Abstract 5695: Nitric oxide-donating naproxen inhibits β-catenin-mediated TCF signaling in colorectal cancer cells more effectively than naproxen

Abstract

Results from recent clinical and epidemiological studies continue to suggest that non-steroidal anti-inflammatory drugs (NSAIDs) are promising chemopreventive agents with activity against colorectal cancer. Nitric oxide (NO)-donating NSAIDs represent a novel class of agents that have been reported to have greater safety and higher efficacy in inhibiting the growth of cancer cells than the parent compounds. However, the mechanism of chemopreventive action of NO-NSAIDs is not well elucidated. Dysregulation of the WNT/ β-catenin pathway is one of the earliest events during tumorigenesis in the colon and thus an attractive molecular target for chemopreventive intervention. The major goal of the current study was to compare the effect of naproxen, an NSAID commonly used to reduce pain, fever and inflammation, and NO-naproxen on β-catenin-mediated TCF4 signaling in colon cancer cells. Human SW480 colon carcinoma cells that express mutant APC were transfected with either pGL3 basic plasmid or a luciferase reporter construct under the control of 3 copies of either wild-type (pGL3-OT) or mutated (pGL3-OF) TCF4 regulatory element using LipofectAmine 2000. Cells were treated with 0.01 - 0.4 mM naproxen or NO-naproxen or vehicle (water or DMSO, respectively) and harvested 48 hrs later. Cell lysates were prepared and luciferase activity was measured using the Promega Luciferase Assay kit. The results demonstrate that NO-naproxen reduces β-catenin-mediated TCF4 transcriptional activity in SW480 cells in a dose dependent manner. At a given dose, the luciferase activity of cells exposed to NO-naproxen was approximately 50% of that of cells treated with the parent compound. In conclusion, these data suggest that the chemopreventive activity of NO-naproxen is attributed in part to its ability to inhibit the transcriptional activation of TCF4; a response that is greater than that of the conventional drug naproxen. The availability of a multiple intestinal neoplasia mouse model that, unlike the conventional strain, develops multiple colorectal adenomas provides a unique opportunity to compare the efficacy of these agents against colorectal tumor growth in vivo. Supported by NIH N01 CN43309. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5695.