Anti-angiogenic effect of tanshinone IIA involves inhibition of the VEGF/VEGFR2 pathway in vascular endothelial cells

Xing,Yingying; Tu,Jiajie; Zheng,Lufeng; Guo,Le; Xi,Tao

doi:10.3892/or.2014.3592

Anti-angiogenic effect of tanshinone IIA involves inhibition of the VEGF/VEGFR2 pathway in vascular endothelial cells

Authors:
- Yingying Xing
- Jiajie Tu
- Lufeng Zheng
- Le Guo
- Tao Xi
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Affiliations: School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu 210009, P.R. China
Published online on: November 7, 2014 https://doi.org/10.3892/or.2014.3592
Pages: 163-170

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Abstract

Tanshinone IIA (TSA) is one of the major lipophilic components of Salvia miltiorrhiza Bunge reported to exhibit an antitumor effect. The exact intracellular signaling mechanisms involved remain elusive and were therefore the subject of this study. The process of angiogenesis is related to tumor progression, invasion and metastasis and is generally perceived as an indicator of tumor prognosis. Among the most critical factors that induce angiogenesis, the vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) pathway and CD146 (melanoma adhesion molecule) play key roles in this process. This study aimed to demonstrate that TSA has potent anti-angiogenic activity in vitro and ex vivo. Additionally, we evaluated the role of TSA in the VEGF/VEGFR2 pathway. Through a series of in vitro experiments, we found that TSA has a negative effect on cell proliferation, migration and tube formation of human umbilical vascular endothelial cells. We further showed that TSA can inhibit angiogenesis using chorioallantoic membrane (CAM) and rat aortic ring assays. Furthermore, western blotting demonstrated that TSA effectively suppressed the expression of VEGR2 and CD146. These results suggest that TSA inhibits angiogenesis by downregulation of the VEGF/VEGFR2 pathway.

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1	Bussolino F, Mantovani A and Persico G: Molecular mechanisms of blood vessel formation. Trends Biochem Sci. 22:251–256. 1997. View Article : Google Scholar : PubMed/NCBI
2	Li W, Li J, Ashok M, et al: A cardiovascular drug rescues mice from lethal sepsis by selectively attenuating a late-acting proinflammatory mediator, high mobility group box 1. J Immunol. 178:3856–3864. 2007. View Article : Google Scholar : PubMed/NCBI
3	Wang AM, Sha SH, Lesniak W and Schacht J: Tanshinone (Salviae miltiorrhizae extract) preparations attenuate aminoglycoside-induced free radical formation in vitro and ototoxicity in vivo. Antimicrob Agents Chemother. 47:1836–1841. 2003. View Article : Google Scholar : PubMed/NCBI
4	Su CC and Lin YH: Tanshinone IIA downregulates the protein expression of ErbB-2 and upregulates TNF-α in colon cancer cells in vitro and in vivo. Int J Mol Med. 22:847–851. 2008.PubMed/NCBI
5	Su CC: Tanshinone IIA potentiates the efficacy of 5-FU in Colo205 colon cancer cells in vivo through downregulation of P-gp and LC3-II. Exp Ther Med. 3:555–559. 2012.PubMed/NCBI
6	Liu F, Yu G, Wang G, et al: An NQO1-initiated and p53-independent apoptotic pathway determines the anti-tumor effect of tanshinone IIA against non-small cell lung cancer. PLoS One. 7:e421382012. View Article : Google Scholar : PubMed/NCBI
7	Somani RR and Bhanushali UV: Targeting angiogenesis for treatment of human cancer. Indian J Pharm Sci. 75:3–10. 2013. View Article : Google Scholar : PubMed/NCBI
8	Welti J, Loges S, Dimmeler S and Carmeliet P: Recent molecular discoveries in angiogenesis and antiangiogenic therapies in cancer. J Clin Invest. 123:3190–3200. 2013. View Article : Google Scholar : PubMed/NCBI
9	Kim KJ, Li B, Winer J, et al: Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature. 362:841–844. 1993. View Article : Google Scholar : PubMed/NCBI
10	Plate KH, Breier G, Weich HA and Risau W: Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature. 359:845–848. 1992. View Article : Google Scholar : PubMed/NCBI
11	Kang Y, Wang F, Feng J, Yang D, Yang X and Yan X: Knockdown of CD146 reduces the migration and proliferation of human endothelial cells. Cell Res. 16:313–318. 2006. View Article : Google Scholar : PubMed/NCBI
12	Jiang T, Zhuang J, Duan H, et al: CD146 is a coreceptor for VEGFR-2 in tumor angiogenesis. Blood. 120:2330–2339. 2012. View Article : Google Scholar : PubMed/NCBI
13	Wang P, Luo Y, Duan H, et al: MicroRNA 329 suppresses angiogenesis by targeting CD146. Mol Cell Biol. 33:3689–3699. 2013. View Article : Google Scholar : PubMed/NCBI
14	Fanjul-Fernández M, Folgueras AR, Cabrera S and López-Otín C: Matrix metalloproteinases: evolution, gene regulation and functional analysis in mouse models. Biochim Biophys Acta. 1803:3–19. 2010. View Article : Google Scholar
15	Gialeli C, Theocharis AD and Karamanos NK: Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting. FEBS J. 278:16–27. 2011. View Article : Google Scholar
16	Tsai MY, Yang RC, Wu HT, Pang JH and Huang ST: Anti-angiogenic effect of tanshinone IIA involves inhibition of matrix invasion and modification of MMP-2/TIMP-2 secretion in vascular endothelial cells. Cancer Lett. 310:198–206. 2011. View Article : Google Scholar : PubMed/NCBI
17	Deryugina EI and Quigley JP: Pleiotropic roles of matrix metalloproteinases in tumor angiogenesis: contrasting, overlapping and compensatory functions. Biochim Biophys Acta. 1803:103–120. 2010. View Article : Google Scholar :
18	Won SH, Lee HJ, Jeong SJ, et al: Tanshinone IIA induces mitochondria dependent apoptosis in prostate cancer cells in association with an inhibition of phosphoinositide 3-kinase/AKT pathway. Biol Pharm Bull. 33:1828–1834. 2010. View Article : Google Scholar : PubMed/NCBI
19	Jiao JW and Wen F: Tanshinone IIA acts via p38 MAPK to induce apoptosis and the down-regulation of ERCC1 and lung-resistance protein in cisplatin-resistant ovarian cancer cells. Oncol Rep. 25:781–788. 2011.
20	Baudin B, Bruneel A, Bosselut N and Vaubourdolle M: A protocol for isolation and culture of human umbilical vein endothelial cells. Nat Protoc. 2:481–485. 2007. View Article : Google Scholar : PubMed/NCBI
21	Burbridge MF and West DC: Rat aortic ring: 3D model of angiogenesis in vitro. Methods Mol Med. 46:185–204. 2001.
22	Yi T, Cho SG, Yi Z, et al: Thymoquinone inhibits tumor angiogenesis and tumor growth through suppressing AKT and extracellular signal-regulated kinase signaling pathways. Mol Cancer Ther. 7:1789–1796. 2008. View Article : Google Scholar : PubMed/NCBI
23	Cross MJ, Dixelius J, Matsumoto T and Claesson-Welsh L: VEGF-receptor signal transduction. Trends Biochem Sci. 28:488–494. 2003. View Article : Google Scholar : PubMed/NCBI
24	Guo ZY and Cao BL: Advances of VEGF related molecular promoting tumor angiogenesis and targeting therapy. Zhonghua Bing Li Xue Za Zhi. 39:282–284. 2010.(In Chinese). PubMed/NCBI
25	Kaspi E, Guillet B, Piercecchi-Marti MD, et al: Identification of soluble CD146 as a regulator of trophoblast migration: potential role in placental vascular development. Angiogenesis. 16:329–342. 2013. View Article : Google Scholar
26	Hua H, Li M, Luo T, Yin Y and Jiang Y: Matrix metalloproteinases in tumorigenesis: an evolving paradigm. Cell Mol Life Sci. 68:3853–3868. 2011. View Article : Google Scholar : PubMed/NCBI
27	Zhang JD and Zhang Y: Interregulation of VEGF/R endostatin and MMP in the angiogenesis of hematologic malignancies--review. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 13:1145–1150. 2005.(In Chinese).
28	Carmeliet P and Jain RK: Angiogenesis in cancer and other diseases. Nature. 407:249–257. 2000. View Article : Google Scholar : PubMed/NCBI
29	Shan YF, Shen X, Xie YK, et al: Inhibitory effects of tanshinone II-A on invasion and metastasis of human colon carcinoma cells. Acta Pharmacol Sin. 30:1537–1542. 2009. View Article : Google Scholar : PubMed/NCBI
30	Yuxian X, Feng T, Ren L and Zhengcai L: Tanshinone II-A inhibits invasion and metastasis of human hepatocellular carcinoma cells in vitro and in vivo. Tumori. 95:789–795. 2009.
31	Los M, Roodhart JM and Voest EE: Target practice: lessons from phase III trials with bevacizumab and vatalanib in the treatment of advanced colorectal cancer. Oncologist. 12:443–450. 2007. View Article : Google Scholar : PubMed/NCBI
32	Tian S, Quan H, Xie C, et al: YN968D1 is a novel and selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase with potent activity in vitro and in vivo. Cancer Sci. 102:1374–1380. 2011. View Article : Google Scholar : PubMed/NCBI
33	Li X, Claesson-Welsh L and Shibuya M: VEGF receptor signal transduction. Methods Enzymol. 443:261–284. 2008. View Article : Google Scholar : PubMed/NCBI
34	Yan X, Lin Y, Yang D, et al: A novel anti-CD146 monoclonal antibody, AA98, inhibits angiogenesis and tumor growth. Blood. 102:184–191. 2003. View Article : Google Scholar : PubMed/NCBI
35	Shaheen RM, Davis DW, Liu W, et al: Antiangiogenic therapy targeting the tyrosine kinase receptor for vascular endothelial growth factor receptor inhibits the growth of colon cancer liver metastasis and induces tumor and endothelial cell apoptosis. Cancer Res. 59:5412–5416. 1999.PubMed/NCBI
36	Eguchi M, Masuda H and Asahara T: Endothelial progenitor cells for postnatal vasculogenesis. Clin Exp Nephrol. 11:18–25. 2007. View Article : Google Scholar : PubMed/NCBI
37	Packard BZ, Artym VV, Komoriya A and Yamada KM: Direct visualization of protease activity on cells migrating in three-dimensions. Matrix Biol. 28:3–10. 2009. View Article : Google Scholar :