A new IkappaB kinase beta inhibitor prevents human breast cancer progression through negative regulation of cell cycle transition.

Abstract

Constitutive nuclear factor-kappaB (NF-kappaB) activity plays a crucial role in the development and progression of lymphoma, leukemia, and some epithelial cancers. Given the contribution of NF-kappaB 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 IkappaB kinase beta 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-kappaB 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-kappaB may contribute to cell proliferation through up-regulation of cell cycle progression; accordingly, inhibition of NF-kappaB activity might have a therapeutic ability in the treatment of human breast cancers.

• Authors: Akane Tanaka, Susumu Muto, Masayo Konno, Akiko Itai, Hiroshi Matsuda
• Journal: Cancer research (Cancer Res) Vol. 66 Issue 1 Pg. 419-26 (Jan 01 2006) ISSN: 0008-5472 [Print] United States
• PMID: 16397257 (Publication Type: Journal Article)

Chemical References

• Benzamides
• NF-kappa B
• Protein Kinase Inhibitors
• RNA, Messenger
• Transforming Growth Factor beta
• N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide
• I-kappa B Kinase

Topics

• Animals
• Benzamides (pharmacology)
• Breast Neoplasms (drug therapy, enzymology, metabolism, pathology)
• Cell Cycle (drug effects, physiology)
• Cell Line, Tumor
• Disease Progression
• Female
• Humans
• I-kappa B Kinase (antagonists & inhibitors, metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• NF-kappa B (antagonists & inhibitors, metabolism)
• Protein Kinase Inhibitors (pharmacology)
• RNA, Messenger (biosynthesis, genetics)
• Transforming Growth Factor beta (biosynthesis, genetics)
• Xenograft Model Antitumor Assays