title: Wogonin induced cytotoxicity in human hepatocellular carcinoma cells by activation of unfolded protein response and inactivation of AKT.
abstract: OBJECTIVE
  To investigate the potential anticancer effects of the natural flavonoid wogonin on human hepatocellular carcinoma (HCC) cells and tumor xenografts and the contribution of the unfolded protein response (UPR) and AKT pathways to the cytotoxicity of wogonin.
  
  
  METHODS
  The HCC cell lines HepG2, SMMC-7721 and Hep3B were treated with wogonin. 3-(4 5-Dimethylthiazol-2-yl)-2 5-diphenyltetrazolium bromide assays were used to evaluate the cell viability. Flow cytometry assays were used to identify the cell death types and measure the concentrations of intracellular H2 O2 and Ca(2+) . Western blotting assays were used to detect the protein expression levels of members in the UPR and AKT pathways. Relative quantitative real-time polymerase chain reaction assays were used to analysis the mRNA expression levels of chop and trb3. Furthermore, the male BALB/c nude mice with SMMC-7721 xenografts were treated with wogonin. The tumor volume, tumor weight and bodyweight were monitored during the tumorigenicity assays.
  
  
  RESULTS
  Wogonin significantly inhibited the viability of HCC cells by inducing apoptosis and necrosis. This cytotoxicity was at least partially attributed to the activation of the UPR pathway and consequent inactivation of AKT signaling, which resulted from the production of intracellular H2 O2 and causal release of endoplasmic reticulum Ca(2+) . Moreover, wogonin evidently repressed the growth of xenografts but slightly influenced the bodyweight of mice.
  
  
  CONCLUSIONS
  Wogonin is a prospect for improving the systemic chemotherapy strategy on HCC by concurrently rectifying the aberrant UPR and AKT signaling pathways, which are crucial to the biology of HCC.
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University.
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.forename: Na
authors.initials: N
authors.lastname: Lu
authors.forename: Haiwei
authors.initials: H
authors.lastname: Zhang
authors.forename: Qinsheng
authors.initials: Q
authors.lastname: Dai
authors.forename: Libin
authors.initials: L
authors.lastname: Wei
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Li
authors.forename: Qidong
authors.initials: Q
authors.lastname: You
authors.forename: Qinglong
authors.initials: Q
authors.lastname: Guo
keywords: AKT; H2O2; cytotoxicity; hepatocellular carcinoma; unfolded protein response; wogonin