title: Antiproliferative Activity of Hinokitiol, a Tropolone Derivative, Is Mediated via the Inductions of p-JNK and p-PLCγ1 Signaling in PDGF-BB-Stimulated Vascular Smooth Muscle Cells.
abstract: Abnormal proliferation of vascular smooth muscle cells (VSMCs) is important in the pathogenesis of vascular disorders such as atherosclerosis and restenosis. Hinokitiol, a tropolone derivative found in Chamacyparis taiwanensis, has been found to exhibit anticancer activity in a variety of cancers through inhibition of cell proliferation. In the present study, the possible anti-proliferative effect of hinokitiol was investigated on VSMCs. Our results showed that hinokitiol significantly attenuated the PDGF-BB-stimulated proliferation of VSMCs without cytotoxicity. Hinokitiol suppressed the expression of proliferating cell nuclear antigen (PCNA), a maker for cell cycle arrest, and caused G0/G1 phase arrest in cell cycle progression. To investigate the mechanism underlying the anti-proliferative effect of hinokitiol, we examined the effects of hinokitiol on phosphorylations of Akt, ERK1/2, p38 and JNK1/2. Phospholipase C (PLC)-γ1 phosphorylation, its phosphorylated substrates and p27kip1 expression was also analyzed. Pre-treatment of VSMCs with hinikitiol was found to significantly inhibit the PDGF-BB-induced phosphorylations of JNK1/2 and PLC-γ1, however no effects on Akt, ERK1/2, and p38. The up-regulation of p27kip1 was also observed in hinokitiol-treated VSMCs. Taken together, our results suggest that hinokitiol inhibits PDGF-BB-induced proliferation of VSMCs by inducing cell cycle arrest, suppressing JNK1/2 phosphorylation and PLC-γ1, and stimulating p27kip1 expression. These findings suggest that hinokitiol may be beneficial for the treatment of vascular-related disorders and diseases.
authors.affiliation: Department of Surgery, MacKay Memorial Hospital and Mackay Medical College, No. 92, Sec. 2, Zhongshan N. Rd., Taipei City 10449, Taiwan. psyangd0039@gmail.com.|Mackay Junior College of Medicine, Nursing, and Management, No. 92, Shengjing Rd., Beitou District, Taipei 112, Taiwan. psyangd0039@gmail.com.|School of Nutrition and Health Sciences, Taipei Medical University, 250 Wu-Hsing St., Taipei 110, Taiwan. psyangd0039@gmail.com.
authors.forename: Po-Sheng
authors.initials: PS
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, School of Medicine, Taipei Medical University, 250 Wu-Hsing St., Taipei 110, Taiwan. mjwang@mail.ntust.edu.tw.|Department of Chemical Engineering, National Taiwan University of Science and Technology, No. 43, Sec. 4, Keelung Rd., Da'an District, Taipei City 10607, Taiwan. mjwang@mail.ntust.edu.tw.
authors.forename: Meng-Jiy
authors.initials: MJ
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, School of Medicine, Taipei Medical University, 250 Wu-Hsing St., Taipei 110, Taiwan. tjaya_2002@yahoo.co.in.
authors.forename: Thanasekaran
authors.initials: T
authors.lastname: Jayakumar
authors.affiliation: Department of Pharmacology, School of Medicine, Taipei Medical University, 250 Wu-Hsing St., Taipei 110, Taiwan. fird@tmu.edu.tw.
authors.forename: Duen-Suey
authors.initials: DS
authors.lastname: Chou
authors.affiliation: Department of Pharmacology, School of Medicine, Taipei Medical University, 250 Wu-Hsing St., Taipei 110, Taiwan. smallko1022@hotmail.com.
authors.forename: Ching-Ya
authors.initials: CY
authors.lastname: Ko
authors.affiliation: Department of Pharmacology, School of Medicine, Taipei Medical University, 250 Wu-Hsing St., Taipei 110, Taiwan. aspirin@tmu.edu.tw.
authors.forename: Ming-Jen
authors.initials: MJ
authors.lastname: Hsu
authors.affiliation: Department of Pharmacology, School of Medicine, Taipei Medical University, 250 Wu-Hsing St., Taipei 110, Taiwan. hsiehcy@tmu.edu.tw.
authors.forename: Cheng-Ying
authors.initials: CY
authors.lastname: Hsieh
mesh_terms: D000818:Animals; D000077214:Becaplermin; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D039821:Monoterpenes / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D051966:Phospholipase C gamma / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D014334:Tropolone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D039821:Monoterpenes; D018809:Proliferating Cell Nuclear Antigen; D020574:Proto-Oncogene Proteins c-sis; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000077214:Becaplermin; D014334:Tropolone; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D051966:Phospholipase C gamma; C009479:beta-thujaplicin