Inhibitory effect of a novel naphthoquinone derivative on proliferation of vascular smooth muscle cells through suppression of platelet-derived growth factor receptor p tyrosine kinase

摘要

This study was designed to investigate the antiproliferative effect of a novel naphthoquinone derivative, 2-undecylsulfonyl-5,8-dimethoxy-l,4-naphthoquinone (2-undecylsulfonyl-DMNQ), on platelet-derived growth factor (PDGF)-stimulated vascular smooth muscle cells (VSMCs) and examine the possible molecular mechanism of its antiproliferative action. 2-Undecylsulfonyl-DMNQ. significantly inhibited PDGF-stimulated cell number and DNA synthesis, and arrested the PDGF-stimulated progression through G_0/G_1 to S phase of cell cycle supported by the suppression of pRb phosphorylation and cyclin Dl/E, CDK2/4 and PCNA expressions. 2-Undecylsulfonyl-DMNQ. dose-dependently inhibited the PDGF-stimulated phosphorylation of phospholipase Cgamma (PLCgamma), protein kinase B (Akt/PKB), signal transducers and activators of transcription 3 (STAT3) and extracellular signal-regulated kinase 1/2 (ERK 1/2). In addition, 2-undecylsulfonyl-DMNQ. inhibited PDGF-induced PDGF receptor P (PDGF-RP) dimerization and the phosphorylation of Tyr~(579/581), Tyr~(716), Tyr~(751) and Tyr~(1021) in PDGF-Rp. However, 2-undecylsulfonyl-DMNQ has no antiproliferative effect on epidermal growth factor (EGF)- or fetal bovine serum (FBS)-stimulated VSMCs. In conclusion, these findings suggest that the antiproliferative effects of 2-undecylsulfonyl-DMNQ. on PDGF-stimulated VSMCs are due to the blockade of receptor dimerization and autophosphorylation on specific tyrosine residues of PDGF-Rp, which resulted in the subsequent suppression of signaling cascades and a cell cycle arrest. Our observation may explain an important mechanism to block the integration of multiple signals generated by growth factor receptor activation for prevention of VSMC proliferation in cardiovascular diseases.