Phytochemicals Showing Antiangiogenic Effect in Pre-clinical Models and
their Potential as an Alternative to Existing Therapeutics

Anna      Senrung; Tanya      Tripathi; Nikita      Aggarwal; Divya      Janjua; Joni      Yadav; Apoorva      Chaudhary; Arun      Chhokar; Udit      Joshi; Alok   Chandra   Bharti
doi:10.2174/0115680266264349231016094456
Abstract

Angiogenesis, the formation of new blood vessels from a pre-existing vascular network, is an important hallmark of several pathological conditions, such as tumor growth and metastasis, proliferative retinopathies, including proliferative diabetic retinopathy and retinopathy of prematurity, age-related macular degeneration, rheumatoid arthritis, psoriasis, and endometriosis. Putting a halt to pathology-driven angiogenesis is considered an important therapeutic strategy to slow down or reduce the severity of pathological disorders. Considering the attrition rate of synthetic antiangiogenic compounds from the lab to reaching the market due to severe side effects, several compounds of natural origin are being explored for their antiangiogenic properties. Employing pre-clinical models for the evaluation of novel antiangiogenic compounds is a promising strategy for rapid screening of antiangiogenic compounds. These studies use a spectrum of angiogenic model systems that include HUVEC two-dimensional culture, nude mice, chick chorioallantoic membrane, transgenic zebrafish, and dorsal aorta from rats and chicks, depending upon available resources. The present article emphasizes the antiangiogenic activity of the phytochemicals shown to exhibit antiangiogenic behavior in these well-defined existing angiogenic models and highlights key molecular targets. Different models help to get a quick understanding of the efficacy and therapeutics mechanism of emerging lead molecules. The inherent variability in assays and corresponding different phytochemicals tested in each study prevent their immediate utilization in clinical studies. This review will discuss phytochemicals discovered using suitable preclinical antiangiogenic models, along with a special mention of leads that have entered clinical evaluation.
Keywords: 2D endothelial cell culture, Dorsal aorta, Chick CAM, Transgenic zebrafish, Nude mice, Antiangiogenic phytochemicals.
[1]
Risau, W. Mechanisms of angiogenesis. Nature,  1997, 386(6626), 671-674.
 [http://dx.doi.org/10.1038/386671a0] [PMID: 9109485]

[2]
Patan, S. Vasculogenesis and angiogenesis. Cancer Treat. Res.,  2004, 117, 3-32.
 [http://dx.doi.org/10.1007/978-1-4419-8871-3_1] [PMID: 15015550]

[3]
Pour, L.; Hájek, R.; Buchler, T.; Maisnar, V.; Smolej, L. Angiogenesis and antiangiogenic cancer therapy. Vnitr. Lek.,  2004, 50(12), 930-938.
 [PMID: 15717808]

[4]
Folkman, J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat. Med.,  1995, 1(1), 27-30.
 [http://dx.doi.org/10.1038/nm0195-27] [PMID: 7584949]

[5]
Loizzi, V.; Del Vecchio, V.; Gargano, G.; De Liso, M.; Kardashi, A.; Naglieri, E.; Resta, L.; Cicinelli, E.; Cormio, G. Biological pathways involved in tumor angiogenesis and bevacizumab based anti-angiogenic therapy with special references to ovarian cancer. Int. J. Mol. Sci.,  2017, 18(9), 1967.
 [http://dx.doi.org/10.3390/ijms18091967] [PMID: 28906427]

[6]
Paleolog, E.M. Angiogenesis in rheumatoid arthritis. Arthritis Res.,  2002, 4(Suppl 3), S81-S90.
 [http://dx.doi.org/10.1186/ar575] [PMID: 12110126]

[7]
Heidenreich, R.; Röcken, M.; Ghoreschi, K. Angiogenesis drives psoriasis pathogenesis. Int. J. Exp. Pathol.,  2009, 90(3), 232-248.
 [http://dx.doi.org/10.1111/j.1365-2613.2009.00669.x] [PMID: 19563608]

[8]
Malecic, N.; Young, H.S. Excessive angiogenesis associated with psoriasis as a cause for cardiovascular ischaemia. Exp. Dermatol.,  2017, 26(4), 299-304.
 [http://dx.doi.org/10.1111/exd.13310] [PMID: 28156019]

