Browse > Article
http://dx.doi.org/10.3746/pnf.2015.20.4.221

Hesperidin Inhibits Vascular Formation by Blocking the AKT/mTOR Signaling Pathways  

Kim, Gi Dae (Department of Food and Nutritional Science, Kyungnam University)
Publication Information
Preventive Nutrition and Food Science / v.20, no.4, 2015 , pp. 221-229 More about this Journal
Abstract
Hesperidin has been shown to possess a potential inhibitory effect on vascular formation in endothelial cells. However, the fundamental mechanism for the anti-angiogenic activity of hesperidin is not fully understood. In the present study, we evaluated whether hesperidin has anti-angiogenic effects in mouse embryonic stem cell (mES)-derived endothelial-like cells, and human umbilical vascular endothelial cells (HUVECs), and evaluated their mechanism via the AKT/mammalian target of rapamycin (mTOR) signaling pathway. The endothelial cells were treated with several doses of hesperidin (12.5, 25, 50, and $100{\mu}M$) for 24 h. Cell viability and vascular formation were analyzed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and tube formation assay, respectively. Alteration of the AKT/mTOR signaling in vascular formation was analyzed by western blot. In addition, a mouse aortic ring assay was used to determine the effect of hesperidin on vascular formation. There were no differences between the viability of mES-derived endothelial-like cells and HUVECs after hesperidin treatment. However, hesperidin significantly inhibited cell migration and tube formation of HUVECs (P<0.05) and suppressed sprouting of microvessels in the mouse aortic ring assay. Moreover, hesperidin suppressed the expression of AKT and mTOR in HUVECs. Taken together, these findings suggest that hesperidin inhibits vascular formation by blocking the AKT/mTOR signaling pathways.
Keywords
hesperidin; vascular formation; AKT/mTOR; HUVECs; mouse embryonic stem cells;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Franco CA, Liebner S, Gerhardt H. 2009. Vascular morphogenesis: a Wnt for every vessel? Curr Opin Genet Dev 19: 476-483.   DOI
2 Gordon MS, Mendelson DS, Kato G. 2010. Tumor angiogenesis and novel antiangiogenic strategies. Int J Cancer 126: 1777-1787.   DOI
3 Cristi E, Perrone G, Toscano G, Verzì A, Nori S, Santini D, Tonini G, Vetrani A, Fabiano A, Rabitti C. 2005. Tumour proliferation, angiogenesis, and ploidy status in human colon cancer. J Clin Pathol 58: 1170-1174.   DOI
4 Kanno S, Oda N, Abe M, Terai Y, Ito M, Shitara K, Tabayashi K, Shibuya M, Sato Y. 2000. Roles of two VEGF receptors, Flt-1 and KDR, in the signal transduction of VEGF effects in human vascular endothelial cells. Oncogene 19: 2138-2146.   DOI
5 Meadows KN, Bryant P, Vincent PA, Pumiglia KM. 2004. Activated Ras induces a proangiogenic phenotype in primary endothelial cells. Oncogene 23: 192-200.   DOI
6 Wu G, Luo J, Rana JS, Laham R, Sellke FW, Li J. 2006. Involvement of COX-2 in VEGF-induced angiogenesis via P38 and JNK pathways in vascular endothelial cells. Cardiovasc Res 69: 512-519.   DOI
7 Bai X, Cerimele F, Ushio-Fukai M, Waqas M, Campbell PM, Govindarajan B, Der CJ, Battle T, Frank DA, Ye K, Murad E, Dubiel W, Soff G, Arbiser JL. 2003. Honokiol, a small molecular weight natural product, inhibits angiogenesis in vitro and tumor growth in vivo. J Biol Chem 278: 35501-35507.   DOI
8 Guru SK, Pathania AS, Kumar S, Ramesh D, Kumar M, Rana S, Kumar A, Malik F, Sharma PR, Chandan BK, Jaglan S, Sharma JP, Shah BA, Tasduq SA, Lattoo SK, Faruk A, Saxena AK, Vishwakarma RA, Bhushan S. 2015. Secalonic acid-D represses HIF-1${\alpha}$/VEGF mediated angiogenesis by regulating the Akt/mTOR/p70S6K signaling cascade. Cancer Res 75: 2886-2896.   DOI
9 Yang Y, Cong H, Han C, Yue L, Dong H, Liu J. 2015. 12-Deoxyphorbol 13-palmitate inhibits the expression of VEGF and HIF-$1{\alpha}$ in MCF-7 cells by blocking the PI3K/Akt/mTOR signaling pathway. Oncol Rep 34: 1755-1760.   DOI
10 Doetschman TC, Eistetter H, Katz M, Schmidt W, Kemler R. 1985. The in vitro development of blastocyst-derived embryonic stem cell lines: formation of visceral yolk sac, blood islands and myocardium. J Embryol Exp Morphol 87: 27-45.
11 Risau W, Sariola H, Zerwes HG, Sasse J, Ekblom P, Kemler R, Doetschman T. 1988. Vasculogenesis and angiogenesis in embryonic-stem-cell-derived embryoid bodies. Development 102: 471-478.
12 Li X, Claesson-Welsh L. 2009. Embryonic stem cell models in vascular biology. J Thromb Haemost 7: 53-56.   DOI
13 Park HJ, Kim MJ, Ha E, Chung JH. 2008. Apoptotic effect of hesperidin through caspase3 activation in human colon cancer cells, SNU-C4. Phytomedicine 15: 147-151.   DOI
14 Kim GD, Kim GJ, Seok JH, Chung HM, Chee KM, Rhee GS. 2008. Differentiation of endothelial cells derived from mouse embryoid bodies: a possible in vitro vasculogenesis model. Toxicol Lett 180: 166-173.   DOI
15 Kim GD, Bae SY, Park HJ, Bae K, Lee SK. 2012. Honokiol inhibits vascular vessel formation of mouse embryonic stem cell-derived endothelial cells via the suppression of PECAM and MAPK/mTOR signaling pathway. Cell Physiol Biochem 30: 758-770.   DOI
16 Benavente-Garcia O, Castillo J. 2008. Update on uses and properties of Citrus flavonoids: new findings in anticancer, cardiovascular, and anti-inflammatory activity. J Agric Food Chem 56: 6185-6205.   DOI
17 Patil JR, Chidambara Murthy KN, Jayaprakasha GK, Chetti MB, Patil BS. 2009. Bioactive compounds from Mexican lime (Citrus aurantifolia) juice induce apoptosis in human pancreatic cells. J Agric Food Chem 57: 10933-10942.   DOI
18 Heuer J, Bremer S, Pohl I, Spielmann H. 1993. Development of an in vitro embryotoxicity test using murine embryonic stem cell cultures. Toxicol In Vitro 7: 551-556.   DOI
19 Scholz G, Pohl I, Genschow E, Klemm M, Spielmann H. 1999. Embryotoxicity screening using embryonic stem cells in vitro: correlation to in vivo teratogenicity. Cells Tissues Organs 165: 203-211.   DOI
20 Baker M, Robinson SD, Lechertier T, Barber PR, Tavora B, D'Amico G, Jones DT, Vojnovic B, Hodivala-Dilke K. 2012. Use of the mouse aortic ring assay to study angiogenesis. Nat Protoc 7: 89-104.
21 Tozer GM, Kanthou C, Baguley BC. 2005. Disrupting tumour blood vessels. Nat Rev Cancer 5: 423-435.   DOI
22 Fresco P, Borges F, Diniz C, Marques MP. 2006. New insights on the anticancer properties of dietary polyphenols. Med Res Rev 26: 747-766.   DOI
23 Karar J, Maity A. 2011. PI3K/AKT/mTOR pathway in angiogenesis. Front Mol Neurosci 4: 51.
24 Kruger EA, Duray PH, Tsokos MG, Venzon DJ, Libutti SK, Dixon SC, Rudek MA, Pluda J, Allegra C, Figg WD. 2000. Endostatin inhibits microvessel formation in the ex vivo rat aortic ring angiogenesis assay. Biochem Biophys Res Commun 268: 183-191.   DOI
25 Beecher GR. 2003. Overview of dietary flavonoids: nomenclature, occurrence and intake. J Nutr 133: 3248S-3254S.   DOI
26 Fotsis T, Pepper MS, Aktas E, Breit S, Rasku S, Adlercreutz H, Wahala K, Montesano R, Schweigerer L. 1997. Flavonoids, dietary-derived inhibitors of cell proliferation and in vitro angiogenesis. Cancer Res 57: 2916-2921.
27 Cao Y, Cao R, Brakenhielm E. 2002. Antiangiogenic mechanisms of diet-derived polyphenols. J Nutr Biochem 13: 380-390.   DOI
28 Tosetti F, Ferrari N, De Flora S, Albini A. 2002. 'Angioprevention': angiogenesis is a common and key target for cancer chemopreventive agents. FASEB J 16: 2-14.   DOI
29 Dorai T, Aggarwal BB. 2004. Role of chemopreventive agents in cancer therapy. Cancer Lett 215: 129-140.   DOI
30 Tong YG, Zhang XW, Geng MY, Yue JM, Xin XL, Tian F, Shen X, Tong LJ, Li MH, Zhang C, Li WH, Lin LP, Ding J. 2006. Pseudolarix acid B, a new tubulin-binding agent, inhibits angiogenesis by interacting with a novel binding site on tubulin. Mol Pharmacol 69: 1226-1233.   DOI
31 Hanahan D, Weinberg RA. 2000. The hallmarks of cancer. Cell 100: 57-70.   DOI
32 Hwang M, Perez CA, Moretti L, Lu B. 2008. The mTOR signaling network: insights from its role during embryonic development. Curr Med Chem 15: 1192-1208.   DOI
33 Chen SH, Murphy DA, Lassoued W, Thurston G, Feldman MD, Lee WM. 2008. Activated STAT3 is a mediator and biomarker of VEGF endothelial activation. Cancer Biol Ther 7: 1994-2003.   DOI
34 Shiojima I, Walsh K. 2002. Role of Akt signaling in vascular homeostasis and angiogenesis. Circ Res 90: 1243-1250.   DOI
35 Cho DH, Choi YJ, Jo SA, Ryou J, Kim JY, Chung J, Jo I. 2006. Troglitazone acutely inhibits protein synthesis in endothelial cells via a novel mechanism involving protein phosphatase 2A-dependent p70 S6 kinase inhibition. Am J Physiol Cell Physiol 291: C317-C326.   DOI
36 Foster KG, Acosta-Jaquez HA, Romeo Y, Ekim B, Soliman GA, Carriere A, Roux PP, Ballif BA, Fingar DC. 2010. Regulation of mTOR complex 1 (mTORC1) by raptor $Ser^{863}$ and multisite phosphorylation. J Biol Chem 285: 80-94.   DOI