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Carcinogenesis Advance Access originally published online on January 3, 2008
Carcinogenesis 2008 29(2):390-397; 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, NY 11794-5200, USA

* To whom correspondence should be addressed. Tel: +1 631 632 9035; Fax: +1 631 632 1992; Email: 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 and SW-480), pancreatic (BxPC-3, MIA PaCa-2) and breast (MDA-MB-231 and MCF-7) cancer cell lines, the effect of NO-ASA on NF-{kappa}B activation, determined by electrophoretic mobility shift assays, immunofluorescence and western blot analyses of nuclear proteins. NO-ASA inhibited NF-{kappa}B activation, as early as 30 min 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 with control, NO-ASA decreased NF-{kappa}B activation in intestinal epithelial cells of APCmin+/– mice by 38.4% (P < 0.01). Western blot 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.

Abbreviations: ASA, aspirin; ELISA, enzyme-linked immunosorbent assay; EMSA, electrophoretic mobility shift assay; IHC, immunohistochemistry; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NO-ASA, nitric oxide-donating aspirin; NSAID, non-steroidal anti-inflammatory drug

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


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