[9]
Laschke, M.W.; Menger, M.D. Basic mechanisms of vascularization in endometriosis and their clinical implications. Hum. Reprod. Update,  2018, 24(2), 207-224.
 [http://dx.doi.org/10.1093/humupd/dmy001] [PMID: 29377994]

[10]
Angiogenesis inhibitors. 2018. Available from:https://www.cancer.gov/about-cancer/treatment/types/immunotherapy/angiogenesis-inhibitors-fact-sheet# (updated April 2, 2018) 

[11]
Blix, H.S.; Viktil, K.K.; Moger, T.A.; Reikvam, A. Drugs with narrow therapeutic index as indicators in the risk management of hospitalised patients. Pharm. Pract.,  2010, 8(1), 50-55.
 [http://dx.doi.org/10.4321/S1886-36552010000100006] [PMID: 25152793]

[12]
Thomson, R.J.; Moshirfar, M.; Ronquillo, Y. Tyrosine Kinase Inhibitors; StatPearls: Treasure Island, FL, 2021. 

[13]
Cancer Drugs That Block Blood Vessel Growth From Inside Cells May Lead to Serious Health Problems in the Long Term, Study Shows.  Available from:https://www.uclahealth.org/news/cancer-drugs-may-lead-to-serious-health-problems-in-the-long-term

[14]
Cragg, G.M.; Newman, D.J.; Snader, K.M. Natural products in drug discovery and development. J. Nat. Prod.,  1997, 60(1), 52-60.
 [http://dx.doi.org/10.1021/np9604893] [PMID: 9014353]

[15]
Nishida, N.; Yano, H.; Nishida, T.; Kamura, T.; Kojiro, M. Angiogenesis in cancer. Vasc. Health Risk Manag.,  2006, 2(3), 213-219.
 [http://dx.doi.org/10.2147/vhrm.2006.2.3.213] [PMID: 17326328]

[16]
Adair, T.H.; Montani, J.P. Integrated systems physiology: From molecule to function to disease. In: Angiogenesis; Morgan & Claypool Life Sciences: San Rafael (CA), 2010. 

[17]
Felmeden, D.; Blann, A.D.; Lip, G.Y. Angiogenesis: Basic pathophysiology and implications for disease. Eur. Heart J.,  2003, 24(7), 586-603.
 [http://dx.doi.org/10.1016/S0195-668X(02)00635-8] [PMID: 12657217]

[18]
Wang, X.; Bove, A.M.; Simone, G.; Ma, B. Molecular bases of VEGFR-2-mediated physiological function and pathological role. Front. Cell Dev. Biol.,  2020, 8, 599281.
 [http://dx.doi.org/10.3389/fcell.2020.599281] [PMID: 33304904]

[19]
Shibuya, M. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) Signaling in angiogenesis: A crucial target for anti- and pro-angiogenic therapies. Genes Cancer,  2011, 2(12), 1097-1105.
 [http://dx.doi.org/10.1177/1947601911423031] [PMID: 22866201]

[20]
Fearnley, G.W.; Smith, G.A.; Abdul-Zani, I.; Yuldasheva, N.; Mughal, N.A.; Homer-Vanniasinkam, S.; Kearney, M.T.; Zachary, I.C.; Tomlinson, D.C.; Harrison, M.A.; Wheatcroft, S.B.; Ponnambalam, S. VEGF-A isoforms program differential VEGFR2 signal transduction, trafficking and proteolysis. Biol. Open,  2016, 5(5), 571-583.
 [http://dx.doi.org/10.1242/bio.017434] [PMID: 27044325]

[21]
Medina-Leyte, D.J.; Domínguez-Pérez, M.; Mercado, I.; Villarreal-Molina, M.T.; Jacobo-Albavera, L. Use of human umbilical vein endothelial cells (HUVEC) as a model to study cardiovascular disease: A review. Appl. Sci.,  2020, 10(3), 938.
 [http://dx.doi.org/10.3390/app10030938]

