Widdrol, a sesquiterpene isolated from Juniperus chinensis, inhibits angiogenesis by targeting vascular endothelial growth factor receptor 2 signaling

Jin,Soojung; Yun,Hee  Jung; Jeong,Hyun  Young; Oh,You  Na; Park,Hyun‑Jin; Yun,Seung-Geun; Kim,Byung  Woo; Kwon,Hyun  Ju

doi:10.3892/or.2015.4075

Widdrol, a sesquiterpene isolated from Juniperus chinensis, inhibits angiogenesis by targeting vascular endothelial growth factor receptor 2 signaling

Authors:
- Soojung Jin
- Hee Jung Yun
- Hyun Young Jeong
- You Na Oh
- Hyun‑Jin Park
- Seung-Geun Yun
- Byung Woo Kim
- Hyun Ju Kwon
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Affiliations: Department of Life Science and Biotechnology, College of Natural Sciences and Human Ecology, Dong-Eui University, Busanjin-gu, Busan 614-714, Republic of Korea, Blue-Bio Industry Regional Innovation Center, Dong-Eui University, Busanjin-gu, Busan 614-714, Republic of Korea
Published online on: June 24, 2015 https://doi.org/10.3892/or.2015.4075
Pages: 1178-1184

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Abstract

Widdrol is an odorous compound derived from Juniperus chinensis that is widely used in traditional medicine to treat fever, inflammation and cancer. It was previously reported that widdrol has antitumor activity by apoptosis induction in cancer cells in vitro. However, its anti-angiogenic activity remains elusive. In the present study, we investigated the anti‑angiogenic activity of widdrol and the molecular mechanisms involved. Widdrol inhibited cell proliferation via G1 phase arrest induction in human umbilical vein endothelial cells (HUVECs) in a dose-dependent manner. Additionally, it was associated with a decreased expression of cyclin-dependent kinase 2 (CDK2) and an increased expression of p21, a CDK inhibitor. Widdrol significantly inhibited the cell migration and tube formation of HUVECs using an in vitro angiogenesis assay. The results showed that widdrol suppressed phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2) and its downstream proteins, such as AKT, focal adhesion kinase (FAK) and endothelial nitric oxide synthase (eNOS). Moreover, widdrol effectively reduced tumor growth and blood vessel formation in colon tumor xenograft mice. Collectively, these results suggested that widdrol may act as a potential anti-angiogenic agent by inhibiting vessel sprouting and growth, which may have implications for angioprevention.

