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-alpha, IFN-gamma, 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-kappaB, Janus-activated
kinase-signal transducer and activator of transcription,
extracellular signal-regulated kinase, p38, c-Jun NH(2)-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 alpha
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.