Effect of cell differentiation for neuroblastoma by vitamin k analogs.
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.
Nakayama
Toshimitsu
T
College of Pharmacy, Nihon University, Chiba, Japan.
Asami
Satoru
S
Ono
Shin-Ichi
S
Miura
Motofumi
M
Hayasaka
Masatoshi
M
Yoshida
Yoshikazu
Y
Toriyama
Masaharu
M
Motohashi
Shigeyasu
S
Suzuki
Takashi
T
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*
D016760:Proto-Oncogene Proteins c-fos; D024483:Vitamin K 3; D020917:Receptor, trkA; D017027:Protein Tyrosine Phosphatases