Pterostilbene inhibits hepatocellular carcinoma through p53/SOD2/ROS-mediated mitochondrial apoptosis

Abstract

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.

Curcumin inhibits superoxide dismutase-induced epithelial-to-mesenchymal transition via the PI3K/Akt/NF-κB pathway in pancreatic cancer cells

“…SOD is one of the primary cellular antioxidants, and it can catalyze the conversion of superoxide anion to H 2 O 2 , which is cleared by catalase (CAT) (13). Due to the cytoprotective effects of SOD, its overexpression has been associated with increased incidence of tumor metastasis (14). In our previous study, we verified that the invasive ability and EMT of pancreatic cancer cells was aggravated by SOD-dependent production of ROS via the extracellular signal-regulated kinase (ERK)/NF-κB signaling pathway (12).…”

Pterostilbene modulates the suppression of multidrug resistance protein�1 and triggers autophagic and apoptotic mechanisms in cisplatin-resistant human oral cancer CAR cells via AKT signaling

“…Previous studies have demonstrated that pterostilbene is an effective antioxidant with anticancer potential, which induces cell death and exhibits anti-metastatic actions ( 16 , 30 , 32 , 34 , 37 ). Furthermore, it has been demonstrated that pterostilbene triggers apoptosis in pancreatic cancer (MIA PaCa-2 and PANC-1) ( 20 , 21 ), breast cancer (MDA-MB-468, MCF-7 and MDA-MB-231) ( 18 , 19 ), lung cancer (LCC, PC9, NCI-H460, SK-MES-1 and A549) ( 22 – 24 , 29 ), osteosarcoma (SOSP-9607) ( 62 ), prostate cancer (PC-3 and LNCaP) ( 25 , 26 ), leukemia (Jurkat, Hut-78, HL60, MOLT4 and K562) ( 37 – 40 ), colon cancer (Colo 205, HCT116 and HT29) ( 27 – 29 ), bladder cancer (T24) ( 30 ), hepatocellular carcinoma (HepG2) ( 35 , 36 ), gastric carcinoma (AGS) ( 31 ) and oral cancer (SAS and OECM-1) ( 32 ) cell lines. In addition, pterostilbene exhibits autophagic effects in various types of cancer ( 29 , 30 , 38 , 39 , 42 ).…”

“…The pharmacological activities of pterostilbene mean that it may be used treat different types of diseases, including cancer, diabetes, inflammation and dyslipidemia ( 13 – 17 ). Studies have also indicated that pterostilbene may exhibit anticancer activity against various types of cancer, including breast ( 18 , 19 ), pancreatic ( 20 , 21 ), lung ( 22 – 24 ), prostate ( 25 , 26 ), colorectal ( 27 – 29 ), bladder ( 30 ), gastric ( 31 ) and oral cancer ( 32 – 34 ), as well as hepatocellular carcinoma ( 35 , 36 ) and leukemia ( 37 – 40 ). The results of in vitro and in vivo studies have demonstrated that pterostilbene induces apoptotic and/or autophagic cell death ( 29 , 32 , 41 , 42 ).…”

Biological Activities of Resveratrol against Cancer

“…In an investigation RSV is reported to reduce ROS production and inhibit cell growth through apoptosis and cell cycle arrest however it also increases iNOS, eNOS and hence increases NOS activity [131]. A recent study revealed that a dimethylated derivative of RSV known as pterostilbene was able to induce caspase-3 and ROS dependent mitochondrial apoptotic pathway which resulted to inhibition of tumor progression in HCC [132]. Study on HCC has discovered that RSV decreased hepatocyte growth factor-induced invasion of HepG2 cell invasion by an unknown mechanism [133].…”