Bortezomib treatment of ovarian cancer cells mediates endoplasmic reticulum stress, cell cycle arrest, and apoptosis

Invest New Drugs. 2009 Dec;27(6):543-51. doi: 10.1007/s10637-008-9206-4. Epub 2008 Nov 28.


Bortezomib, an approved drug for the treatment of certain haematological neoplasms, is currently being tested in clinical trials as a potential therapeutic agent against several types of solid cancer, including ovarian cancer. We have analyzed the effect of bortezomib on ovarian cancer cells and tissue explants either as a single agent or in combination with carboplatin, taxol, or TRAIL (tumor necrosis factor-related apoptosis-inducing ligand). Bortezomib alone efficiently induced apoptosis in ovarian cancer cells. Apoptosis was preceded by an upregulation of the endoplasmic reticulum stress sensor ATF3, and increased the expression of cytoplasmic heat shock proteins. Bortezomib enhanced the sensitivity of ovarian cancer cells and tissue explants to an apoptosis-inducing TRAIL receptor antibody by upregulating the TRAIL receptor DR5. In contrast to the synergistic effect observed for TRAIL, the efficacy of the taxol treatment was reduced by bortezomib, and bortezomib inhibited the G2/M phase accumulation of ovarian cancer cells treated with taxol. Bortezomib alone or in combination with taxol induced a cell cycle arrest within the S phase, and downregulation of cdk1, a cyclin-dependent kinase that is necessary for the entry into the M phase. Thus, bortezomib can be regarded as a promising agent for the treatment of ovarian cancer and could either be administered as a single agent or in combination with TRAIL. However, a combination treatment with taxanes may not be beneficial and may even be less effective.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Apoptosis / drug effects*
  • Boronic Acids / pharmacology*
  • Boronic Acids / therapeutic use*
  • Bortezomib
  • CDC2 Protein Kinase / metabolism
  • Cell Cycle Checkpoints / drug effects*
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Endoplasmic Reticulum Stress / drug effects*
  • Female
  • G2 Phase Cell Cycle Checkpoints / drug effects
  • Humans
  • M Phase Cell Cycle Checkpoints / drug effects
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / pathology*
  • Paclitaxel / pharmacology
  • Paclitaxel / therapeutic use
  • Protein Array Analysis
  • Pyrazines / pharmacology*
  • Pyrazines / therapeutic use*
  • Stress, Physiological / drug effects
  • Time Factors
  • Up-Regulation / drug effects


  • Boronic Acids
  • Cell Cycle Proteins
  • Pyrazines
  • Bortezomib
  • CDC2 Protein Kinase
  • Paclitaxel