[22]
Jaffe, E.A.; Nachman, R.L.; Becker, C.G.; Minick, C.R. Culture of human endothelial cells derived from umbilical veins. Identification by morphologic and immunologic criteria. J. Clin. Invest.,  1973, 52(11), 2745-2756.
 [http://dx.doi.org/10.1172/JCI107470] [PMID: 4355998]

[23]
Maruyama, Y. The human endothelial cell in tissue culture. Cell Tissue Res.,  1963, 60(1), 69-79.
 [http://dx.doi.org/10.1007/BF00329383] [PMID: 13933209]

[24]
Fearnley, G.W.; Smith, G.A.; Odell, A.F.; Latham, A.M.; Wheatcroft, S.B.; Harrison, M.A.; Tomlinson, D.C.; Ponnambalam, S. Vascular endothelial growth factor A-stimulated signaling from endosomes in primary endothelial cells. Methods Enzymol.,  2014, 535, 265-292.
 [http://dx.doi.org/10.1016/B978-0-12-397925-4.00016-X] [PMID: 24377929]

[25]
Jackson, T.; Zheng, X. A cell-based model of endothelial cell migration, proliferation and maturation during corneal angiogenesis. Bull. Math. Biol.,  2010, 72(4), 830-868.
 [http://dx.doi.org/10.1007/s11538-009-9471-1] [PMID: 20052558]

[26]
Lee, E.; Rosca, E.V.; Pandey, N.B.; Popel, A.S. Small peptides derived from somatotropin domain-containing proteins inhibit blood and lymphatic endothelial cell proliferation, migration, adhesion and tube formation. Int. J. Biochem. Cell Biol.,  2011, 43(12), 1812-1821.
 [http://dx.doi.org/10.1016/j.biocel.2011.08.020] [PMID: 21920451]

[27]
Noren, D.P.; Chou, W.H.; Lee, S.H.; Qutub, A.A.; Warmflash, A.; Wagner, D.S.; Popel, A.S.; Levchenko, A. Endothelial cells decode VEGF-mediated Ca 2+ signaling patterns to produce distinct functional responses. Sci. Signal.,  2016, 9(416), ra20.
 [http://dx.doi.org/10.1126/scisignal.aad3188] [PMID: 26905425]

[28]
Kamiloglu, S.; Sari, G.; Ozdal, T.; Capanoglu, E. Guidelines for cell viability assays. Food Front.,  2020, 1(3), 332-349.
 [http://dx.doi.org/10.1002/fft2.44]

[29]
Crane, A.M.; Bhattacharya, S.K. The use of bromodeoxyuridine incorporation assays to assess corneal stem cell proliferation. Methods Mol. Biol.,  2013, 1014, 65-70.
 [http://dx.doi.org/10.1007/978-1-62703-432-6_4] [PMID: 23690005]

[30]
Pijuan, J.; Barceló, C.; Moreno, D.F.; Maiques, O.; Sisó, P.; Marti, R.M.; Macià, A.; Panosa, A. in vitro cell migration, invasion, and adhesion assays: From cell imaging to data analysis. Front. Cell Dev. Biol.,  2019, 7, 107.
 [http://dx.doi.org/10.3389/fcell.2019.00107] [PMID: 31259172]

[31]
Justus, CR; Leffler, N; Ruiz-Echevarria, M; Yang, LV in vitro cell migration and invasion assays. J. Vis. Exp.,  2014, 88, 51046.

[32]
Donovan, D.; Brown, N.J.; Bishop, E.T.; Lewis, C.E. Comparison of three in vitro human ‘angiogenesis’ assays with capillaries formed in vivo. Angiogenesis,  2001, 4(2), 113-121.
 [http://dx.doi.org/10.1023/A:1012218401036] [PMID: 11806243]

[33]
DeCicco-Skinner, K.L.; Henry, G.H.; Cataisson, C.; Tabib, T.; Gwilliam, J.C.; Watson, N.J.; Bullwinkle, E.M.; Falkenburg, L.; O’Neill, R.C.; Morin, A.; Wiest, J.S. Endothelial cell tube formation assay for the in vitro study of angiogenesis. J. Vis. Exp.,  2014, (91), e51312.
 [PMID: 25225985]

[34]
Senger, D.R.; Davis, G.E. Angiogenesis. Cold Spring Harb. Perspect. Biol.,  2011, 3(8), a005090.
 [http://dx.doi.org/10.1101/cshperspect.a005090] [PMID: 21807843]

[35]
Adair, TH.; Montani, JP. Overview of angiogenesis In: Angiogenesis; Morgan & Claypool Life Sciences: San Rafael, CA, 2010. 

