Resveratrol is a naturally occurring polyphenol with cancer chemopreventive properties. The objective of the current study was to investigate the effect of resveratrol on the human colonic adenocarcinoma cell line Caco-2. The compound inhibited cell growth and proliferation of Caco-2 cells in a dose-dependent manner (12.5-200 micromol/L) as assessed by crystal violet assay, [(3)H]thymidine and [(14)C]leucine incorporation. Furthermore, apoptosis was determined by measuring caspase-3 activity, which increased significantly after 24 and 48 h of treatment with 200 micromol/L resveratrol. Perturbed cell cycle progression from the S to G2 phase was observed for concentrations up to 50 micromol/L, whereas higher concentrations led to reversal of the S phase arrest. These effects were specific for resveratrol; they were not observed after incubation with the stilbene analogs stilbenemethanol and rhapontin. Levels of cyclin D1 and cyclin-dependent kinase (cdk) 4 proteins were decreased, as revealed by immunoblotting. In addition, resveratrol enhanced the expression of cyclin E and cyclin A. The protein levels of cdk2, cdk6 and proliferating cell nuclear antigen were unaffected. Similar results were obtained for the colon carcinoma cell line HCT-116, indicating that cell cycle inhibition by resveratrol is independent of cyclooxygenase inhibition. The phosphorylation state of the retinoblastoma protein in Caco-2 cells was shifted from hyperphosphorylated to hypophosphorylated at 200 micromol/L, which may account for reversal of the S phase block at concentrations exceeding 50 micromol/L. These findings suggest that resveratrol exerts chemopreventive effects on colonic cancer cells by inhibition of the cell cycle.
Piceatannol, a naturally occurring analog of resveratrol, was previously identified as the active ingredient in herbal preparations in folk medicine and as an inhibitor of p72(Syk). We studied the effects of piceatannol on growth, proliferation, differentiation and cell cycle distribution profile of the human colon carcinoma cell line Caco-2. Growth of Caco-2 and HCT-116 cells was analyzed by crystal violet assay, which demonstrated dose- and time-dependent decreases in cell numbers. Treatment of Caco-2 cells with piceatannol reduced proliferation rate. No effect on differentiation was observed. Determination of cell cycle distribution by flow cytometry revealed an accumulation of cells in the S phase. Immunoblotting demonstrated that cyclin-dependent kinases (cdk) 2 and 6, as well as cdc2 were expressed at steady-state levels, whereas cyclin D1, cyclin B1 and cdk 4 were downregulated. The abundance of p27(Kip1) was also reduced, whereas the protein level of cyclin E was enhanced. Cyclin A levels were enhanced only at concentrations up to 100 micromol/L. These changes also were observed in studies with HCT-116 cells. On the basis of our findings, piceatannol can be considered to be a promising chemopreventive or anticancer agent.
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