Antiandrogens are initially effective in controlling prostate cancer (CaP), the second most common cancer in men, but resistance, associated with the loss of androgenregulated 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 ¼ 17 lM, CDK1 IC 50 ¼ 26 lM), 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 ¼ 38 lM) and CWR22Rv1 (GI 50 ¼ 46 lM) showed similar sensitivity to NU2058 (GI 50 ¼ 10-17 lM) compared to androgen-sensitive LNCaP cells (GI 50 ¼ 15 lM). In LNCaP cells and their Casodex-resistant derivative, LNCaP-cdxR, growth inhibition by NU2058 was accompanied by a concentrationdependent 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 ¼ 673 lM Casodex) but not in LNCaP-cdxR cells (GI 50 ¼ 2475 lM Casodex).
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