of p21(Cip1-Waf-1), a cyclin dependent kinase (CDK) inhibitor normally degraded by the 26S proteasome, occurred by 3 h and correlated with cell cycle arrest. When BxPC3 pancreatic cancer xenografts were established in athymic nu/nu mice, weekly administration of 1 mg/kg PS-341 significantly inhibited tumor growth. Both cellular apoptosis and p21(Cip1-Waf-1) protein levels were increased in PS-341 treated xenografts. Inhibition of tumor xenograft growth was greatest (89%) when PS-341 was combined with the tumoricidal agent CPT-11. Combined CPT-11/PS-341 therapy, but not single agent therapy, yielded highly apoptotic tumors, significantly inhibited tumor cell proliferation, and blocked NF-kappaB activation indicating this systemic therapy was effective at the cancer cell level. 26S proteasome inhibition may represent a new therapeutic approach against this highly resistant and lethal malignancy.

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / pathology
  • Adenocarcinoma / physiopathology
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Boronic Acids / metabolism
  • Boronic Acids / pharmacology*
  • Bortezomib
  • Camptothecin / analogs & derivatives
  • Camptothecin / pharmacology
  • Cell Cycle / drug effects
  • Cell Division / drug effects
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / drug effects*
  • Cyclins / metabolism
  • Dipeptides / metabolism
  • Dipeptides / pharmacology
  • Drug Resistance, Neoplasm
  • Humans
  • Irinotecan
  • Mice
  • Mice, Nude
  • Mitogens / administration & dosage
  • NF-kappa B / antagonists & inhibitors*
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / pathology*
  • Pancreatic Neoplasms / physiopathology
  • Peptide Hydrolases / drug effects*
  • Peptide Hydrolases / metabolism
  • Protease Inhibitors / pharmacology
  • Proteasome Endopeptidase Complex*
  • Pyrazines / metabolism
  • Pyrazines / pharmacology*
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays / methods

Substances

  • Antineoplastic Agents
  • Boronic Acids
  • CDKN1A protein, human
  • Cdkn1a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Dipeptides
  • Mitogens
  • NF-kappa B
  • Protease Inhibitors
  • Pyrazines
  • Bortezomib
  • Irinotecan
  • Peptide Hydrolases
  • Proteasome Endopeptidase Complex
  • ATP dependent 26S protease
  • Camptothecin