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.

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  • Sasaki Eiji
    Pharmacology Research Laboratory, Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., 224-2, Ebisuno, Hiraishi, Kawauchi-cho, Tokushima 771-0194, Japan
  • Nozawa Yoshihisa
    Pharmacology Research Laboratory, Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., 224-2, Ebisuno, Hiraishi, Kawauchi-cho, Tokushima 771-0194, Japan
  • Miyoshi Kazuhisa
    Pharmacology Research Laboratory, Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., 224-2, Ebisuno, Hiraishi, Kawauchi-cho, Tokushima 771-0194, Japan
  • Kanda Atsuhiro
    Pharmacology Research Laboratory, Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., 224-2, Ebisuno, Hiraishi, Kawauchi-cho, Tokushima 771-0194, Japan
  • Yamasaki Yasundo
    Cardiovascular Science Research Laboratory, Hanno Research Center, Taiho Pharmaceutical Co., Ltd., 1-27 Misugidai, Hanno City, Saitama 357-8527, Japan
  • Miyake Hidekazu
    Cardiovascular Science Research Laboratory, Hanno Research Center, Taiho Pharmaceutical Co., Ltd., 1-27 Misugidai, Hanno City, Saitama 357-8527, Japan
  • Matsuura Naosuke
    Pharmacology Research Laboratory, Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., 224-2, Ebisuno, Hiraishi, Kawauchi-cho, Tokushima 771-0194, Japan

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Abstract

The purpose of this study was to determine the effect of a recently synthesized durg, TAS-301 [3-bis(4-methoxyphenyl)methylene-2-indolinone], on vascular smooth muscle cell (VSMC) proliferation and the intracellular signal transduction pathways involved in VSMC proliferation. In an in vitro assay, TAS-301 inhibited the proliferation of rat VSMCs stimulated by platelet-derived growth factor (PDGF)-BB, basic fibroblast growth factor, or 2% fetal bovine serum in a concentration-dependent manner. TAS-301 dosedependently inhibited the PDGF-induced Ca2+ influx; the concentration for the inhibition of Ca2+ influx was nearly identical to that for inhibition of VSMC proliferation. 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 PDGF-induced activation of protein kinase C (PKC) and the phorbol 12-myristate 13-acetate-mediated induction of activator protein 1 (AP-1) in a concentration-dependent manner. These findings indicate that TAS-301 inhibited the proliferation of VSMCs by blocking voltage-independent Ca2+ influx and downstream signals such as the Ca2+/PKC signaling pathway, leading to AP-1 induction.

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