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
- Yohan Kim Jung-Jin Lee Sang-Gil Lee Sang-Hyuk Jung Joo-Hui Han So Young Yang Eunju Yun Gyu-Yong Song
- 대한생리학회-대한약리학회
- The Korean Journal of Physiology & Pharmacology
- 제17권 제3호
- 등재여부 : KCI등재
- 2013.01
- 203 - 208 (6 pages)
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 receptorՂ(PDGF-RՂ) 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 PLCՃ1. Therefore, our results indicate that 2-nonylamino-DMNQ inhibits PDGF-induced VSMC proliferation by blocking PDGF-RՂ autophosp- horylation, and subsequently PDGF-RՂ-mediated downstream signaling pathways.