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Growth Inhibition of Human Colon Cancer Cells by Nitric Oxide (NO)-Donating Aspirin Is Associated with Cyclooxygenase-2 Induction and ß-Catenin/T-Cell Factor Signaling, Nuclear Factor-B, and NO Synthase 2 Inhibition

Implications for Chemoprevention

¹ American Health Foundation Cancer Center, Institute for Cancer Prevention, Valhalla, New York;
² Sarah C. Upham Division of Gastroenterology, New York Medical College, Valhalla, New York;
³ Department of Physiology and Pharmacology, City University of New York Medical School, New York, New York;
⁴ Chemoprevention Branch, National Cancer Institute, NIH, Bethesda, Maryland

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 ß-catenin/T-cell factor signaling pathway, nuclear factor-B, and NO synthase 2 and on cyclooxygenase (COX) expression, all presumed to participate in colon carcinogenesis. Besides inhibiting cell growth, NO-ASA inhibited the ß-catenin/T-cell factor signaling pathway (IC₅₀, 1.1 µM), nuclear factor-B 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.

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