Oxidative/nitrosative stress and generation of pro-inflammatory cytokines are hallmarks of inflammation. Since chronic inflammation is implicated in several pathological conditions in humans, including cancers of the colon, anti-inflammatory compounds may be useful chemopreventive agents against colon cancer. We previously showed that pterostilbene (trans-3,5-dimethoxy-4\#8217;-hydroxystilbene), a structural analogue of resveratrol, is present in blueberries and that pterostilbene inhibited expression of certain inflammation-related genes in the colon and suppressed aberrant crypt foci formation in an azoxymethane-induced model of colon carcinogenesis in rats. Here, we examined molecular mechanisms of the anti-inflammatory action of pterostilbene in colon cancer. Treating HT-29 colon cancer cells with a combination of cytokines (tumor necrosis factor-\#945;, interferon-\#947;, and bacterial endotoxin lipopolysaccharide) induced inflammation-related genes such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). The induction of iNOS and COX-2 mRNA and protein was significantly suppressed by treatment with pterostilbene in cultured colon cancer cells. To identify upstream signaling pathways contributing to the anti-inflammatory activity of pterostilbene, we investigated the effect of pterostilbene on multiple signaling pathways including NF-\#954;B, JAK-STAT, ERK, p38, JNK, and PI-3-kinase. Cytokine induction of the p38-ATF2 pathway was significantly inhibited by pterostilbene among the different mediators of signaling evaluated. By silencing the expression of the p38\#945; isoform, there was significant reduction in cytokine induction of iNOS and COX-2. Our data suggest that the p38 MAP kinase cascade is a key signal transduction pathway for eliciting the anti-inflammatory action of pterostilbene in cultured colon cancer cells.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2981.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

American Association for Cancer Research
2009