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

Oncogene volume 26, pages 7611–7619 (2007)Cite this article

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 μ M, CDK1 IC50=26 μ 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 (GI50=38 μ M) and CWR22Rv1 (GI50=46 μ M) showed similar sensitivity to NU2058 (GI50=10–17 μ M) compared to androgen-sensitive LNCaP cells (GI50=15 μ 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 (GI50=6±3 μ M Casodex) but not in LNCaP-cdxR cells (GI50=24±5 μ M Casodex).

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Acknowledgements

We thank AICR for financial support, AstraZeneca for Casodex and Professor RJ Griffin (Northern Institute for Cancer Research, School of Natural Sciences-Chemistry, Newcastle University) for NU2058.

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  1. Northern Institute for Cancer Research, Newcastle University, Framlington Place, Newcastle upon Tyne, UK

    A C Rigas, C N Robson & N J Curtin

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  1. A C Rigas
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  2. C N Robson
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  3. N J Curtin
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Correspondence to N J Curtin.

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Rigas, A., Robson, C. & Curtin, N. Therapeutic potential of CDK inhibitor NU2058 in androgen-independent prostate cancer. Oncogene 26, 7611–7619 (2007). https://doi.org/10.1038/sj.onc.1210586

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