Carcinogenesis Advance Access published online on June 24, 2004
Carcinogenesis, doi:10.1093/carcin/bgh211
© 2004 by Oxford University Press
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1 Department of Pharmacology, College of Medicine, National Taiwan University, Taipei 10018, Taiwan
* To whom correspondence should be addressed. E-mail: ccchen{at}ha.mc.ntu.edu.tw.
The transcription factor NF-
Revised May 20, 2004
Accepted June 6, 2004
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
Inhibition of ICAM-1 gene expression, monocyte adhesion, and cancer cell invasion by targeting IKK complex: molecular and functional study of novel
-methylene-
-butyrolactone derivatives
2 School of Chemistry, Kaohsiung Medical University, Kaohsiung, Taiwan
Abstract 
B is a regulator related to cellular inflammation, immune responses and carcinogenesis. Therefore, components of the NF-B-activating singnaling pathways are frequent targets for the anti-inflammatory and anti-cancer agents. In this study, CYL-19s and CYL-26z, two synthetic 
-methylene-
-butyrolactone derivatives, were shown to inhibit the TNF--induced intercellular adhesion molecule-1 (ICAM-1) expression in human A549 alveolar epithelial cells and the adhesion of U937 cells to these cells. RT-PCR analysis also demonstrated their inhibitory effects on TNF--induced ICAM-1 mRNA expression. TNF--induced ICAM-1 and NF-B-dependent promoter activities were attenuated by CYL-19s and CYL-26z. ICAM-1 promoter activities induced by the overexpression of wild-type NF-B-inducing kinase (NIK) and IB kinase 
(IKK) were also inhibited by both compounds. Furthermore, CYL-19s and CYL-26z inhibited the TNF--induced phosphorylation and degradation of IB and NF-B specific DNA-protein binding activity via targeting IKK complex directly, without any effect on the activations of other kinases such as ERK1/2 and p38. In addition to ICAM-1 expression, CYL-19s and CYL-26z also suppressed other NF-B-mediated gene expressions such as matrix metalloproteinase-9 (MMP-9) mRNA and cyclooxygnease-2 (COX-2) protein. In Matrigel assays, ICAM-1 and COX-2 expressions induced by TNF- elicited A549 and NCI-H292 cell invasion respectively, and these effects were inhibited by both compounds. In summary, our data demonstrated that CYL-19s and CYL-26z down-regulate the TNF--induced inflammatory genes expression through suppression of IKK activity and NF-B activation. These agents may be effective in the anti-inflammatory and anti-cancer therapy.-methylene--butyrolactone; COX; ICAM-1; MMP-9; TNF-; NF-B.
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