title: Inhibitory effects of docetaxel on platelet-derived growth factor (PDGF)-BB-induced proliferation of vascular smooth muscle cells through blocking PDGF-receptor β phosphorylation.
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.[Supplementary Figures: available only at http://dx.doi.org/10.1254/jphs.10276FP].
authors.affiliation: College of Pharmacy, CBITRC, Chungbuk National University, Korea.
authors.forename: Eun Seok
authors.initials: ES
authors.lastname: Park
authors.forename: Jae-Myung
authors.initials: JM
authors.lastname: Yoo
authors.forename: Yong
authors.initials: Y
authors.lastname: Lim
authors.forename: Munkhtsetseg
authors.initials: M
authors.lastname: Tudev
authors.forename: Hwan-Soo
authors.initials: HS
authors.lastname: Yoo
authors.forename: Jin Tae
authors.initials: JT
authors.lastname: Hong
authors.forename: Yeo-Pyo
authors.initials: YP
authors.lastname: Yun
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D000077214:Becaplermin; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004261:DNA Replication / Q000187:drug effects; D000077143:Docetaxel; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000187:drug effects / Q000502:physiology*; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D043823:Taxoids / Q000494:pharmacology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D043823:Taxoids; D000077143:Docetaxel; D000077214:Becaplermin