Antiproliferative activity of NQ304, a synthetic 1,4-naphthoquinone, is mediated via the suppressions of the PI3K/Akt and ERK1/2 signaling pathways in PDGF-BB-stimulated vascular smooth muscle cells.
Platelet derived growth factor (PDGF)-BB is one of the most potent vascular smooth muscle cell (VSMC) proliferative factors, and abnormal VSMC proliferation by PDGF-BB plays an important role in the development and progression of atherosclerosis. The aim of this study was to assess the effect of NQ304 [2-chloro-3-(4-hexylphenyl)-amino-1,4-naphthoquinone], a newly synthesized 1,4-naphthoquinone derivative, on the proliferation of PDGF-BB-stimulated rat aortic VSMCs. Antiproliferative effects of NQ304 on rat aortic VSMCs were examined by direct cell counting and by using [(3)H] thymidine incorporation assays. It was found that NQ304 potently the growth of VSMCs. Preincubation with NQ304 (1-10 microM) significantly inhibited proliferation and DNA synthesis of 50 ng/ml PDGF-BB-stimulated rat aortic VSMCs in a concentration-dependent manner. In addition, we investigated the mechanism of proliferation suppression by NQ304 in PDGF-BB-stimulated rat aortic VSMCs, and found that PDGF-BB-stimulated immediate-early gene expression (c-fos), activator protein (AP)-1 activation, extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation, and Akt kinase were significantly inhibited by NQ304. An examination of the suppressive effects of NQ304 on PDGF-BB-stimulated VSMC cycle progression showed that NQ304 (10 microM) induced the G1 phase arrest of PDGF-BB-stimulated cell cycle progression by elevating p21(cip1) mRNA expression. These findings suggest that the inhibitory effects of NQ304 on DNA synthesis, proliferation, and cell cycle progression on PDGF-BB-stimulated VSMCs are mediated via the downregulations of AP-1 activation and c-fos expression achieved in turn via the suppressions of the phosphatidylinositol 3-kinase (PI3K)/Akt and ERK1/2 signaling pathways.
Kim
Tack-Joong
TJ
Research Center for Bioresource and Health, College of Pharmacy, Chungbuk National University, 48 Gaesin-Dong, Heungduk-Gu, Cheongju, Chungbuk, Korea.
Yun
Yeo-Pyo
YP
D000818:Animals; D001011:Aorta / Q000187:drug effects; D000077214:Becaplermin; D002318:Cardiovascular Diseases / Q000188:drug therapy; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D016193:G1 Phase / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D009285:Naphthoquinones / Q000494:pharmacology* / Q000627:therapeutic use; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism
D050759:Cyclin-Dependent Kinase Inhibitor p21; D006131:Growth Inhibitors; D009285:Naphthoquinones; D010982:Platelet-Derived Growth Factor; D016760:Proto-Oncogene Proteins c-fos; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D000077214:Becaplermin; D004247:DNA; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C407362:NQ304