title: AD-1, a novel ginsenoside derivative, shows anti-lung cancer activity via activation of p38 MAPK pathway and generation of reactive oxygen species.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  These data support development of AD-1 as a potential agent for lung cancer therapy.
authors.affiliation: Medical College of Zhejiang University, Hangzhou, China.
authors.forename: Lin-Hui
authors.initials: LH
authors.lastname: Zhang
authors.forename: Yong-Liang
authors.initials: YL
authors.lastname: Jia
authors.forename: Xi-Xi
authors.initials: XX
authors.lastname: Lin
authors.forename: Hong-Quan
authors.initials: HQ
authors.lastname: Zhang
authors.forename: Xin-Wei
authors.initials: XW
authors.lastname: Dong
authors.forename: Jun-Ming
authors.initials: JM
authors.lastname: Zhao
authors.forename: Jian
authors.initials: J
authors.lastname: Shen
authors.forename: Hui-Juan
authors.initials: HJ
authors.lastname: Shen
authors.forename: Fen-Fen
authors.initials: FF
authors.lastname: Li
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Yan
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Yu-Qing
authors.initials: YQ
authors.lastname: Zhao
authors.forename: Qiang-Min
authors.initials: QM
authors.lastname: Xie
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D036145:Ginsenosides / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D017382:Reactive Oxygen Species / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000097669:Dammaranes
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D036145:Ginsenosides; D017382:Reactive Oxygen Species; D048051:p38 Mitogen-Activated Protein Kinases; C582879:20(R)-25-methoxyldammarane-3beta,12beta,20-triol; D000097669:Dammaranes