Pterostilbene inhibited tumor invasion via suppressing multiple signal transduction pathways in human hepatocellular carcinoma cells

Abstract

Pterostilbene, a natural dimethylated analog of resveratrol, is known to have diverse pharmacologic activities including anticancer, anti-inflammation, antioxidant, apoptosis, anti-proliferation and analgesic potential. However, the effects of pterostilbene in preventing invasion of cancer cells have not been studied. Here, we report our finding that pterostilbene significantly suppressed 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced invasion, migration and metastasis of human hepatoma cells (HepG(2) cells). Increase in the enzyme activity, protein and messenger RNA levels of matrix metalloproteinase (MMP)-9 were observed in TPA-treated HepG(2) cells, and these were blocked by pterostilbene. In addition, pterostilbene can inhibit TPA-induced expression of vascular endothelial growth factor, epidermal growth factor and epidermal growth factor receptor. Transient transfection experiments also showed that pterostilbene strongly inhibited TPA-stimulated nuclear factor kappa B (NF-kappaB) and activator protein-1 (AP-1)-dependent transcriptional activity in HepG(2) cells. Moreover, pterostilbene can suppress TPA-induced activation of extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, c-Jun N-terminal kinases 1/2 and phosphatidylinositol 3-kinase/Akt and protein kinase C that are upstream of NF-kappaB and AP-1. Significant therapeutic effects were further demonstrated in vivo by treating nude mice with pterostilbene (50 and 250 mg/kg intraperitoneally) after inoculation with HepG(2) cells into the tail vein. Presented data reveal that pterostilbene is a novel, effective, anti-metastatic agent that functions by downregulating MMP-9 gene expression.

Natural Polyphenols that Display Anticancer Properties through Inhibition of Kinase Activity

“…resveratrol and pterostilbene for example, influence their antioxidative effects, and therefore their potential anticancer activity [97]. Resveratrol and pterostilbene could display distinct anticancer activity through the modulation of distinct signaling pathways [16,[40][41][42]98,99].…”

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

“…Alosi et al (2010) showed that pterostilbene induced a significant concentration-and time-dependent decrease in the breast cancer cell viability. Other studies showed that pterostilbene suppressed multiple signals associated with TPA-induced metastasis (Pan et al 2009) and induced apoptosis (Hasiah et al 2011) on hepatocellular carcinoma cells. The molecular mechanisms of cell cycle arrest by naturally occurring phenolic compounds, such as stilbenes, remain largely unclear but appear to involve modulation of multiple cell cycle regulatory proteins.…”

Pterostilbene induces cell cycle arrest and apoptosis in MOLT4 human leukemia cells

“…However, pterostilbene has greater bioavailability than resveratrol [6], and the results of many studies suggest that it may be a promising chemotherapeutic agent. Pterostilbene has been found to exert antiproliferative and proapoptotic effects in various cancer types, such as lung, gastric and prostate cancer as well as in melanoma, hepatoma and leukemic cell lines [7][8][9][10][11][12]. However, the mechanisms of pterostilbene activity in cancer cell lines have not been fully elucidated.…”

“…Interstingly pterostilbene has been found to induce both apoptosis and autophagy in bladder [13] and breast cancer cells [14]. Pterostilbene inhibited 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced invasion, migration and metastasis of human hepatoma HepG2 cells by the down-regulation of metalloproteinase-9 (MMP-9) gene expression [11]. Moreover, pterostilbene suppressed heregulin-b-mediated cell invasion, motility and cell transformation of MCF-7 human breast carcinoma cells by decreasing the MMP-9 activity [15].…”