NO-donating aspirin inhibits the activation of NF-kappaB in human cancer cell lines and Min mice.

Abstract

Nitric oxide-donating aspirin (NO-ASA) is a promising agent for the control of cancer, whose mechanism of action remains unclear. NF-kappaB 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-kappaB activation, determined by electrophoretic mobility shift assays, immunofluorescence and western blot analyses of nuclear proteins. NO-ASA inhibited NF-kappaB activation, as early as 30 min and with IC(50)s ranging between 0.83 and 64 microM. 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-kappaB 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-kappaB. Compared with control, NO-ASA decreased NF-kappaB activation in intestinal epithelial cells of APC(min+/-) mice by 38.4% (P < 0.01). Western blot and immunofluorescence analyses revealed that the nuclear levels of the p50 and p65 NF-kappaB subunits were virtually unaffected, suggesting an inhibitory mechanism different from suppressed subunit translocation into the nucleus. Inhibition of NF-kappaB activation by NO-ASA may account, at least in part, for its chemopreventive efficacy.

• Authors: Jennie L Williams, Ping Ji, Nengtai Ouyang, Xiaoping Liu, Basil Rigas
• Journal: Carcinogenesis (Carcinogenesis) Vol. 29 Issue 2 Pg. 390-7 (Feb 2008) ISSN: 1460-2180 [Electronic] England
• PMID: 18174252 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antineoplastic Agents
• NF-kappa B
• NF-kappa B p50 Subunit
• Transcription Factor RelA
• Nitric Oxide
• Aspirin

Topics

• Adenocarcinoma (metabolism)
• Animals
• Antineoplastic Agents (pharmacology)
• Aspirin (pharmacology)
• Cell Line, Tumor
• Cell Proliferation
• Female
• Humans
• Kinetics
• Mice
• Mice, Transgenic
• NF-kappa B (metabolism)
• NF-kappa B p50 Subunit (metabolism)
• Nitric Oxide
• Transcription Factor RelA (metabolism)