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

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 mu M, CDK1 IC50 26 mu 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 (GI(50)=38 mu M) and CWR22Rv1 (GI(50)=46 mu M) showed similar sensitivity to NU2058 (GI(50)=10-17 mu M) compared to androgen-sensitive LNCaP cells (GI(50)=15 mu 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 ( GI(50)=6 +/- 3 mu M Casodex) but not in LNCaP-cdxR cells (GI(50)=24 +/- 5 lM Casodex).