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Molecules 2015, 20(5), 8198-8212; doi:10.3390/molecules20058198

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

Department of Surgery, MacKay Memorial Hospital and Mackay Medical College, No. 92, Sec. 2, Zhongshan N. Rd., Taipei City 10449, Taiwan
Mackay Junior College of Medicine, Nursing, and Management, No. 92, Shengjing Rd., Beitou District, Taipei 112, Taiwan
School of Nutrition and Health Sciences, Taipei Medical University, 250 Wu-Hsing St., Taipei 110, Taiwan
Department of Pharmacology, School of Medicine, Taipei Medical University, 250 Wu-Hsing St., Taipei 110, Taiwan
Department of Chemical Engineering, National Taiwan University of Science and Technology, No. 43, Sec. 4, Keelung Rd., Da’an District, Taipei City 10607, Taiwan
These authors contributed equally to this work.
Authors to whom correspondence should be addressed.
Academic Editor: Derek J. McPhee
Received: 27 January 2015 / Revised: 22 April 2015 / Accepted: 28 April 2015 / Published: 7 May 2015
(This article belongs to the Section Natural Products)
View Full-Text   |   Download PDF [4335 KB, uploaded 7 May 2015]   |  


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. View Full-Text
Keywords: VSMC; hinokitiol; JNK1/2; PLC-γ1; PCNA; G0/G1 VSMC; hinokitiol; JNK1/2; PLC-γ1; PCNA; G0/G1

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Yang, P.-S.; Wang, M.-J.; Jayakumar, T.; Chou, D.-S.; Ko, C.-Y.; Hsu, M.-J.; Hsieh, C.-Y. 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. Molecules 2015, 20, 8198-8212.

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