Nakayama Toshimitsu, Asami Satoru, Ono Shin-Ichi, Miura Motofumi, Hayasaka Masatoshi, Yoshida Yoshikazu, Toriyama Masaharu, Motohashi Shigeyasu, Suzuki Takashi
College of Pharmacy, Nihon University, Chiba, Japan.
Jpn J Clin Oncol. 2009 Apr;39(4):251-9. doi: 10.1093/jjco/hyp011. Epub 2009 Mar 8.
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.
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.
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.
Vitamin K3 analogs may have potential as clinical therapeutic agents for NB.
