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

Lookup NU author(s): Dr Anastasia Hepburn, Professor Craig Robson, Professor Nicola Curtin

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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 μM, CDK1 IC50 = 26 μM), 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 μM) and CWR22Rv1 (GI50 = 46 μM) showed similar sensitivity to NU2058 (GI50 = 10-17 μM) compared to androgen-sensitive LNCaP cells (GI50 = 15 μM). 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 = 6 ± 3 μM Casodex) but not in LNCaP-cdxR cells (GI50 = 24 ± 5 μM Casodex). © 2007 Nature Publishing Group All rights reserved.


Publication metadata

Author(s): Rigas AC, Robson CN, Curtin NJ

Publication type: Article

Publication status: Published

Journal: Oncogene

Year: 2007

Volume: 26

Issue: 55

Pages: 7611-7619

ISSN (print): 0950-9232

ISSN (electronic): 1476-5594

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/sj.onc.1210586

DOI: 10.1038/sj.onc.1210586

PubMed id: 17599054


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