title: Da0324, an inhibitor of nuclear factor-κB activation, demonstrates selective antitumor activity on human gastric cancer cells.
abstract: BACKGROUND
  The transcription factor nuclear factor-κB (NF-κB) is constitutively activated in a variety of human cancers, including gastric cancer. NF-κB inhibitors that selectively kill cancer cells are urgently needed for cancer treatment. Curcumin is a potent inhibitor of NF-κB activation. Unfortunately, the therapeutic potential of curcumin is limited by its relatively low potency and poor cellular bioavailability. In this study, we presented a novel NF-κB inhibitor named Da0324, a synthetic asymmetric mono-carbonyl analog of curcumin. The purpose of this study is to research the expression of NF-κB in gastric cancer and the antitumor activity and mechanism of Da0324 on human gastric cancer cells.
  
  
  METHODS
  The expressions between gastric cancer tissues/cells and normal gastric tissues/cells of NF-κB were evaluated by Western blot. The inhibition viability of compounds on human gastric cancer cell lines SGC-7901, BGC-823, MGC-803, and normal gastric mucosa epithelial cell line GES-1 was assessed with the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay. Absorption spectrum method and high-performance liquid chromatography method detected the stability of the compound in vitro. The compound-induced changes of inducible NF-κB activation in the SGC-7901 and BGC-823 cells were examined by Western blot analysis and immunofluorescence methods. The antitumor activity of compound was performed by clonogenic assay, matrigel invasion assay, flow cytometric analysis, Western blot analysis, and Hoechst 33258 staining assay.
  
  
  RESULTS
  High levels of p65 were found in gastric cancer tissues and cells. Da0324 displayed higher growth inhibition against several types of gastric cancer cell lines and showed relatively low toxicity to GES-1. Moreover, Da0324 was more stable than curcumin in vitro. Western blot analysis and immunofluorescence methods showed that Da0324 blocked NF-κB activation. In addition, Da0324 significantly inhibited tumor proliferation and invasion, arrested the cell cycle, and induced apoptosis in vitro.
  
  
  CONCLUSIONS
  The asymmetric mono-carbonyl analog of curcumin Da0324 exhibited significantly improved antigastric cancer activity. Da0324 may be a promising NF-κB inhibitor for the selective targeting of cancer cells. However, further studies are needed in animals to validate these findings for the therapeutic use of Da0324.
authors.affiliation: Department of Digestive Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China; Department of Epidemiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China.
authors.forename: Rong
authors.initials: R
authors.lastname: Jin
authors.affiliation: Department of Digestive Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, People's Republic of China.
authors.forename: Yiqun
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Department of Digestive Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, People's Republic of China.
authors.forename: Qiuxiang
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, People's Republic of China; College of Information Science and Computer Engineering, Wenzhou Medical College, Wenzhou, People's Republic of China.
authors.forename: Wulan
authors.initials: W
authors.lastname: Li
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, People's Republic of China.
authors.forename: Dahui
authors.initials: D
authors.lastname: Chen
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, People's Republic of China; School of Basic Medical Sciences, Wenzhou Medical College, Wenzhou, People's Republic of China.
authors.forename: Hui
authors.initials: H
authors.lastname: Ye
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, People's Republic of China.
authors.forename: Chengguang
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Department of Digestive Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, People's Republic of China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Du
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, People's Republic of China.
authors.forename: Dengjian
authors.initials: D
authors.lastname: Shi
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, People's Republic of China.
authors.forename: Jianzhang
authors.initials: J
authors.lastname: Wu
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, People's Republic of China.
authors.forename: Guang
authors.initials: G
authors.lastname: Liang
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001597:Benzylidene Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003474:Curcumin / Q000031:analogs & derivatives* / Q000737:chemistry; D003517:Cyclopentanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D016328:NF-kappa B / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001597:Benzylidene Compounds; D003517:Cyclopentanes; C000611310:Da0324; D016328:NF-kappa B; D003474:Curcumin
keywords: NF-κB inhibitor; anticancer drug; apoptosis; asymmetric MACs; curcumin; gastric cancer