title: Houttuyninum, an active constituent of Chinese herbal medicine, inhibits phosphorylation of HER2/neu receptor tyrosine kinase and the tumor growth of HER2/neu-overexpressing cancer cells.
abstract: OBJECTIVE
  The overexpression of HER2/neu receptor plays a key role in tumorigenesis and tumor progression. Small molecules targeting HER2/neu have therapeutic value in cancers that overexpress HER2. In this present study, the effect of houttuyninum, a component in the Chinese herbal medicine Houttuynia cordata Thunb, on HER2/neu tyrosine phosphorylation and its in vivo antitumour activity was investigated.
  
  
  METHODS
  The phosphorylation and expression of proteins were determined by Western blot analysis. The MTT assay was employed to examine the inhibition of cell proliferation in vitro. Xenografts were established in nude mice for evaluating the antitumour activity of houttuyninum in vivo.
  
  
  RESULTS
  Houttuyninum inhibited phosphorylation of HER2 in a dose-dependent manner with an IC50 of 5.52 μg/ml without reducing HER2/neu protein expression in MDA-MB-453 cells. Houttuyninum also inhibited the activation of ERK1/2 and AKT, downstream molecules in the HER2/neu-mediated signal transduction pathway. In contrast, tyrosine phosphorylation of EGFR was unaffected when the concentration of houttuyninum was increased to 40 μg/ml in both A431 cells and MDA-MB-468 cells. Additionally, houttuyninum preferentially inhibited the growth of MDA-MB-453 cells that overexpressed HER2/neu; the MDA-MB-468 cells that overexpress EGFR remained unaffected. Administration of houttuyninum in vivo resulted in a significant reduction of phosphorylated HER2 levels and in tumor volumes of the BT474 and N87 xenografts, which both overexpress HER2/neu.
  
  
  CONCLUSIONS
  Our findings showed that houttuyninum can inhibit the HER2/neu signalling pathway and the tumor growth of cancer cells that overexpress HER2/neu. This drug may provide therapeutic value in the treatment of cancers that involve overexpression of HER2/neu.
authors.affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou 510060, PR China.
authors.forename: Ning-Ning
authors.initials: NN
authors.lastname: Zhou
authors.forename: Jun
authors.initials: J
authors.lastname: Tang
authors.forename: Wen-Dan
authors.initials: WD
authors.lastname: Chen
authors.forename: Gong-Kan
authors.initials: GK
authors.lastname: Feng
authors.forename: Bin-Fen
authors.initials: BF
authors.lastname: Xie
authors.forename: Zong-Chao
authors.initials: ZC
authors.lastname: Liu
authors.forename: Dajun
authors.initials: D
authors.lastname: Yang
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Zhu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D020794:Receptor Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D004365:Drugs, Chinese Herbal; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D018840:HSP70 Heat-Shock Proteins; D051058:Oncogene Protein v-akt; D020794:Receptor Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; C572988:houttuyninum; C508053:ERBB2 protein, human