title: Japonicone A suppresses growth of Burkitt lymphoma cells through its effect on NF-κB.
abstract: OBJECTIVE
  NF-κB, a transcriptional regulator of diverse genes involved in cell survival, proliferation, adhesion, and apoptosis, has been implicated in various malignancies. We discovered a potent natural NF-κB inhibitor, Japonicone A, from the traditional herb Inula japonica Thunb, evaluated its preclinical pharmacology and therapeutic activity, and investigated the underlying mechanisms of action for its antitumor activity.
  
  
  METHODS
  Various types of cancer and normal cells were exposed to Japonicone A for cytotoxicity screening, followed by determination of cell apoptosis and cell-cycle arrest. Western blotting, immunostaining, and gene reporter assay were used to analyze NF-κB activity. Two xenograft models were used for therapeutic efficacy evaluation.
  
  
  RESULTS
  Japonicone A killed cancer cells but had low cytotoxicity to normal cells. Burkitt lymphoma cells were particularly sensitive. Japonicone A inhibited the growth and proliferation of Raji, BJAB, and NAMALWA lymphoma cells and resulted in G2-M phase arrest and apoptosis. Furthermore, exposure of cells to Japonicone A caused inactivation of the TNF-α-TAK1-IKK-NF-κB axis and inhibition of TNF-α-stimulated NF-κB activity and nuclear translocation, followed by downregulation of NF-κB target genes involved in cell apoptosis (Bcl-2, Bcl-xL, XIAP, TRAF2) and in the cell cycle and growth (cyclin D, c-Myc). Moreover, Japonicone A inhibited local growth and dissemination of cancer cells to multiple organs in vivo.
  
  
  CONCLUSIONS
  Japonicone A exerts significant anticancer effects on Burkitt lymphoma cells in vitro and in vivo through targeting of the NF-κB signaling cascade. These results highlight the potential of Japonicone A as a chemotherapeutic agent and warrant its development as a therapy for lymphomas.
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, P.R. China.
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Li
authors.forename: Xinying
authors.initials: X
authors.lastname: Yang
authors.forename: Yanling
authors.initials: Y
authors.lastname: Liu
authors.forename: Nuoxi
authors.initials: N
authors.lastname: Gong
authors.forename: Wenbo
authors.initials: W
authors.lastname: Yao
authors.forename: Peizhan
authors.initials: P
authors.lastname: Chen
authors.forename: Jiangjiang
authors.initials: J
authors.lastname: Qin
authors.forename: Huizi
authors.initials: H
authors.lastname: Jin
authors.forename: Jingquan
authors.initials: J
authors.lastname: Li
authors.forename: Ruiai
authors.initials: R
authors.lastname: Chu
authors.forename: Lei
authors.initials: L
authors.lastname: Shan
authors.forename: Ruiwen
authors.initials: R
authors.lastname: Zhang
authors.forename: Weidong
authors.initials: W
authors.lastname: Zhang
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002051:Burkitt Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D021381:Protein Transport; D045787:Sesquiterpenes, Eudesmane / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D045789:Sesquiterpenes, Guaiane / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D051550:I-kappa B Kinase; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D045787:Sesquiterpenes, Eudesmane; D045789:Sesquiterpenes, Guaiane; D014409:Tumor Necrosis Factor-alpha; D000099151:MAP Kinase Kinase Kinase 7; C585467:japonicone A