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Japanese Journal of Clinical Oncology Advance Access published online on March 8, 2009
Japanese Journal of Clinical Oncology, doi:10.1093/jjco/hyp011
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© The Author (2009). Published by Oxford University Press. All rights reserved

Effect of Cell Differentiation for Neuroblastoma by Vitamin K Analogs

Toshimitsu Nakayama1, Satoru Asami1, Shin-ichi Ono1, Motofumi Miura2, Masatoshi Hayasaka3, Yoshikazu Yoshida3, Masaharu Toriyama2, Shigeyasu Motohashi2 and Takashi Suzuki1,4

1 Research Unit of Clinical Medicine, College of Pharmacy, Nihon University
2 Research Unit of Molecular Chemistry, College of Pharmacy, Nihon University, Chiba
3 Department of Hospital Pharmacy, School of Medicine, Nihon University
4 Department of Pediatrics and Child Health, School of Medicine, Nihon University, Tokyo, Japan

For reprints and all correspondence: Takashi Suzuki, Research Unit of Clinical Medicine, College of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi-shi, Chiba 274-8555, Japan. E-mail: suzuki.takashi85{at}nihon-u.ac.jp

Received November 19, 2008; accepted January 16, 2009

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.

Key Words: vitamin K3 • neuroblastoma • TrkA • PTPase • differentiation


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