Carcinogenesis. 2009 Jul;30(7):1234-42. doi: 10.1093/carcin/bgp121. Epub 2009 May 15.
Pterostilbene inhibited tumor invasion via suppressing multiple signal transduction pathways in human hepatocellular carcinoma cells.
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.
J Agric Food Chem. 2013 May 8;61(18):4326-35. doi: 10.1021/jf4004175. Epub 2013 Apr 24.
Long-term ethanol exposure-induced hepatocellular carcinoma cell migration and invasion through lysyl oxidase activation are attenuated by combined treatment with pterostilbene and curcumin analogues.
Ethanol consumption induces hepatocellular carcinoma (HCC) cell metastasis by changing the extracellular matrix (ECM). Lysyl oxidase (LOX) catalyzes the cross-linkage of collagen or elastin in the ECM. LOX protein and mRNA overexpression (>21-fold compared with controls, n = 6) was detected in cirrhotic HCC patients with a history of alcoholism. LOX protein expression was induced in HCC cells after long-term treatment with ethanol (10 mM) for 20-40 passages (denoted E20-E40 cells). Pterostilbene (PSB, 1 μM) displayed significant potency to reduce LOX-mediated activity in E40 cells when combined with curcumin and its analogues. The ability of E40 cells to form colonies in soft agar was reduced by both genetic depletion of LOX and by chemical inhibitors of LOX expression. This study suggests that targeting LOX expression with food components such as PSB and curcumin may be a novel strategy to overcome ethanol-induced HCC cell metastasis in liver cancer patients.
Nat Prod Commun. 2015 Aug;10(8):1403-8.
In Vitro Safety/Protection Assessment of Resveratrol and Pterostilbene in a Human Hepatoma Cell Line (HepG2).
The aim of this work was to evaluate in vitro the genotoxic and/or antigenotoxic effects of resveratrol (RESV) and pterostilbene (PTER) on HepG2 cells. Moreover, additional tests were performed to evaluate early and late apoptosis events induced by the tested stilbenes. RESV and PTER did not show any genotoxic activity. As regards antigenotoxicity testing, RESV and PTER showed a typical, U-shaped hormetic dose-response relationship characterized by a biphasic trend with small quantities having opposite effects to large ones. HepG2 cells treated with PTER exhibited a marked increase in early apoptosis (40.1%) at 250 microM; whereas, the highest concentration tested for both RESV and PTER significantly increased the proportion of HepG2 cells undergoing late apoptosis (32.5 and 51.2%, respectively). The observed pro-apoptotic activity could, at least in part, explain the hormetic response observed when the compounds were tested for antigenotoxicity (i.e., in the presence of induced DNA damage).
Oncol Rep. 2016 Dec;36(6):3233-3240. doi: 10.3892/or.2016.5151. Epub 2016 Oct 5.
Pterostilbene inhibits hepatocellular carcinoma through p53/SOD2/ROS-mediated mitochondrial apoptosis.
Hepatocellular carcinoma (HCC) is one of the most common malignancies and the second cause of cancer-related deaths around the world. Pterostilbene (PTE), is a natural analog of resveratrol, possessing diverse pharmacological activities. In the present study, we aimed to examine the effect of PTE on tumor growth in mouse models of HCC and to elucidate the possible molecular mechanism in vivo and in vitro. We showed that PTE dose-dependently suppressed tumor growth in mice induced by diethylnitrosamine plus carbon tetrachloride, as evidenced by a decrease in the number of tumors and in the maximum size of the tumors. PTE concentration-dependently inhibited cell viability and proliferation in HepG2 cells. PTE increased caspase-3 activities and apoptosis in liver tumor tissues and cells, indicating the activation of the mitochondrial apoptotic pathway. PFTα, superoxide dismutase 2 (SOD2) lentivirus and N-acetylcysteine (NAC) significantly inhibited PTE-induced inhibition of tumor growth and cell proliferation and increase in apoptosis. PTE dose-dependently increased reactive oxygen species (ROS) levels both in liver tumor tissues and cells, which were inhibited by PFTα, SOD2 lentivirus and NAC. PTE resulted in a significant decrease in SOD2 expression in liver tumor tissues and cells, which were inhibited by PFTα, but not NAC, indicating that PTE-induced ROS generation was attributed to p53-mediated downregulation of SOD2. Collectively, PTE increased p53 expression, decreased SOD2 expression, and resulted in an increase in the ROS levels and the activation of the mitochondrial apoptotic pathway, leading to inhibition of tumor growth and cell proliferation. These data demonstrated that the p53/SOD2/ROS pathway is critical for PTE-mediated inhibition of tumor growth and HCC cell proliferation.