[36]
Ko, J.; Lung, M. in vitro human umbilical vein endothelial cells (HUVEC) tube-formation assay. Bio Protoc.,  2012, 2(18)
 [http://dx.doi.org/10.21769/BioProtoc.260]

[37]
Saraswati, S.; Agrawal, S.S. Brucine, an indole alkaloid from Strychnos nux-vomica attenuates VEGF-induced angiogenesis via inhibiting VEGFR2 signaling pathway in vitro and in vivo. Cancer Lett.,  2013, 332(1), 83-93.
 [http://dx.doi.org/10.1016/j.canlet.2013.01.012] [PMID: 23348691]

[38]
Bellacen, K; Lewis, EC Aortic ring assay. J. Vis. Exp.,  2009, 33, 1564.

[39]
Auerbach, R.; Kubai, L.; Knighton, D.; Folkman, J. A simple procedure for the long-term cultivation of chicken embryos. Dev. Biol.,  1974, 41(2), 391-394.
 [http://dx.doi.org/10.1016/0012-1606(74)90316-9] [PMID: 4452416]

[40]
Dupont, É.; Falardeau, P.; Mousa, S.A.; Dimitriadou, V.; Pepin, M.C.; Wang, T.; Alaoui-Jamali, M.A. Antiangiogenic and antimetastatic properties of Neovastat (AE-941), an orally active extract derived from cartilage tissue. Clin. Exp. Metastasis,  2002, 19(2), 145-153.
 [http://dx.doi.org/10.1023/A:1014546909573] [PMID: 11964078]

[41]
Ribatti, D. The chick embryo chorioallantoic membrane (CAM). A multifaceted experimental model. Mech. Dev.,  2016, 141, 70-77.
 [http://dx.doi.org/10.1016/j.mod.2016.05.003] [PMID: 27178379]

[42]
Li, Q.; Wang, Y.; Zhang, L.; Chen, L.; Du, Y.; Ye, T.; Shi, X. Naringenin exerts anti-angiogenic effects in human endothelial cells: Involvement of ERRα/VEGF/KDR signaling pathway. Fitoterapia,  2016, 111, 78-86.
 [http://dx.doi.org/10.1016/j.fitote.2016.04.015] [PMID: 27105956]

[43]
Fang, J.; Zhou, Q.; Liu, L.Z.; Xia, C.; Hu, X.; Shi, X.; Jiang, B.H. Apigenin inhibits tumor angiogenesis through decreasing HIF-1 and VEGF expression. Carcinogenesis,  2006, 28(4), 858-864.
 [http://dx.doi.org/10.1093/carcin/bgl205] [PMID: 17071632]

[44]
Doucette, C.D.; Hilchie, A.L.; Liwski, R.; Hoskin, D.W. Piperine, a dietary phytochemical, inhibits angiogenesis. J. Nutr. Biochem.,  2013, 24(1), 231-239.
 [http://dx.doi.org/10.1016/j.jnutbio.2012.05.009] [PMID: 22902327]

[45]
Mostafa, L.K.; Jones, D.B.; Wright, D.H. Mechanism of the induction of angiogenesis by human neoplastic lymphoid tissue: Studies on the chorioallantoic membrane (CAM) of the chick embryo. J. Pathol.,  1980, 132(3), 191-205.
 [http://dx.doi.org/10.1002/path.1711320302] [PMID: 6159466]

[46]
Ribatti, D. The chick embryo chorioallantoic membrane as an in vivo assay to study antiangiogenesis. Pharmaceuticals,  2010, 3(3), 482-513.
 [http://dx.doi.org/10.3390/ph3030482] [PMID: 27713265]

[47]
Fergelot, P.; Bernhard, J.C.; Soulet, F.; Kilarski, W.W.; Léon, C.; Courtois, N.; Deminière, C.; Herbert, J.M.J.; Antczak, P.; Falciani, F.; Rioux-Leclercq, N.; Patard, J.J.; Ferrière, J.M.; Ravaud, A.; Hagedorn, M.; Bikfalvi, A. The experimental renal cell carcinoma model in the chick embryo. Angiogenesis,  2013, 16(1), 181-194.
 [http://dx.doi.org/10.1007/s10456-012-9311-z] [PMID: 23076651]

[48]
Guerra, J.; Tobia, C.; Presta, M.; Barbieri, A. Zebrafish embryo as an experimental model to study tumor angiogenesis. Tumor Vascularization; Elsevier, 2020, pp. 129-145.

[49]
Shi, Y.W.; Yuan, W.; Wang, X.; Gong, J.; Zhu, S.X.; Chai, L.L.; Qi, J.L.; Qin, Y.Y.; Gao, Y.; Zhou, Y.L.; Fan, X.L.; Ji, C.Y.; Wu, J.Y.; Wang, Z.W.; Liu, D. Combretastatin A-4 efficiently inhibits angiogenesis and induces neuronal apoptosis in zebrafish. Sci. Rep.,  2016, 6(1), 30189.
 [http://dx.doi.org/10.1038/srep30189] [PMID: 27452835]

[50]
Paulissen, S.M.; Castranova, D.M.; Krispin, S.M.; Burns, M.C.; Menéndez, J.; Torres-Vázquez, J.; Weinstein, B.M. Anatomy and development of the pectoral fin vascular network in the zebrafish. Development,  2022, 149(5), dev199676.
 [http://dx.doi.org/10.1242/dev.199676] [PMID: 35132436]

[51]
Hlushchuk, R.; Brönnimann, D.; Correa Shokiche, C.; Schaad, L.; Triet, R.; Jazwinska, A.; Tschanz, S.A.; Djonov, V. Zebrafish caudal fin angiogenesis assay—advanced quantitative assessment including 3-way correlative microscopy. PLoS One,  2016, 11(3), e0149281.
 [http://dx.doi.org/10.1371/journal.pone.0149281] [PMID: 26950851]

[52]
Lam, I.K.; Alex, D.; Wang, Y.H.; Liu, P.; Liu, A.L.; Du, G.H.; Yuen Lee, S.M. in vitro and in vivo structure and activity relationship analysis of polymethoxylated flavonoids: Identifying sinensetin as a novel antiangiogenesis agent. Mol. Nutr. Food Res.,  2012, 56(6), 945-956.
 [http://dx.doi.org/10.1002/mnfr.201100680] [PMID: 22707269]

[53]
Brown, A.P.; Citrin, D.E.; Camphausen, K.A. Clinical biomarkers of angiogenesis inhibition. Cancer Metastasis Rev.,  2008, 27(3), 415-434.
 [http://dx.doi.org/10.1007/s10555-008-9143-x] [PMID: 18414993]

[54]
Verhoeven, D.; Buyssens, N. Desmin-positive stellate cells associated with angiogenesis in a tumour and non-tumour system. Virchows Arch. B Cell Pathol. Incl. Mol. Pathol.,  1988, 54(5), 263-272.
 [PMID: 2451344]

[55]
Arentz, G.; Chataway, T.; Price, T.J.; Izwan, Z.; Hardi, G.; Cummins, A.G.; Hardingham, J.E. Desmin expression in colorectal cancer stroma correlates with advanced stage disease and marks angiogenic microvessels. Clin. Proteomics,  2011, 8(1), 16.
 [http://dx.doi.org/10.1186/1559-0275-8-16] [PMID: 22141345]

[56]
Fox, S.B.; Harris, A.L. Histological quantitation of tumour angiogenesis. Acta Pathol. Microbiol. Scand. Suppl.,  2004, 112(7-8), 413-430.
 [http://dx.doi.org/10.1111/j.1600-0463.2004.apm11207-0803.x] [PMID: 15563306]

