Exploring the molecular mechanisms of OSU-03012 on vascular smooth muscle cell proliferation.
Restenosis is resulted from the proliferation and migration of vascular smooth muscle cells (VSMCs) from the arterial media into the intima within the vessel lumen following percutaneous transluminal coronary angioplasty (PTCA). OSU-03012, a synthetic compound (2-amino-N-{4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-phenyl} acetamide) acting as a PDK-1 inhibitor, is used as an apoptosis-promoting anticancer drug. However, whether OSU-03012 can inhibit VSMC proliferation and migration following PTCA remains unclear. In this study, we used A10 smooth muscle cells cultured in 10% FBS for stimulating proliferation and evaluated the inhibitory effects of OSU-03012 on cell proliferation and migration. The data demonstrated that OSU-03012 dose-dependently inhibited A10 cell proliferation examined by Trypan blue, MTT and morphological alteration assays, and inhibited the levels of proliferation-related proteins, proliferating cell nuclear antigen (PCNA), phosphorylated ERK examined by western blotting. Additionally, 10 μM OSU-03012 also enhanced apoptosis examined using DAPI assay by regulating apoptosis-related proteins. Furthermore, compared with the control group, A10 cells treated with 10 μM OSU-03012 showed a lower number of migrating cells examined by Boyden Chamber assay, and a dose-dependently reduced NFκB-dependent and interferon-stimulated response element (ISRE) promoter luciferase activities, implying the anti-migration and anti-inflammation effects of OSU03012. Taken together, this study provides insights into the pharmacological mechanisms of OSU-03012 in preventing smooth muscle cell proliferation, migration, and inflammation supporting the novel discovery of OSU-03012 as an adjuvant therapy for balloon injury-induced restenosis.
Kuo
Wei-Wen
WW
Department of Biological Science and Technology, College of Life Sciences, China Medical University, Taichung, Taiwan, ROC.
Weng
Jing-Ru
JR
Huang
Chih-Yang
CY
Tsai
Chang-Hai
CH
Liu
Wei-Hung
WH
Wen
Cheng-Hao
CH
Tsai
Shih-Chang
SC
Wu
Chieh-Hsi
CH
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004591:Electrophoresis, Polyacrylamide Gel; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D016328:NF-kappa B / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D013449:Sulfonamides / Q000494:pharmacology*
D016328:NF-kappa B; C500894:OSU 03012; D011720:Pyrazoles; D013449:Sulfonamides