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1	Folkman J: Tumor angiogenesis: Therapeutic implications. N Engl J Med. 285:1182–1186. 1971. View Article : Google Scholar : PubMed/NCBI
2	Kerbel RS: Tumor angiogenesis: Past, present and the near future. Carcinogenesis. 21:505–515. 2000. View Article : Google Scholar : PubMed/NCBI
3	Alon T, Hemo I, Itin A, Pe'er J, Stone J and Keshet E: Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity. Nat Med. 1:1024–1028. 1995. View Article : Google Scholar : PubMed/NCBI
4	Ferrara N: Vascular endothelial growth factor: Molecular and biological aspects. Curr Top Microbiol Immunol. 237:1–30. 1999.PubMed/NCBI
5	Dvorak HF, Brown LF, Detmar M and Dvorak AM: Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol. 146:1029–1039. 1995.PubMed/NCBI
6	Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R and Zeiher AM: Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature. 399:601–605. 1999. View Article : Google Scholar : PubMed/NCBI
7	Olsson AK, Dimberg A, Kreuger J and Claesson-Welsh L: VEGF receptor signalling - in control of vascular function. Nat Rev Mol Cell Biol. 7:359–371. 2006. View Article : Google Scholar : PubMed/NCBI
8	Ferrara N and Kerbel RS: Angiogenesis as a therapeutic target. Nature. 438:967–974. 2005. View Article : Google Scholar : PubMed/NCBI
9	Zheng X, Li A, Zhao L, Zhou T, Shen Q, Cui Q and Qin X: Key role of microRNA-15a in the KLF4 suppressions of proliferation and angiogenesis in endothelial and vascular smooth muscle cells. Biochem Biophys Res Commun. 437:625–631. 2013. View Article : Google Scholar : PubMed/NCBI
10	Roberts JM, Koff A, Polyak K, Firpo E, Collins S, Ohtsubo M and Massagué J: Cyclins, Cdks, and cyclin kinase inhibitors. Cold Spring Harb Symp Quant Biol. 59:31–38. 1994. View Article : Google Scholar : PubMed/NCBI
11	Sherr CJ and Roberts JM: CDK inhibitors: Positive and negative regulators of G1-phase progression. Genes Dev. 13:1501–1512. 1999. View Article : Google Scholar : PubMed/NCBI
12	Kwon HJ, Hong YK, Park C, Choi YH, Yun HJ, Lee EW and Kim BW: Widdrol induces cell cycle arrest, associated with MCM down-regulation, in human colon adenocarcinoma cells. Cancer Lett. 290:96–103. 2010. View Article : Google Scholar
13	Kwon HJ, Lee EW, Hong YK, Yun HJ and Kim BW: Widdrol from Juniperus chinensis induces apoptosis in human colon adenocarcinoma HT29 cells. Biotechnol Bioprocess Eng. 15:167–172. 2010. View Article : Google Scholar
14	Martínez-Poveda B, Muñoz-Chápuli R, Rodríguez-Nieto S, Quintela JM, Fernández A, Medina MA and Quesada AR: IB05204, a dichloropyridodithienotriazine, inhibits angiogenesis in vitro and in vivo. Mol Cancer Ther. 6:2675–2685. 2007. View Article : Google Scholar : PubMed/NCBI
15	Argov M, Kashi R, Peer D and Margalit R: Treatment of resistant human colon cancer xenografts by a fluoxetine-doxorubicin combination enhances therapeutic responses comparable to an aggressive bevacizumab regimen. Cancer Lett. 274:118–125. 2009. View Article : Google Scholar
16	Folkman J: Role of angiogenesis in tumor growth and metastasis. Semin Oncol. 29(Suppl 16): 15–18. 2002. View Article : Google Scholar
17	He D, Jin J, Zheng Y, Bruce IC, Tam S and Ma X: Anti-angiogenesis effect of trichosanthin and the underlying mechanism. Biochem Biophys Res Commun. 430:735–740. 2013. View Article : Google Scholar
18	Rössler J, Taylor M, Geoerger B, Farace F, Lagodny J, Peschka-Süss R, Niemeyer CM and Vassal G: Angiogenesis as a target in neuroblastoma. Eur J Cancer. 44:1645–1656. 2008. View Article : Google Scholar : PubMed/NCBI
19	Shizukuda Y, Tang S, Yokota R and Ware JA: Vascular endothelial growth factor-induced endothelial cell migration and proliferation depend on a nitric oxide-mediated decrease in protein kinase Cdelta activity. Circ Res. 85:247–256. 1999. View Article : Google Scholar : PubMed/NCBI
20	Taimeh Z, Loughran J, Birks EJ and Bolli R: Vascular endothelial growth factor in heart failure. Nat Rev Cardiol. 10:519–530. 2013. View Article : Google Scholar : PubMed/NCBI
21	Eskens FA and Verweij J: The clinical toxicity profile of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors; a review. Eur J Cancer. 42:3127–3139. 2006. View Article : Google Scholar : PubMed/NCBI
22	Saraswati S, Kanaujia PK, Kumar S, Kumar R and Alhaider AA: Tylophorine, a phenanthraindolizidine alkaloid isolated from Tylophora indica exerts antiangiogenic and antitumor activity by targeting vascular endothelial growth factor receptor 2-mediated angiogenesis. Mol Cancer. 12:822013. View Article : Google Scholar : PubMed/NCBI
23	Takahashi S: Vascular endothelial growth factor (VEGF), VEGF receptors and their inhibitors for antiangiogenic tumor therapy. Biol Pharm Bull. 34:1785–1788. 2011. View Article : Google Scholar : PubMed/NCBI
24	Cheng JQ, Lindsley CW, Cheng GZ, Yang H and Nicosia SV: The Akt/PKB pathway: Molecular target for cancer drug discovery. Oncogene. 24:7482–7492. 2005. View Article : Google Scholar : PubMed/NCBI
25	Jiang BH and Liu LZ: AKT signaling in regulating angiogenesis. Curr Cancer Drug Targets. 8:19–26. 2008. View Article : Google Scholar : PubMed/NCBI
26	Yue GG, Chan BC, Kwok HF, Wong YL, Leung HW, Ji CJ, Fung KP, Leung PC, Tan NH and Lau CB: Anti-angiogenesis and immunomodulatory activities of an anti-tumor sesquiterpene bigelovin isolated from Inula helianthus-aquatica. Eur J Med Chem. 59:243–252. 2013. View Article : Google Scholar
27	Hong SW, Jung KH, Lee HS, Son MK, Yan HH, Kang NS, Lee J and Hong SS: SB365, Pulsatilla saponin D, targets c-Met and exerts antiangiogenic and antitumor activities. Carcinogenesis. 34:2156–2169. 2013. View Article : Google Scholar : PubMed/NCBI
28	Wang Y, Ma W and Zheng W: Deguelin, a novel anti-tumorigenic agent targeting apoptosis, cell cycle arrest and anti-angiogenesis for cancer chemoprevention. Mol Clin Oncol. 1:215–219. 2013.
29	Xiao D and Singh SV: Phenethyl isothiocyanate inhibits angiogenesis in vitro and ex vivo. Cancer Res. 67:2239–2246. 2007. View Article : Google Scholar : PubMed/NCBI
30	Liu JX, Luo MQ, Xia M, Wu Q, Long SM, Hu Y, Gao GC, Yao XL, He M, Su H, et al: Marine compound catunaregin inhibits angiogenesis through the modulation of phosphorylation of akt and eNOS in vivo and in vitro. Mar Drugs. 12:2790–2801. 2014. View Article : Google Scholar : PubMed/NCBI
31	Favot L, Keravis T and Lugnier C: Modulation of VEGF-induced endothelial cell cycle protein expression through cyclic AMP hydrolysis by PDE2 and PDE4. Thromb Haemost. 92:634–645. 2004.PubMed/NCBI
32	Shi F, Wang YC, Zhao TZ, Zhang S, Du TY, Yang CB, Li YH and Sun XQ: Effects of simulated microgravity on human umbilical vein endothelial cell angiogenesis and role of the PI3K-Akt-eNOS signal pathway. PLoS One. 7:e403652012. View Article : Google Scholar : PubMed/NCBI