title: Effect of cell differentiation for neuroblastoma by vitamin k analogs.
abstract: BACKGROUND
  Lack of receptor tyrosine kinase (TrkA), a high-affinity nerve growth factor (NGF) receptor, is closely associated with the malignant progression of neuroblastoma (NB) and its prognosis. Vitamin K3 (VK3) analogs inhibit the activity of protein tyrosine phosphatases (PTPases), which causes hydrolysis of the phosphate groups bound to the tyrosine residues on tyrosine kinase, resulting in sustained tyrosine phosphorylation.
  
  
  METHODS
  In order to reverse this abnormal NGF/TrkA signal transduction in NB cells, we synthesized new VK3 analogs and examined their activity against NB cells.
  
  
  RESULTS
  VK3 analogs increased or maintained the expression level of c-fos mRNA in the NB cells, which express the downstream genes of NGF/TrkA signal transduction. Moreover, the expression level of GAP-43 mRNA, which is a marker of neurite outgrowth and neuronal differentiation, was increased and morphological differentiation was also observed. VK3 analogs (especially COOH analog) continued to express c-fos and GAP-43 mRNAs and induced differentiation of NB cells after stimulation of NGF by strong inhibition of PTPase without affecting TrkA autophosphorylation.
  
  
  CONCLUSIONS
  Vitamin K3 analogs may have potential as clinical therapeutic agents for NB.
authors.affiliation: College of Pharmacy, Nihon University, Chiba, Japan.
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Nakayama
authors.forename: Satoru
authors.initials: S
authors.lastname: Asami
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Ono
authors.forename: Motofumi
authors.initials: M
authors.lastname: Miura
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Hayasaka
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Yoshida
authors.forename: Masaharu
authors.initials: M
authors.lastname: Toriyama
authors.forename: Shigeyasu
authors.initials: S
authors.lastname: Motohashi
authors.forename: Takashi
authors.initials: T
authors.lastname: Suzuki
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D016501:Neurites / Q000473:pathology; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D020917:Receptor, trkA / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D024483:Vitamin K 3 / Q000031:analogs & derivatives*
chemical_list: D016760:Proto-Oncogene Proteins c-fos; D024483:Vitamin K 3; D020917:Receptor, trkA; D017027:Protein Tyrosine Phosphatases