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

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 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.