[57]
Hlatky, L.; Hahnfeldt, P.; Folkman, J. Clinical application of antiangiogenic therapy: Microvessel density, what it does and doesn’t tell us. J. Natl. Cancer Inst.,  2002, 94(12), 883-893.
 [http://dx.doi.org/10.1093/jnci/94.12.883] [PMID: 12072542]

[58]
Nico, B.; Benagiano, V.; Mangieri, D.; Maruotti, N.; Vacca, A.; Ribatti, D. Evaluation of microvascular density in tumors: Pro and contra. Histol. Histopathol.,  2008, 23(5), 601-607.
 [PMID: 18283645]

[59]
Malinda, K.M. in vivo matrigel migration and angiogenesis assay. Methods Mol. Biol.,  2009, 467, 287-294.
 [http://dx.doi.org/10.1007/978-1-59745-241-0_17] [PMID: 19301678]

[60]
Lung, HL; Lung, ML in vivo matrigel plug angiogenesis assay. Bio-protocol,  2012, 2(18)

[61]
Kastana, P.; Zahra, F.T.; Ntenekou, D.; Katraki-Pavlou, S.; Beis, D.; Lionakis, M.S.; Mikelis, C.M.; Papadimitriou, E. Matrigel plug assay for in vivo evaluation of angiogenesis. Methods Mol. Biol.,  2019, 1952, 219-232.
 [http://dx.doi.org/10.1007/978-1-4939-9133-4_18] [PMID: 30825178]

[62]
Kim, S.M.; Lee, J.H.; Sethi, G.; Kim, C.; Baek, S.H.; Nam, D.; Chung, W.S.; Kim, S.H.; Shim, B.S.; Ahn, K.S. Bergamottin, a natural furanocoumarin obtained from grapefruit juice induces chemosensitization and apoptosis through the inhibition of STAT3 signaling pathway in tumor cells. Cancer Lett.,  2014, 354(1), 153-163.
 [http://dx.doi.org/10.1016/j.canlet.2014.08.002] [PMID: 25130169]

[63]
Jung, J.E.; Kim, H.S.; Lee, C.S.; Park, D.H.; Kim, Y.N.; Lee, M.J.; Lee, J.W.; Park, J.W.; Kim, M.S.; Ye, S.K.; Chung, M.H. Caffeic acid and its synthetic derivative CADPE suppress tumor angiogenesis by blocking STAT3-mediated VEGF expression in human renal carcinoma cells. Carcinogenesis,  2007, 28(8), 1780-1787.
 [http://dx.doi.org/10.1093/carcin/bgm130] [PMID: 17557905]

[64]
Cui, K.; Liu, J.; Huang, L.; Qin, B.; Yang, X.; Li, L.; Liu, Y.; Gu, J.; Wu, W.; Yu, Y.; Sang, A. Andrographolide attenuates choroidal neovascularization by inhibiting the HIF-1α/VEGF signaling pathway. Biochem. Biophys. Res. Commun.,  2020, 530(1), 60-66.
 [http://dx.doi.org/10.1016/j.bbrc.2020.06.130] [PMID: 32828316]

[65]
Peyman, G.A.; Kivilcim, M.; Morales, A.M.; DellaCroce, J.T.; Conway, M.D. Inhibition of corneal angiogenesis by ascorbic acid in the rat model. Graefes Arch. Clin. Exp. Ophthalmol.,  2007, 245(10), 1461-1467.
 [http://dx.doi.org/10.1007/s00417-007-0542-4] [PMID: 17318569]

[66]
Izumi-Nagai, K.; Nagai, N.; Ohgami, K.; Satofuka, S.; Ozawa, Y.; Tsubota, K.; Ohno, S.; Oike, Y.; Ishida, S. Inhibition of choroidal neovascularization with an anti-inflammatory carotenoid astaxanthin. Invest. Ophthalmol. Vis. Sci.,  2008, 49(4), 1679-1685.
 [http://dx.doi.org/10.1167/iovs.07-1426] [PMID: 18385091]

[67]
Arbiser, J.L.; Klauber, N.; Rohan, R.; van Leeuwen, R.; Huang, M.T.; Fisher, C.; Flynn, E.; Byers, H.R. Curcumin is an in vivo inhibitor of angiogenesis. Mol. Med.,  1998, 4(6), 376-383.
 [http://dx.doi.org/10.1007/BF03401744] [PMID: 10780880]

