title: Chemoprevention of dietary digitoflavone on colitis-associated colon tumorigenesis through inducing Nrf2 signaling pathway and inhibition of inflammation.
abstract: BACKGROUND
  Nuclear factor-erythroid 2-related factor 2 (Nrf2) has emerged as a novel target for the prevention of colorectal cancer (CRC). Many chemopreventive compounds associated with Nrf2 activation are effective in preclinical systems and many on-going clinical trials are showing promising findings. In present study we evaluated the cytoprotective effect and chemopreventive properties of dietary digitoflavone.
  
  
  METHODS
  A cell based Antioxidant Response Element (ARE)-driven luciferase reporter system was applied to screen potential Nrf2 activators. Activation of Nrf2 by digitoflavone was confirmed through mRNA, protein and GSH level assay in Caco-2 cell line. The cytoprotective effect of digitoflavone was evaluated in H2O2-induced oxidative stress model and further signaling pathways analysis was used to determine the target of digitoflavone induced Nrf2 activation. An AOM-DSS induced colorectal cancer model was used to assess the chemopreventive effect of digitoflavone.
  
  
  RESULTS
  Micromolarity (10 μM) level of digitoflavone increased Nrf2 expressing, nuclear translocation and expression of downstream phase II antioxidant enzymes. Furthermore, digitoflavone decreased H2O2-induced oxidative stress and cell death via p38 MAPK-Nrf2/ARE pathway. In vivo study, 50 mg/kg digitoflavone significantly reduced AOM-DSS induced tumor incidence, number and size.
  
  
  CONCLUSIONS
  These observations suggest that digitoflavone is a novel Nrf2 pathway activator, and protects against oxidative stress-induced cell injury. The results of the present study add further evidence of the molecular mechanisms that allow digitoflavone to exert protective effects and reaffirm its potential role as a chemopreventive agent in colorectal carcinogenesis.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Xueting
authors.initials: X
authors.lastname: Cai
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Sun
authors.forename: Chunping
authors.initials: C
authors.lastname: Hu
authors.forename: Zhanpeng
authors.initials: Z
authors.lastname: Yan
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Xu
authors.forename: Wuguang
authors.initials: W
authors.lastname: Lu
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Wang
authors.affiliation: Laboratory of Cellular and Molecular Biology, Jiangsu Province Institute of Traditional Chinese Medicine, 100#, Shizi Street, Hongshan Road, Nanjing 210028, Jiangsu, China. pcao79@yahoo.com.
authors.forename: Peng
authors.initials: P
authors.lastname: Cao
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D015153:Blotting, Western; D018938:Caco-2 Cells; D063646:Carcinogenesis / Q000187:drug effects*; D018890:Chemoprevention; D003092:Colitis / Q000473:pathology; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000517:prevention & control; D004032:Diet; D047309:Flavones / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D057809:HEK293 Cells; D019073:HT29 Cells; D056945:Hep G2 Cells; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D047309:Flavones; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D017382:Reactive Oxygen Species