Pterostilbene Induces Apoptosis and Cell Cycle Arrest in Human Gastric Carcinoma Cells

Abstract

Pterostilbene, an active constituent of blueberries, is known to possess anti-inflammatory activity and also induces apoptosis in various types of cancer cells. Here, the effects of pterostilbene on cell viability in human gastric carcinoma AGS cells were investigated. This study demonstrated that pterostilbene was able to inhibit cell proliferation and induce apoptosis in a concentration- and time-dependent manner. Pterostilbene-induced cell death was characterized with changes in nuclear morphology, DNA fragmentation, and cell morphology. The molecular mechanism of pterostilbene-induced apoptosis was also investigated. The results show the caspase-2, -3, -8, and -9 are all activated by pterostilbene, together with cleavage of the downstream caspase-3 target DNA fragmentation factor (DFF-45) and poly(ADP-riobse) polymerase. Moreover, the results indicate that the Bcl-family of proteins, the mitochondrial pathway, and activation of the caspase cascade are responsible for pterostilbene-induced apoptosis. Pterostilbene markedly enhanced the expression of growth arrest DNA damage-inducible gene 45 and 153 (GADD45 and GADD153) in a time-dependent manner. Flow cytometric analysis indicated that pterostilbene blocked cell cycle progression at G1 phase in a dose- and time-dependent manner. Pterostilbene increased the p53, p21, p27, and p16 proteins and decreased levels of cyclin A, cyclin E, cyclin-dependent kinase 2 (Cdk2), Cdk4, and Cdk6, but the expression of cyclin D1 was not affected. Over a 24 h exposure to pterostilbene, the degree of phosphorylation of Rb was decreased after 6 h. In summary, pterostilbene induced apoptosis in AGS cells through activating the caspase cascade via the mitochondrial and Fas/FasL pathway, GADD expression, and by modifying cell cycle progress and changes in several cycle-regulating proteins. The induction of apoptosis by pterostilbene may provide a pivotal mechanism of the antitumor effects and for treatment of human gastric cancer.

Anti-proliferative effect of pterostilbene on rat hepatoma cells in culture

“…These data suggest that resveratrol inhibits the proliferation of cancer cells through the modification of Cyclin-CDK complexes, Rb protein expression, E2F transcription factors, led to a cell cycle arrest and the inhibition of proliferative activity. Pan et al (2007) investigated the effect of pterostilbene in human gastric carcinoma cells and found that pterostilbene inhibits the cell proliferation and induce apoptosis by the modification of Cyclin-CDK complexes and modifying cell cycle progress similar to that of resveratrol. Pterostilbene increased the p53, p21, p27, and p16 protein levels and decreased the levels of Cyclin A, Cyclin E, CDK2, CDK4, and CDK6.…”

“…These effects were observed in association with the loss of mitotoxic and metastatic potential of MCF-7 cells, which was abolished in the presence of catalase and autophagic inhibitor. Another study on gastric cancer carcinoma showed that pterostilbene causes increased ROS, which altered mitochondrial transmembrane potential, causing release of cytochrome-c, followed by activation of caspase triggering programmed cell death (Pan et al 2007). …”

“…Previous study demonstrated the effect of pterostilbene on several types of cancer such as breast (Chakraborty et al 2012), skin (Ferrer et al 2005), and gastric cancer (Pan et al 2007). Alosi et al (2010) showed that pterostilbene induced a significant concentration-and time-dependent decrease in the breast cancer cell viability.…”

Natural Polyphenols that Display Anticancer Properties through Inhibition of Kinase Activity

“…The most known stilbenoid derivative is trans-resveratrol (16, 3,5,4'-trihydroxystilbene, Table 2), isolated from a large variety of plants and found in the diet as for example in red wine, peanuts, mulberries and grapes [40]. Red wine contains 1.5 to 3.0 mg of resveratrol per 1 L. Trans-pterostilbene (17), another stilbenoid derivative reported to target kinase activity, is shown in Table 2 [41,42].…”

“…Additionally, protein kinase C (PKC) was targeted by this polyphenol as part of the process resulting in the inhibition of oncogene signal transduction [41]. Pterostilbene (17), a natural analogue of resveratrol (16), was reported to induce apoptosis and cell cycle arrest in human gastric carcinoma cells and this anticancer effect was associated with the down-regulation of cyclin-dependent kinase 2 (Cdk2), Cdk4 and Cdk6 [42]. Wilson et al [96] recently reported toxicity towards Caenorhabditis elegans adults for trimethoxylated and dimethoxylated stilbenes, as well as the monomethoxylated stilbene desoxyrhapontigenin.…”