Abstract. The abnormal proliferation of vascular smooth muscle cells (VSMCs) in arterial wall is an important pathogenic factor for vascular disorders such as atherosclerosis and restenosis after angioplasty. The present study was designed to investigate the inhibitory effects of docetaxel on VSMC proliferation, as well as the molecular mechanism of this inhibition. Docetaxel at 10, 20 and 40 μM significantly inhibited both the proliferation and the DNA synthesis of fetal bovine serum (FBS)-and platelet-derived growth factor (PDGF)-BB-stimulated VSMCs in a concentration-dependent manner. In accordance with these findings, docetaxel blocked the FBS-and PDGF-BB-induced progression of synchronized cells through the G0/G1 phase of the cell cycle. Docetaxel also decreased the expressions of cell cycle-related proteins, including cyclin-dependent kinase (CDK) 2, cyclin E, CDK4, cyclin D1, retinoblastoma protein, and proliferative cell nuclear antigen in PDGF-BB-stimulated VSMCs. Docetaxel significantly inhibited the phosphorylation of extracellular signal-regulated kinase 1/2, Akt, and phospholipase C-γ1, downstream molecule in the PDGF-BB signaling pathway. Docetaxel suppressed the phosphorylation of PDGF receptor (PDGF-R) β, the upstream molecule in PDGF-BB signaling cascade, suggesting that the inhibitory effect of docetaxel on the proliferation of VSMCs may occur by blocking PDGF-Rβ phosphorylation. Thus, docetaxel may be a potential antiproliferative agent for the treatment of atherosclerosis and angioplasty restenosis.

(PDGF)-BB is a potent growth factor produced by platelets, VSMCs, and endothelial cells in the injured vascular wall (Majesky et al., 1990;Miyauchi et al., 1998). PDGF initiates the activation of intracellular signal transduction pathways that contribute to VSMC proliferation, migration, and collagen Atherosclerosis and post-angiography restenosis are associated with intimal thickening and concomitant vascular smooth muscle cell (VSMC) proliferation. Obovatol, a major biphenolic component isolated from the Magnolia obovata leaf, is known to have antiinfl ammatory and anti-tumor activities. The goal of the present study was to enhance the inhibitory effects of obovatol to improve its potential as a preventive or therapeutic agent in atherosclerosis and restenosis. Platelet-derived growth factor (PDGF)-BB-induced proliferation of rat aortic smooth muscle cells (RASMCs) was examined in the presence or absence of a newly synthesized obovatol derivative, OD78. The observed anti-proliferative effect of OD78 was further investigated by cell counting and [ 3 H]-thymidine incorporation assays. Treatment with 1-4 μM OD78 dose-dependently inhibited the proliferation and DNA synthesis of 25 ng/ ml PDGF-BB-stimulated RASMCs. Accordingly, OD78 blocked PDGF-BB-induced progression from the G 0 /G 1 to S phase of the cell cycle in synchronized cells. OD78 decreased the expression levels of CDK4, cyclin E, and cyclin D1 proteins, as well as the phosphorylation of retinoblastoma protein and proliferating cell nuclear antigen; however, it did not change the CDK2 expression level. In addition, OD78 inhibited downregulation of the cyclin-dependent kinase inhibitor (CKI) p27 kip1 . However, OD78 did not affect the CKI p21 cip1 or phosphorylation of early PDGF signaling pathway. These results suggest that OD78 may inhibit PDGF-BBinduced RASMC proliferation by perturbing cell cycle progression, potentially through p27 kip1 pathway activation. Consequently, OD78 may be developed as a potential anti-proliferative agent for the treatment of atherosclerosis and angioplasty restenosis. (Ammon and Wahl, 1991). PDGF-BB propagates mitogenic signals through the autophosphorylation of its respective PDGF beta-receptor (Rβ) on tyrosine residues, thus triggering downstream signal transduction and cell cycle progression (Blenis, 1993;Heldin et al., 1998;Ahn et al., 1999).Cell cycle phases are coordinated by the expression and activation of regulatory proteins, including complexes of cyclins and cyclin-dependent kinases (CDK) (Braun-Dullaeus et al., 1998). The kinase activity of these CDK-cyclin complexes is further negatively regulated by two classes of cyclin-dependent kinase inhibitors (CKIs) (Sherr and Roberts, 1999). INK4 family members (p16 INK4a and p15 INK4b ) inhibit only CDK4 and CDK6 (Ortega et al., 2002), while cip family members (p21 cip1