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

Akane Tanaka, Susumu Muto, Masayo Konno, Akiko Itai, Hiroshi Matsuda
2006 Cancer Research  
Constitutive nuclear factor-KB (NF-KB) activity plays a crucial role in the development and progression of lymphoma, leukemia, and some epithelial cancers. Given the contribution of NF-KB 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 IKB kinase B inhibitor, IMD-0354, suppressed the growth of human breast cancer cells, MDA-MB-231, HMC1-8, and
more » ... 7, by arresting cell cycle and inducing apoptosis. In an electrophoretic mobility shift assay and a reporter assay, IMD-0354 abolished the NF-KB activity in MDA-MB-231 cells in a dose-dependent manner. In the cells incubated with IMD-0354, cell cycle arrested at the G 0 -G 1 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-KB may contribute to cell proliferation through upregulation of cell cycle progression; accordingly, inhibition of NF-KB activity might have a therapeutic ability in the treatment of human breast cancers. (Cancer Res 2006; 66(1): 419-26) Requests for reprints: Hiroshi Matsuda,
doi:10.1158/0008-5472.can-05-0741 pmid:16397257 fatcat:mhwbmf775zfuzpzeyttnbwn3qy