[68]
Mahoney, J.M.; Waterbury, L.D. Drug effects on the neovascularization response to silver nitrate cauterization of the rat cornea. Curr. Eye Res.,  1985, 4(5), 531-535.
 [http://dx.doi.org/10.3109/02713688508999984] [PMID: 2410194]

[69]
Kenyon, B.M.; Voest, E.E.; Chen, C.C.; Flynn, E.; Folkman, J.; D’Amato, R.J. A model of angiogenesis in the mouse cornea. Invest. Ophthalmol. Vis. Sci.,  1996, 37(8), 1625-1632.
 [PMID: 8675406]

[70]
Seyhan, A.A. Lost in translation: the valley of death across preclinical and clinical divide – identification of problems and overcoming obstacles. Transl. Med. Commun.,  2019, 4(1), 18.
 [http://dx.doi.org/10.1186/s41231-019-0050-7]

[71]
Yamaguchi, S.; Kaneko, M.; Narukawa, M. Approval success rates of drug candidates based on target, action, modality, application, and their combinations. Clin. Transl. Sci.,  2021, 14(3), 1113-1122.
 [http://dx.doi.org/10.1111/cts.12980] [PMID: 33831276]

[72]
Ades, E.W.; Candal, F.J.; Swerlick, R.A.; George, V.G.; Summers, S.; Bosse, D.C.; Lawley, T.J. HMEC-1: Establishment of an immortalized human microvascular endothelial cell line. J. Invest. Dermatol.,  1992, 99(6), 683-690.
 [http://dx.doi.org/10.1111/1523-1747.ep12613748] [PMID: 1361507]

[73]
Oosterhoff, LA; Kruitwagen, HS; Spee, B; van Steenbeek, FG Isolation and culture of primary endothelial cells from canine arteries and veins. J. Vis. Exp.,  2016, 117, 54786.

[74]
Geraghty, R.J.; Capes-Davis, A.; Davis, J.M.; Downward, J.; Freshney, R.I.; Knezevic, I.; Lovell-Badge, R.; Masters, J.R.W.; Meredith, J.; Stacey, G.N.; Thraves, P.; vias, M. Guidelines for the use of cell lines in biomedical research. Br. J. Cancer,  2014, 111(6), 1021-1046.
 [http://dx.doi.org/10.1038/bjc.2014.166] [PMID: 25117809]

[75]
Aplin, A.C.; Fogel, E.; Zorzi, P.; Nicosia, R.F. The aortic ring model of angiogenesis. Methods Enzymol.,  2008, 443, 119-136.
 [http://dx.doi.org/10.1016/S0076-6879(08)02007-7] [PMID: 18772014]

[76]
Nicosia, R.F. The aortic ring model of angiogenesis: A quarter century of search and discovery. J. Cell. Mol. Med.,  2009, 13(10), 4113-4136.
 [http://dx.doi.org/10.1111/j.1582-4934.2009.00891.x] [PMID: 19725916]

[77]
Gao, Y.; Lu, N.; Ling, Y.; Chen, Y.; Wang, L.; Zhao, Q.; Qi, Q.; Liu, W.; Zhang, H.; You, Q.; Guo, Q. Oroxylin A inhibits angiogenesis through blocking vascular endothelial growth factor-induced KDR/Flk-1 phosphorylation. J. Cancer Res. Clin. Oncol.,  2010, 136(5), 667-675.
 [http://dx.doi.org/10.1007/s00432-009-0705-2] [PMID: 19888602]

[78]
Russell, W.M.S.; Burch, R.L. The principles of humane experimental technique. 1992. Available from:https://caat.jhsph.edu/principles/chap4d

[79]
Division of animaly facility: ICMR, National institute of nutrition.  Available from:https://www.nin.res.in/researchdivision/animal_facility.html

[80]
Laboratory Animal Services: Current price list.  Available from:https://www.adelaide.edu.au/animal-services/products-services/current-price-list

[81]
Laboratory animal welfare.  Available from:https://grants.nih.gov/grants/olaw/references/ilar91.htm

