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

Abstract
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).
AuthorsA C Rigas, C N Robson, N J Curtin
JournalOncogene (Oncogene) Vol. 26 Issue 55 Pg. 7611-9 (Dec 6 2007) ISSN: 1476-5594 [Electronic] England
PMID17599054 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • 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
Topics
  • 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, 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)

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