title: Atorvastatin reduces vascular endothelial growth factor (VEGF) expression in human non-small cell lung carcinomas (NSCLCs) via inhibition of reactive oxygen species (ROS) production.
abstract: The high metastatic potential of non-small cell lung cancers (NSCLCs) is closely correlated with the elevated expression of vascular endothelial growth factor (VEGF) and resultant tumor angiogenesis. However, no effective strategies against VEGF expression have been available in NSCLCs therapy. This study demonstrated that elevated reactive oxygen species (ROS) levels derived from both mitochondria and NADPH oxidase were required for VEGF expression in NSCLC cells. Atorvastatin administration could significantly inhibit VEGF expression both in vitro and in vivo via inhibition of ROS production. Atorvastatin inhibited ROS generation partly through suppression of Rac1/NADPH oxidase activity. Specifically, atorvastatin could upregulate the activity of glutathione peroxidase (GPx) and catalase, which are responsible for elimination of hydrogen peroxide (H(2)O(2)) in the mitochondria and peroxisomes, respectively. Thus, inhibition of ROS production by concomitant suppression of Rac1/NADPH oxidase activity and upregulation of the activity of GPx and catalase contributes critically to atorvastatin-reduced VEGF expression in NSCLCs. Atorvastatin may be a potential alternative against VEGF expression and angiogenesis in NSCLCs therapy.
authors.affiliation: Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, and Institute of System Biomedicine, Peking University, Beijing 100191, PR China.
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.forename: Bing
authors.initials: B
authors.lastname: Liu
authors.forename: Jiayi
authors.initials: J
authors.lastname: Yuan
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.forename: Jingjie
authors.initials: J
authors.lastname: Zhang
authors.forename: Yu
authors.initials: Y
authors.lastname: An
authors.forename: Lu
authors.initials: L
authors.lastname: Tie
authors.forename: Yan
authors.initials: Y
authors.lastname: Pan
authors.forename: Xuejun
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000069059:Atorvastatin; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D002374:Catalase / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005979:Glutathione Peroxidase / Q000378:metabolism; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D019255:NADPH Oxidases / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D006538:Heptanoic Acids; D011758:Pyrroles; D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A; D000069059:Atorvastatin; D002374:Catalase; D005979:Glutathione Peroxidase; D019255:NADPH Oxidases; D020830:rac1 GTP-Binding Protein