¹Northern Institute for Cancer Research, Newcastle University, Framlington Place, Newcastle upon Tyne, UK

Correspondence: Professor N Curtin, Northern Institute for Cancer Research, Paul O' Gorman Building, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK. E-mail: n.j.curtin@ncl.ac.uk

Received 11 July 2006; Revised 24 April 2007; Accepted 11 May 2007; Published online 18 June 2007.

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 IC₅₀=17 M, CDK1 IC₅₀=26 M), 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 (GI₅₀=38 M) and CWR22Rv1 (GI₅₀=46 M) showed similar sensitivity to NU2058 (GI₅₀=10–17 M) compared to androgen-sensitive LNCaP cells (GI₅₀=15 M). 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 (GI₅₀=63 M Casodex) but not in LNCaP-cdxR cells (GI₅₀=245 M Casodex).