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).