This Article Full Text Full Text (PDF) All Versions of this Article: 1940-6207.CAPR-08-0224v1 2/7/650    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Paul, S. Articles by Suh, N. PubMed PubMed Citation Articles by Paul, S. Articles by Suh, N. Related Collections Preclinical Intervention Preclinical Intervention: In Vitro: Drugs, Mechanisms

Anti-inflammatory Action of Pterostilbene Is Mediated through the p38 Mitogen-Activated Protein Kinase Pathway in Colon Cancer Cells

Authors' Affiliations: ¹ Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey; ² United States Department of Agriculture, Agricultural Research Service, Natural Products Utilization Research Unit, University of Mississippi; and ³ The Cancer Institute of New Jersey, New Brunswick, New Jersey

Requests for reprints: Nanjoo Suh, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, NJ 08854. Phone: 732-445-3400, ext. 226; Fax: 732-445-0687; E-mail: nsuh{at}rci.rutgers.edu.

Oxidative/nitrosative stress and generation of proinflammatory cytokines are hallmarks of inflammation. Because chronic inflammation is implicated in several pathologic conditions in humans, including cancers of the colon, anti-inflammatory compounds may be useful chemopreventive agents against colon cancer. Stilbenes, such as resveratrol, have diverse pharmacologic activities, which include anti-inflammation, cancer prevention, a cholesterol-lowering effect, enhanced insulin sensitivity, and increased life span. We previously showed that pterostilbene (trans-3,5-dimethoxy-4'-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 rats. Here, we examined molecular mechanisms of the action of pterostilbene in colon cancer. Pterostilbene reduced cell proliferation, down-regulated the expression of c-Myc and cyclin D1, and increased the level of cleaved poly(ADP-ribose) polymerase. A combination of cytokines (tumor necrosis factor-, IFN-, and bacterial endotoxin lipopolysaccharide) induced inflammation-related genes such as inducible nitric oxide synthase and cyclooxygenase-2, which was significantly suppressed by treatment with pterostilbene. We further identified upstream signaling pathways contributing to the anti-inflammatory activity of pterostilbene by investigating multiple signaling pathways, including nuclear factor-B, Janus-activated kinase-signal transducer and activator of transcription, extracellular signal-regulated kinase, p38, c-Jun NH₂-terminal kinase, and phosphatidylinositol 3-kinase. Cytokine induction of the p38-activating transcription factor 2 pathway was markedly inhibited by pterostilbene among the different mediators of signaling evaluated. By silencing the expression of the p38 isoform, there was significant reduction in cytokine induction of inducible nitric oxide synthase and cyclooxygenase-2. Our data suggest that the p38 mitogen-activated protein kinase cascade is a key signal transduction pathway for eliciting the anti-inflammatory action of pterostilbene in cultured HT-29 colon cancer cells.

Key Words: pterostilbene • colon cancer • inflammation • inducible nitric oxide synthase • cyclooxygenase-2 • p38