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 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).
Rigas
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Northern Institute for Cancer Research, Newcastle University, Framlington Place, Newcastle upon Tyne, UK.
Robson
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Curtin
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NJ
D000728:Androgens / Q000378:metabolism; D000813:Anilides / Q000627:therapeutic use*; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D006147:Guanine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D009570:Nitriles / Q000627:therapeutic use*; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D016160:Retinoblastoma Protein / Q000378:metabolism; D014105:Tosyl Compounds / Q000627:therapeutic use*
D000728:Androgens; D000813:Anilides; C466913:NU2058; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D016160:Retinoblastoma Protein; D014105:Tosyl Compounds; D050760:Cyclin-Dependent Kinase Inhibitor p27; D006147:Guanine; C053541:bicalutamide; D016203:CDC2 Protein Kinase; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases