title: Gamabufotalin, a bufadienolide compound from toad venom, suppresses COX-2 expression through targeting IKKβ/NF-κB signaling pathway in lung cancer cells.
abstract: BACKGROUND
  Gamabufotalin (CS-6), a major bufadienolide of Chansu, has been used for cancer therapy due to its desirable metabolic stability and less adverse effect. However, the underlying mechanism of CS-6 involved in anti-tumor activity remains poorly understood.
  
  
  METHODS
  The biological functions of gamabufotalin (CS-6) were investigated by migration, colony formation and apoptosis assays in NSCLC cells. The nuclear localization and interaction between transcriptional co-activator p300 and NF-κB p50/p65 and their binding to COX-2 promoter were analyzed after treatment with CS-6. Molecular docking study was used to simulate the interaction of CS-6 with IKKβ. The in vivo anti-tumor efficacy of CS-6 was also analyzed in xenografts nude mice. Western blot was used to detect the protein expression level.
  
  
  RESULTS
  Gamabufotalin (CS-6) strongly suppressed COX-2 expression by inhibiting the phosphorylation of IKKβ via targeting the ATP-binding site, thereby abrogating NF-κB binding and p300 recruitment to COX-2 promoter. In addition, CS-6 induced apoptosis by activating the cytochrome c and caspase-dependent apoptotic pathway. Moreover, CS-6 markedly down-regulated the protein levels of COX-2 and phosphorylated p65 NF-κB in tumor tissues of the xenograft mice, and inhibited tumor weight and size.
  
  
  CONCLUSIONS
  Our study provides pharmacological evidence that CS-6 exhibits potential use in the treatment of COX-2-mediated diseases such as lung cancer.
authors.forename: Zhenlong
authors.initials: Z
authors.lastname: Yu
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.affiliation: Institute of Cancer Stem Cell; College of Pharmacy, Dalian Medical University, Lvshun South Road No 9, Dalian 116044, China. maxc1978@163.com.
authors.forename: Xiaochi
authors.initials: X
authors.lastname: Ma
authors.forename: Baojing
authors.initials: B
authors.lastname: Zhang
authors.forename: Peipei
authors.initials: P
authors.lastname: Dong
authors.forename: Lin
authors.initials: L
authors.lastname: Huang
authors.forename: Xiuli
authors.initials: X
authors.lastname: Wang
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.forename: Xiaokui
authors.initials: X
authors.lastname: Huo
authors.forename: Wendan
authors.initials: W
authors.lastname: Yu
authors.forename: Canhui
authors.initials: C
authors.lastname: Yi
authors.forename: Yao
authors.initials: Y
authors.lastname: Xiao
authors.forename: Wenjing
authors.initials: W
authors.lastname: Yang
authors.forename: Yu
authors.initials: Y
authors.lastname: Qin
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Yuan
authors.forename: Songshu
authors.initials: S
authors.lastname: Meng
authors.forename: Quentin
authors.initials: Q
authors.lastname: Liu
authors.forename: Wuguo
authors.initials: W
authors.lastname: Deng
mesh_terms: D000664:Amphibian Venoms / Q000737:chemistry; D000818:Animals; D002018:Bufanolides / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D009368:Neoplasm Transplantation; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011487:Protein Conformation; D023041:Xenograft Model Antitumor Assays
chemical_list: D000664:Amphibian Venoms; D002018:Bufanolides; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C004600:bufotalin