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A New IB Kinase ß Inhibitor Prevents Human Breast Cancer Progression through Negative Regulation of Cell Cycle Transition

¹ Laboratory of Veterinary Molecular Pathology and Therapeutics, Division of Animal Science, Graduate School, Institute of Symbiotic Science and Technology, Tokyo University of Agriculture and Technology, Fuchu and ² Institute of Medicinal Molecular Design, Inc., Hongo, Tokyo, Japan

Requests for reprints: Hiroshi Matsuda, Laboratory of Veterinary Molecular Pathology and Therapeutics, Division of Animal Science, Graduate School, Institute of Symbiotic Science and Technology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, Japan. Phone: 81-42-367-5784; Fax: 81-42-367-5916; E-mail: hiro{at}cc.tuat.ac.jp.

Constitutive nuclear factor-B (NF-B) activity plays a crucial role in the development and progression of lymphoma, leukemia, and some epithelial cancers. Given the contribution of NF-B in carcinogenesis, a novel approach that interferes with its activity might have therapeutic potential against cancers that respond poorly to conventional treatments. Here, we have shown that a new IB kinase ß inhibitor, IMD-0354, suppressed the growth of human breast cancer cells, MDA-MB-231, HMC1-8, and MCF-7, by arresting cell cycle and inducing apoptosis. In an electrophoretic mobility shift assay and a reporter assay, IMD-0354 abolished the NF-B activity in MDA-MB-231 cells in a dose-dependent manner. In the cells incubated with IMD-0354, cell cycle arrested at the G₀-G₁ phase and apoptotic cells were increased. The expression of some cell cycle regulatory molecules and antiapoptotic molecules was suppressed in cells treated with IMD-0354. On the other hand, cyclin-dependent kinase suppressor p27Kip1 was up-regulated by the addition of IMD-0354. Daily administration of IMD-0354 inhibited tumor expansion in immunodeficient mice into which MDA-MB-231 cells were transplanted. These results indicate that NF-B may contribute to cell proliferation through up-regulation of cell cycle progression; accordingly, inhibition of NF-B activity might have a therapeutic ability in the treatment of human breast cancers. (Cancer Res 2006; 66(1): 419-26)

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