Pterostilbene exerts antitumor activity via the Notch1 signaling pathway in human lung adenocarcinoma cells

• Published in: PloS one 2013-05, Vol.8 (5), p.e62652
• Main Authors: Yang, Yang, Yan, Xiaolong, Duan, Weixun, Yan, Juanjuan, Yi, Wei, Liang, Zhenxin, Wang, Ning, Li, Yue, Chen, Wensheng, Yu, Shiqiang, Jin, Zhenxiao, Yi, Dinghua
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Activation; Adenocarcinoma; Adenocarcinoma - drug therapy; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Adenocarcinoma of Lung; AKT protein; Animals; Anticancer properties; Antineoplastic Agents - pharmacology; Antitumor activity; Apoptosis; Biology; Cancer; Cancer therapies; Cell Line, Tumor; Cell Shape; Cell survival; Cell Survival - drug effects; Chemistry; Dipeptides - pharmacology; Drug Resistance, Neoplasm; Drug Synergism; Glutathione; Glutathione - metabolism; Heart surgery; Humans; Immunoglobulins; Inhibitors; Intracellular; Kinases; Leukemia; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lungs; Male; Mammals; Medicine; Membrane potential; Membrane Potential, Mitochondrial - drug effects; Mice; Mice, Nude; Mitochondria; Molecular modelling; Notch protein; Notch1 protein; Oxygen; Pathways; Proto-Oncogene Proteins c-akt - metabolism; Reactive oxygen species; Reactive Oxygen Species - metabolism; Receptor, Notch1 - antagonists & inhibitors; Receptor, Notch1 - genetics; Receptor, Notch1 - metabolism; Secretase; Signal Transduction; Signaling; siRNA; Stilbenes - pharmacology; Survival; Thoracic surgery; Tumor Burden - drug effects; Tumors; Viability; Xenograft Model Antitumor Assays
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0062652

Although pterostilbene (PTE) has been shown to have potent antitumor activities against various cancer types, the molecular mechanisms of these activities remain unclear. In this study, we investigated the antitumor activity of PTE against human lung adenocarcinoma in vitro and in vivo and explored the role of the Notch1 signaling pathway in this process. PTE treatment resulted in a dose- and time-dependent decrease in the viability of A549 cells. Additionally, PTE exhibited strong antitumor activity, as evidenced not only by a reduced mitochondrial membrane potential (MMP) and a decreased intracellular glutathione content but also by increases in the apoptotic index and the level of reactive oxygen species (ROS). Furthermore, PTE treatment induced the activation of the Notch1 Intracellular Domain (NICD) protein and activated Hes1. DAPT (a gamma secretase inhibitor) and Notch1 siRNA prevented the induction of NICD and Hes1 activation by PTE treatment and sensitized the cells to PTE treatment. The down-regulation of Notch signaling also prevented the activation of pro-survival pathways (most notably the PI3K/Akt pathway) after PTE treatment. In summary, lung adenocarcinoma cells may enhance Notch1 activation as a protective mechanism in response to PTE treatment. Combining a gamma secretase inhibitor with PTE treatment may represent a novel approach for treating lung adenocarcinoma by inhibiting the survival pathways of cancer cells.