Pre-clinical evaluation of cyclin-dependent kinase 2 and 1 inhibition in anti-estrogen-sensitive and resistant breast cancer cells
| Autor: | J Bentley, Lan Z. Wang, Johnson N, Craig N. Robson, Nicola J. Curtin, David R. Newell, Geoffrey I. Shapiro |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Cancer Research
medicine.medical_specialty CDK NU2058 Antineoplastic Agents Breast Neoplasms 03 medical and health sciences breast cancer 0302 clinical medicine Breast cancer Estrogen Receptor Modulators Cyclin-dependent kinase Cell Line Tumor Internal medicine CDC2 Protein Kinase Humans Medicine Protein Kinase Inhibitors Cell Proliferation 030304 developmental biology 0303 health sciences biology business.industry Kinase Cell Cycle Cyclin-Dependent Kinase 2 Cyclin-dependent kinase 2 Cancer Cell cycle medicine.disease 3. Good health Endocrinology Oncology NU6102 030220 oncology & carcinogenesis Cancer research biology.protein Female Breast disease biological phenomena cell phenomena and immunity Translational Therapeutics business |
| Zdroj: | British Journal of Cancer |
| ISSN: | 1532-1827 0007-0920 |
| DOI: | 10.1038/sj.bjc.6605479 |
| Popis: | Background: Cellular proliferation, driven by cyclin-dependent kinases (CDKs) and their cyclin partners, is deregulated in cancer. Anti-estrogens, such as tamoxifen, antagonise estrogen-induced ERα transactivation of cyclin D1, resulting in reduced CDK4/6 activity, p27Kip1-mediated inhibition of CDK2 and growth arrest. We hypothesised that direct inhibition of CDK2 and CDK1 may overcome the major clinical problem of anti-estrogen resistance. Methods: The cellular effects of CDK2/1 siRNA knockdown and purine-based CDK2/1 inhibitors, NU2058 and NU6102, were measured in anti-estrogen-sensitive and resistant breast cancer cell lines. Results: CDK2 knockdown caused G1 accumulation, whereas CDK1 depletion caused G2/M slowing, and dual CDK1/2 depletion resulted in further G2/M accumulation and cell death in both anti-estrogen-sensitive and resistant cells, confirming CDK2 and CDK1 as targets for breast cancer therapy. In contrast to tamoxifen, which only affected hormone-sensitive cells, NU2058 and NU6102 reduced CDK2-mediated phosphorylation of pRb, E2F transcriptional activity and proliferation, ultimately resulting in cell death, in both anti-estrogen-sensitive and resistant cells. Both drugs caused G2/M arrest, reflective of combined CDK2/1 knockdown, with a variable degree of G1 accumulation. Conclusion: These studies confirm the therapeutic potential of CDK2 and CDK1 inhibitors for cancer therapy, and support their use as an alternative treatment for endocrine-resistant breast cancer. |
| Databáze: | OpenAIRE |
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