Therapeutic potential of CDK inhibitor NU2058 in androgen-independent prostate cancer

Oncogene. 2007 Dec 6;26(55):7611-9. doi: 10.1038/sj.onc.1210586. Epub 2007 Jun 18.


Antiandrogens are initially effective in controlling prostate cancer (CaP), the second most common cancer in men, but resistance, associated with the loss of androgen-regulated cell cycle control, is a major problem. At present there is no effective treatment for androgen-independent prostate cancer (AIPC). Cellular proliferation is driven by cyclin-dependent kinases (CDKs) with kinase inhibitors (for example, p27) applying the breaks. We present the first investigation of the therapeutic potential of CDK inhibitors, using the guanine-based CDK inhibitor NU2058 (CDK2 IC(50)=17 microM, CDK1 IC(50)=26 microM), in comparison with the antiandrogen bicalutamide (Casodex) in AIPC cells. A panel of AIPC cells was found to be resistant to Casodex-induced growth inhibition, but with the exception of PC3 (GI(50)=38 microM) and CWR22Rv1 (GI(50)=46 microM) showed similar sensitivity to NU2058 (GI(50)=10-17 microM) compared to androgen-sensitive LNCaP cells (GI(50)=15 microM). In LNCaP cells and their Casodex-resistant derivative, LNCaP-cdxR, growth inhibition by NU2058 was accompanied by a concentration-dependent increase in p27 levels, reduced CDK2 activity and pRb phosphorylation, a decrease in early gene expression and G1 cell cycle phase arrest in both cell lines. In response to Casodex, there were similar observations in LNCaP cells (GI(50)=6+/-3 microM Casodex) but not in LNCaP-cdxR cells (GI(50)=24+/-5 microM Casodex).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgens / metabolism
  • Anilides / therapeutic use*
  • CDC2 Protein Kinase / antagonists & inhibitors
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cyclin-Dependent Kinase 2 / antagonists & inhibitors
  • Cyclin-Dependent Kinase Inhibitor p27 / metabolism
  • Cyclin-Dependent Kinases / antagonists & inhibitors*
  • Guanine / analogs & derivatives*
  • Guanine / therapeutic use
  • Humans
  • Male
  • Nitriles / therapeutic use*
  • Phosphorylation / drug effects
  • Prostatic Neoplasms / drug therapy*
  • Protein Kinase Inhibitors / therapeutic use*
  • Retinoblastoma Protein / metabolism
  • Tosyl Compounds / therapeutic use*


  • Androgens
  • Anilides
  • NU2058
  • Nitriles
  • Protein Kinase Inhibitors
  • Retinoblastoma Protein
  • Tosyl Compounds
  • Cyclin-Dependent Kinase Inhibitor p27
  • Guanine
  • bicalutamide
  • CDC2 Protein Kinase
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases