title: A novel cyclophane compound, CPPy, facilitates NGF-induced TrkA signal transduction and induces cell differentiation in neuroblastoma.
abstract: Neuroblastoma (NB) often causes spontaneously regression, and can mature to ganglioneuroma. The form with the most favorable prognosis expresses high levels of TrkA, a high-affinity receptor for nerve growth factor (NGF), whereas advanced NB and associated cell lines have abnormalities in the NGF/TrkA signaling pathway. A novel cyclophane, cyclophane pyridine (CPPy), was designed to conserve the tyrosine phosphorylation of TrkA, thereby enhancing NGF/TrkA signal transduction. We investigated whether this compound improved NGF-induced tyrosine phosphorylation of the Y490 domain of TrkA and conserved the expression of an early gene (c-fos) in human NB cell lines (IMR-32 and NB-39). As determined by Western blotting, TrkA (Y490) phosphorylation was enhanced by the combination of CPPy (10(-8) M) and NGF (100 ng/ml) compared with NGF alone. CPPy also conserved NGF-induced c-fos mRNA expression. Moreover, CPPy induced the morphological differentiation of NB cells, leading to expression of the neuronal marker gene GAP-43. These data suggest that CPPy can induce the differentiation of NB cell lines by facilitating NGF-induced TrkA/Ras/MAPK signal transduction, and may therefore be an effective therapeutic agent for NB.
authors.affiliation: Clinical Pharmacy, College of Pharmacy, Nihon University, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Keiichi
authors.initials: K
authors.lastname: Tabata
authors.forename: Satoru
authors.initials: S
authors.lastname: Asami
authors.forename: Muneharu
authors.initials: M
authors.lastname: Miyake
authors.forename: Takashi
authors.initials: T
authors.lastname: Suzuki
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D004988:Ethers, Cyclic / Q000494:pharmacology*; D019922:GAP-43 Protein / Q000378:metabolism; D016762:Genes, fos; D006801:Humans; D007700:Kinetics; D015394:Molecular Structure; D020932:Nerve Growth Factor / Q000378:metabolism / Q000494:pharmacology; D009447:Neuroblastoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D010766:Phosphorylation / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D011726:Pyridinium Compounds / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D020917:Receptor, trkA / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C519680:CPPy compound; D004988:Ethers, Cyclic; D019922:GAP-43 Protein; D016760:Proto-Oncogene Proteins c-fos; D011725:Pyridines; D011726:Pyridinium Compounds; D012333:RNA, Messenger; D020932:Nerve Growth Factor; D020917:Receptor, trkA