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
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.