RT Journal Article
SR Electronic
T1 Growth Inhibition of Human Colon Cancer Cells by Nitric Oxide (NO)-Donating Aspirin Is Associated with Cyclooxygenase-2 Induction and β-Catenin/T-Cell Factor Signaling, Nuclear Factor-κB, and NO Synthase 2 Inhibition
JF Cancer Research
JO Cancer Res
FD American Association for Cancer Research
SP 7613
OP 7618
VO 63
IS 22
A1 Williams, Jennie L.
A1 Nath, Niharika
A1 Chen, Jie
A1 Hundley, Thomas R.
A1 Gao, Jianjun
A1 Kopelovich, Levy
A1 Kashfi, Khosrow
A1 Rigas, Basil
YR 2003
UL http://cancerres.aacrjournals.org/content/63/22/7613.abstract
AB Nitric oxide (NO)-releasing aspirin (ASA), consisting of a traditional ASA molecule to which a NO-donating moiety is covalently bound, is a promising colon cancer chemopreventive agent. NO-ASA inhibits colon cancer cell growth more potently than ASA by inhibiting cell proliferation and enhancing cell killing. We examined in cultured human colon cancer cells the effect of NO-ASA on the β-catenin/T-cell factor signaling pathway, nuclear factor-κB, and NO synthase 2 and on cyclooxygenase (COX) expression, all presumed to participate in colon carcinogenesis. Besides inhibiting cell growth, NO-ASA inhibited the β-catenin/T-cell factor signaling pathway (IC50, 1.1 μm), nuclear factor-κB DNA binding (IC50, 7.5 μm), and NO synthase 2 expression (IC50, 2 μm). Interestingly, NO-ASA induced COX-2 expression, although it had no effect on COX-1. COX-2 induction was accompanied by increased prostaglandin E2 production. These effects occurred at NO-ASA concentrations below or near its IC50 for cell growth (IC50, 2–50 μm). The metabolism of NO-ASA by these cells is characterized by a rapid deacetylation step and the formation of a conjugate with glutathione. NO-ASA had no effect on intracellular cyclic GMP concentrations. We propose a model incorporating the pleiotropic effects of NO-ASA on cell signaling and postulate that collectively these effects may contribute to its strong chemopreventive effect. ©2003 American Association for Cancer Research.