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Carcinogenesis Advance Access published online on January 3, 2008
Carcinogenesis, doi:10.1093/carcin/bgm275
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

NO-donating aspirin inhibits the activation of NF-{kappa}B in human cancer cell lines and Min mice

Jennie L. Williams, Ping Ji, Nengtai Ouyang, Xiaoping Liu and Basil Rigas

Division of Cancer Prevention, Department of Medicine, State University of New York at Stony Brook, Stony Brook, New York 11794-5200

Corresponding author: Basil Rigas, Division of Cancer Prevention, SUNY at Stony Brook, Life Sciences Building, Room 006, Stony Brook, NY 11794-5200, Tel: 631-632-9035; Fax: 631-632-1992; e-mail: basil.rigas{at}stonybrook.edu

Nitric oxide-donating aspirin (NO-ASA) is a promising agent for the control of cancer, whose mechanism of action remains unclear. NF-{kappa}B is an important signaling molecule in the pathogenesis of cancer. We studied in several human colon (HT-29, HCT-15, LoVo, HCT116, SW-480), pancreatic (BxPC-3, MIA PaCa-2) and breast (MDA-MB231, MCF7) cancer cell lines, the effect of NO-ASA on NF-{kappa}B activation, determined by electrophoretic mobility shift assays (EMSAs), immunofluorescence, and Western blot analyses of nuclear proteins. NO-ASA inhibited NF-{kappa}B activation, as early as 30 minutes and with IC50s ranging between 0.83 and 64 µM. Such inhibition was also observed at NO-ASA concentrations that had an insignificant or marginal effect on cell growth. The effect of NO-ASA on NF-{kappa}B binding to DNA was significantly correlated with its effect on cell growth (P<0.05) indicating that the growth inhibitory effect of NO-ASA may be mediated by its effect on NF-{kappa}B. Compared to control, NO-ASA decreased NF-{kappa}B activation in intestinal epithelial cells of APCmin mice by 38.4% (P<0.01). Western and immunofluorescence analyses revealed that the nuclear levels of the p50 and p65 NF-{kappa}B subunits were virtually unaffected, suggesting an inhibitory mechanism different from suppressed subunit translocation into the nucleus. Inhibition of NF-{kappa}B activation by NO-ASA may account, at least in part, for its chemopreventive efficacy.

Received August 3, 2007; revised November 26, 2007; accepted November 26, 2007.


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