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KCI등재 학술저널

5,8-Dimethoxy-2-Nonylamino-Naphthalene-1,4-DioneInhibitsVascular Smooth Muscle Cell Proliferation by Blocking Autophosphorylation of PDGF-Receptor Ղ

5,8-Dimethoxy-2-Nonylamino-Naphthalene-1,4-DioneInhibitsVascular Smooth Muscle Cell Proliferation by Blocking Autophosphorylation of PDGF-Receptor Ղ

As the abnormal proliferation of vascular smooth muscle cells (VSMCs) plays a critical role in the development of atherosclerosis and vascular restenosis, a candidate drug with antiproliferative properties is needed. We investigated the antiproliferative action and underlying mechanism of a newly synthesized naphthoquinone derivative, 5,8-dimethoxy-2-nonylamino-naphthalene-1,4-dione (2-nonylamino- DMNQ), using VSMCs treated with platelet-derived growth factor (PDGF). 2-Nonylamino-DMNQ inhibited proliferation and cell number of VSMCs induced by PDGF, but not epidermal growth factor (EGF), in a concentration-dependent manner without any cytotoxicity. This derivative suppressed PDGF-induced [<sup>3</sup>H]-thymidine incorporation, cell cycle progression from G<sub>0</sub>/G<sub>1</sub> to S phase, and the phosphorylation of phosphor-retinoblastoma protein (pRb) as well as the expression of cyclin E/D, cyclin-dependent kinase (CDK) 2/4, and proliferating cell nuclear antigen (PCNA). Importantly, 2-nonylamino-DMNQ inhibited the phosphorylation of PDGF receptor&#1346;(PDGF-R&#1346;) enhanced by PDGF at Tyr<sup>579</sup>, Tyr<sup>716</sup>, Tyr<sup>751</sup>, and Tyr<sup>1021</sup> residues. Subsequently, 2-nonylamino-DMNQ inhibited PDGF- induced phosphorylation of STAT3, ERK1/2, Akt, and PLC&#1347;1. Therefore, our results indicate that 2-nonylamino-DMNQ inhibits PDGF-induced VSMC proliferation by blocking PDGF-R&#1346; autophosp- horylation, and subsequently PDGF-R&#1346;-mediated downstream signaling pathways.

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