Pre-clinical evaluation of cyclin-dependent kinase 2 and 1 inhibition in anti-estrogen-sensitive and resistant breast cancer cells

被引：53

作者：

Johnson, N. ^{[1
,2
]}

Bentley, J. ^{[1
]}

Wang, L-Z ^{[1
]}

Newell, D. R. ^{[1
]}

Robson, C. N. ^{[1
]}

Shapiro, G. I. ^{[2
]}

Curtin, N. J. ^{[1
]}

机构：

[1] Newcastle Univ, No Inst Canc Res, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England

[2] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

来源：

BRITISH JOURNAL OF CANCER | 2010年 / 102卷 / 02期

关键词：

breast cancer; CDK; NU2058; NU6102; ANTIESTROGEN RESISTANCE; DNA-DAMAGE; CDK2; P27(KIP1); CYCLIN-DEPENDENT-KINASE-2; PHOSPHORYLATION; CHECKPOINT; TAMOXIFEN; PROTEIN; PURINE;

D O I：

10.1038/sj.bjc.6605479

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 ER alpha transactivation of cyclin D1, resulting in reduced CDK4/6 activity, p27(Kip1)-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. British Journal of Cancer (2010) 102, 342-350. doi:10.1038/sj.bjc.6605479 www.bjcancer.com Published online 15 December 2009 (C) 2010 Cancer Research UK

引用

页码：342 / 350

页数：9

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