AD-1, a novel ginsenoside derivative, shows anti-lung cancer activity via activation of p38 MAPK pathway and generation of reactive oxygen species

• Published in: Biochimica et biophysica acta Vol. 1830; no. 8; pp. 4148 - 4159
• Main Authors: Zhang, Lin-Hui, Jia, Yong-Liang, Lin, Xi-Xi, Zhang, Hong-Quan, Dong, Xin-Wei, Zhao, Jun-Ming, Shen, Jian, Shen, Hui-Juan, Li, Fen-fen, Yan, Xiao-Feng, Li, Wei, Zhao, Yu-Qing, Xie, Qiang-Min
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.08.2013
• Subjects: acetylcysteine; AD-1; Angiogenesis Inhibitors - pharmacology; Animals; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; body weight; Cell cycle; cell cycle checkpoints; Cell Cycle Checkpoints - drug effects; Cell Proliferation - drug effects; cell viability; Cells, Cultured; cytotoxicity; drugs; epithelial cells; flow cytometry; Ginsenoside; Ginsenosides - pharmacology; growth retardation; Humans; immunohistochemistry; Lung cancer; lung neoplasms; Lung Neoplasms - drug therapy; Male; MAP Kinase Signaling System - drug effects; Mice; mitogen-activated protein kinase; neoplasm cells; oral administration; p38 Mitogen-Activated Protein Kinases - metabolism; Panax; phosphorylation; reactive oxygen species; Reactive Oxygen Species - metabolism; signal transduction; Signaling pathway; therapeutics; vascular endothelial growth factors; viability; Western blotting; PBS; 25-OCH3-PPD; VEGF; Lung cancer; MTT; Ginsenoside; MMP; Signaling pathway; ROS; Cell cycle; AD-1; Rg3; MAPKs; ERK; Apoptosis
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2013.04.008

Ginseng is a traditional Chinese herb that has been used for thousands of years. In the present study, effects and mechanisms of AD-1 were evaluated for its development as a novel anti-lung cancer drug. The cytotoxic activity was evaluated by MTT assay. Flow cytometry was employed to detect cell cycle, apoptosis and ROS. Western blot and immunohistochemistry were used to analyze signaling pathways. Lung cancer xenograft models were established by subcutaneous implantation of A549 or H292 cells into nude mice. AD-1 concentration-dependently reduces lung cancer cell viability without affecting normal human lung epithelial cell viability. In A549 and H292 lung cancer cells, AD-1 induces G0/G1 cell cycle arrest, apoptosis and ROS production. The apoptosis can be attenuated by a ROS scavenger — N-acetylcysteine (NAC). In addition, AD-1 up-regulates the expression of p38 and ERK phosphorylation. Addition of a p38 inhibitor SB203580, suppresses the AD-1-induced decrease in cell viability. Furthermore, genetic silencing of p38 attenuates the expression of p38 and decreases the AD-1-induced apoptosis. Treatment with NAC reduces AD-1-induced p38 phosphorylation, which indicates that ROS generation is involved in the AD-1-induced p38 activation. In mice, oral administration of AD-1 (10–40mg/kg) dose-dependently inhibited the growth of xenograft tumors without affecting body weight and decreases the expression of VEGF, MMP-9 and CD34 in tumor tissue. TUNEL staining confirms that the tumors from AD-1 treated mice exhibit a markedly higher apoptotic index. These data support development of AD-1 as a potential agent for lung cancer therapy. •AD-1 extracted from ginseng berry exhibited anti-lung cancer activity.•AD-1 inhibited the tumor cell viability and the growth of xenograft tumors.•AD-1 induced G0/G1 cell cycle arrest and apoptosis.•AD-1 increased in ROS production and p38 expression in A549 cells.•The up-regulation of p38 expression results in enhanced cell apoptosis.