title: Inhibitory effects of BST406, a newly synthesized benzylideneacetophenone derivative, on abnormal vascular smooth muscle cell proliferation.
abstract: Benzylideneacetophenone analogues are known to have several significant biological activities, including antiinflammatory, antitumor, antibacterial, antiviral, and gastric-protective activities. However, the antiproliferative effects of benzylideneacetophenone analogues on vascular smooth muscle cells (VSMCs) are unknown. The aim of this study was to elucidate the antiproliferative effects and molecular mechanism of BST406, a newly synthesized benzylideneacetophenone derivative, on platelet-derived growth factor (PDGF)-BB-stimulated rat aortic VSMCs. BST406 inhibited [(3)H]-thymidine incorporation into DNA in VSMCs following treatment with PDGFBB 25 ng/ml. PDGF-BB-stimulated DNA synthesis was significantly reduced. Moreover, pretreatment with BST406 (0-10microM) suppressed the proliferation of PDGF-BB-stimulated cells in a concentration-dependent manner. We also investigated the mechanism of the antiproliferative effects of BST406 in PDGF-BB-stimulated VSMCs. In Western blot analysis, PDGF-BB-stimulated (25 ng/ml) phospholipase-C (PLC)gamma1 and Akt phosphorylation was inhibited by BST406 (0-10microM). However, BST406 did not inhibit the PDGF-receptor beta-chain (PDGF-Rbeta) and extracellular-regulated kinase 1 and 2 (ERK1/2) phosphorylation induced by PDGF-BB. To confirm that the inhibitory effects of BST406 are mediated through the inhibition of PLCgamma1 or Akt, the effects of inhibitors on cell viability were examined. U73122 completely inhibited PDGF-BB-induced proliferation of VSMCs. However, LY294002 10microM had no significant effects on PDGF-BB-induced proliferation. These findings suggest that the inhibitory effects of BST406 on the proliferation of PDGF-BB-stimulated VSMCs are mediated by suppression of the PLCgamma1 signaling pathways. Our observations may explain, in part, the mechanistic basis for the prevention of cardiovascular disease (such as atherosclerosis and restenosis after coronary angioplasty) by BST406.
authors.affiliation: Division of Biological Science and Technology, College of Science and Technology, Yonsei University, Wonju 220-710, Korea. ktj@yonsei.ac.kr
authors.forename: Tack-Joong
authors.initials: TJ
authors.lastname: Kim
authors.forename: Hyeong-Jun
authors.initials: HJ
authors.lastname: Han
authors.forename: Yong-Jae
authors.initials: YJ
authors.lastname: Kim
authors.forename: Jae-Chul
authors.initials: JC
authors.lastname: Jung
authors.forename: Ji-Yeon
authors.initials: JY
authors.lastname: Yu
authors.forename: Jung-Jin
authors.initials: JJ
authors.lastname: Lee
authors.forename: Yeo-Pyo
authors.initials: YP
authors.lastname: Yun
mesh_terms: D000818:Animals; D000840:Anisoles / Q000138:chemical synthesis / Q000494:pharmacology*; D001011:Aorta / Q000166:cytology; D015153:Blotting, Western; D002317:Cardiovascular Agents / Q000494:pharmacology*; D002318:Cardiovascular Diseases / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D049109:Cell Proliferation / Q000187:drug effects*; D004247:DNA / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D007554:Isotopes; D007659:Ketones / Q000138:chemical synthesis / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051966:Phospholipase C gamma / Q000378:metabolism; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013194:Staining and Labeling; D013936:Thymidine / Q000378:metabolism
chemical_list: D000840:Anisoles; C554446:BST 406; D002317:Cardiovascular Agents; D004791:Enzyme Inhibitors; D007554:Isotopes; D007659:Ketones; D010982:Platelet-Derived Growth Factor; D004247:DNA; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D051966:Phospholipase C gamma; D013936:Thymidine