Eiji Sasaki1, Yoshihisa Nozawa1, Kazuhisa Miyoshi1,
Atsuhiro Kanda1, Yasundo Yamasaki2,*,
Hidekazu Miyake2 and Naosuke Matsuura1
1Pharmacology Research Laboratory, Tokushima Research Center,
Taiho Pharmaceutical Co., Ltd.,
224-2, Ebisuno, Hiraishi, Kawauchi-cho, Tokushima 771-0194, Japan
2Cardiovascular Science Research Laboratory, Hanno Research Center,
Taiho Pharmaceutical Co., Ltd.,
1-27 Misugidai, Hanno City, Saitama 357-8527, Japan
*Corresponding author.ﾊﾊFAX:+81-429-72-0034
E-mail: yamasaki@taiho.co.jp
Abstract: The purpose of this study was to determine the effect of
a recently synthesized drug, 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 dose-dependently 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ﾊC
(PKC) and the phorbol 12-myristate 13-acetate-mediated induction of activator
proteinﾊ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.
Keywords: TAS-301, Vascular smooth muscle cell proliferation, Receptor-operated
calcium influx,
Signal transduction
Copyrightｩ The Japanese Pharmacological Society 2000
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