Bortezomib inhibits docetaxel-induced apoptosis via a p21-dependent mechanism in human prostate cancer cells

Mol Cancer Ther. 2006 Aug;5(8):2043-50. doi: 10.1158/1535-7163.MCT-05-0437.

Abstract

Bortezomib (PS-341, Velcade) is a peptide boronate inhibitor of the 20S proteasome that is currently being combined with taxanes in several clinical trials in patients with prostate cancer. Here, we report that bortezomib inhibited docetaxel-induced M-phase arrest and apoptosis in androgen-dependent LNCaP-Pro5 cells. Direct analysis of kinase activity in immune complex kinase assays revealed that docetaxel activated cyclin-dependent kinase (CDK) 1 (CDC2) and that bortezomib blocked this activation. The effects of bortezomib were associated with accumulation of p21 and mimicked by chemical CDK inhibitors or by transfecting cells with a small interfering RNA construct specific for CDK1. Transient transfection with p21 also inhibited docetaxel-induced apoptosis; conversely, p21 silencing reversed the antagonistic effects of bortezomib on docetaxel-induced apoptosis. Together, our data show that bortezomib interferes with docetaxel-induced apoptosis via a p21-dependent mechanism that is associated with CDK1 inhibition. These observations may have important implications for the ongoing bortezomib-docetaxel combination trials as well as trials using bortezomib and other cell cycle-sensitive agents.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Boronic Acids / pharmacology*
  • Bortezomib
  • CDC2 Protein Kinase / drug effects
  • CDC2 Protein Kinase / metabolism
  • Cell Division / drug effects
  • Cell Proliferation / drug effects
  • Cyclin-Dependent Kinase Inhibitor p21 / drug effects
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
  • Docetaxel
  • Humans
  • Male
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / pathology
  • Pyrazines / pharmacology*
  • Taxoids / pharmacology*
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Boronic Acids
  • Cyclin-Dependent Kinase Inhibitor p21
  • Pyrazines
  • Taxoids
  • Docetaxel
  • Bortezomib
  • CDC2 Protein Kinase