TAS-301 blocks receptor-operated calcium influx and inhibits rat vascular smooth muscle cell proliferation induced by basic fibroblast growth factor and platelet-derived growth factor

Citation
E. Sasaki et al., TAS-301 blocks receptor-operated calcium influx and inhibits rat vascular smooth muscle cell proliferation induced by basic fibroblast growth factor and platelet-derived growth factor, JPN J PHARM, 84(3), 2000, pp. 252-258
Citations number
31
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JAPANESE JOURNAL OF PHARMACOLOGY
ISSN journal
00215198 → ACNP
Volume
84
Issue
3
Year of publication
2000
Pages
252 - 258
Database
ISI
SICI code
0021-5198(200011)84:3<252:TBRCIA>2.0.ZU;2-2
Abstract
The purpose of this study was to determine the effect of a recently synthes ized drug, TAS-301 [3-bis(4-methoxyphenyl)methylene-2-indolinone], on vascu lar smooth muscle cell (VSMC) proliferation and the intracellular signal tr ansduction pathways involved in VSMC proliferation. In an in vitro assay, T AS-301 inhibited the proliferation of rat VSMCs stimulated by platelet-deri ved growth factor (PDGF)-BB, basic fibroblast growth factor, or 2% fetal bo vine serum in a concentration-dependent manner. TAS-301 dose dependently in hibited the PDGF-induced Ca2+ influx; the concentration for the inhibition of Ca2+ influx was nearly identical to that for inhibition of VSMC prolifer ation. The Ca2+ influx induced by PDGF was also attenuated by NiCl2 but not by nifedipine, suggesting that PDGF-induced Ca2+ influx would be mediated by some non-voltage-dependent mechanisms. Furthermore, TAS-301 inhibited PD GF-induced activation of protein kinase C (PKC) and the phorbol 12-myristat e 13-acetate-mediated induction of activator protein 1 (AP-1) in a concentr ation-dependent manner. These findings indicate that TAS-301 inhibited the proliferation of VSMCs by blocking voltage-independent Ca2+ influx and down stream signals such as the Ca2+/PKC signaling pathway, leading to AP-1 indu ction.