Carcinogenesis Advance Access originally published online on June 24, 2004
Carcinogenesis 2004 25(10):1925-1934; doi:10.1093/carcin/bgh211
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Carcinogenesis vol.25 no.10 © Oxford University Press 2004; all rights reserved.
ARTICLE |
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
1 Department of Pharmacology, College of Medicine, National Taiwan University, Taipei 10018, Taiwan and 2 School of Chemistry, Kaohsiung Medical University, Kaohsiung, Taiwan
3 To whom correspondence should be addressed Email: ccchen{at}ha.mc.ntu.edu.tw
The transcription factor nuclear factor-kappaB (NF-
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 anticancer agents. In this study, CYL-19 s and CYL-26z, two synthetic 
-methylene-
-butyrolactone derivatives, were shown to inhibit the tumor necrosis factor-alpha (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-19 s and CYL-26z. ICAM-1 promoter activities induced by the over-expression of wild-type NF-B-inducing kinase and IB kinase ß (IKKß) were also inhibited by both compounds. Furthermore, CYL-19 s 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-19 s 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-19 s 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 anticancer therapy.
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