[82]
Eckrich, J.; Kugler, P.; Buhr, C.R.; Ernst, B.P.; Mendler, S.; Baumgart, J.; Brieger, J.; Wiesmann, N. Monitoring of tumor growth and vascularization with repetitive ultrasonography in the chicken chorioallantoic-membrane-assay. Sci. Rep.,  2020, 10(1), 18585.
 [http://dx.doi.org/10.1038/s41598-020-75660-y] [PMID: 33122780]

[83]
Schmitd, LB; Liu, M; Scanlon, CS; Banerjee, R; D'Silva, NJ The chick chorioallantoic membrane in vivo model to assess perineural invasion in head and neck cancer. J. Vis. Exp.,  2019, 148, 59296.

[84]
Ribatti, D. The chick embryo chorioallantoic membrane as a model for tumor biology. Exp. Cell Res.,  2014, 328(2), 314-324.
 [http://dx.doi.org/10.1016/j.yexcr.2014.06.010] [PMID: 24972385]

[85]
White, R.; Rose, K.; Zon, L. Zebrafish cancer: The state of the art and the path forward. Nat. Rev. Cancer,  2013, 13(9), 624-636.
 [http://dx.doi.org/10.1038/nrc3589] [PMID: 23969693]

[86]
Astone, M.; Dankert, E.N.; Alam, S.K.; Hoeppner, L.H. Fishing for cures: The alLURE of using zebrafish to develop precision oncology therapies. NPJ Precis. Oncol.,  2017, 1(1), 39.
 [http://dx.doi.org/10.1038/s41698-017-0043-9] [PMID: 29376139]

[87]
Yan, C.; Do, D.; Yang, Q.; Brunson, D.C.; Rawls, J.F.; Langenau, D.M. Single-cell imaging of human cancer xenografts using adult immunodeficient zebrafish. Nat. Protoc.,  2020, 15(9), 3105-3128.
 [http://dx.doi.org/10.1038/s41596-020-0372-y] [PMID: 32826993]

[88]
Howe, K.; Clark, M.D.; Torroja, C.F.; Torrance, J.; Berthelot, C.; Muffato, M.; Collins, J.E.; Humphray, S.; McLaren, K.; Matthews, L.; McLaren, S.; Sealy, I.; Caccamo, M.; Churcher, C.; Scott, C.; Barrett, J.C.; Koch, R.; Rauch, G.J.; White, S.; Chow, W.; Kilian, B.; Quintais, L.T.; Guerra-Assunção, J.A.; Zhou, Y.; Gu, Y.; Yen, J.; Vogel, J.H.; Eyre, T.; Redmond, S.; Banerjee, R.; Chi, J.; Fu, B.; Langley, E.; Maguire, S.F.; Laird, G.K.; Lloyd, D.; Kenyon, E.; Donaldson, S.; Sehra, H.; Almeida-King, J.; Loveland, J.; Trevanion, S.; Jones, M.; Quail, M.; Willey, D.; Hunt, A.; Burton, J.; Sims, S.; McLay, K.; Plumb, B.; Davis, J.; Clee, C.; Oliver, K.; Clark, R.; Riddle, C.; Elliott, D.; Threadgold, G.; Harden, G.; Ware, D.; Begum, S.; Mortimore, B.; Kerry, G.; Heath, P.; Phillimore, B.; Tracey, A.; Corby, N.; Dunn, M.; Johnson, C.; Wood, J.; Clark, S.; Pelan, S.; Griffiths, G.; Smith, M.; Glithero, R.; Howden, P.; Barker, N.; Lloyd, C.; Stevens, C.; Harley, J.; Holt, K.; Panagiotidis, G.; Lovell, J.; Beasley, H.; Henderson, C.; Gordon, D.; Auger, K.; Wright, D.; Collins, J.; Raisen, C.; Dyer, L.; Leung, K.; Robertson, L.; Ambridge, K.; Leongamornlert, D.; McGuire, S.; Gilderthorp, R.; Griffiths, C.; Manthravadi, D.; Nichol, S.; Barker, G.; Whitehead, S.; Kay, M.; Brown, J.; Murnane, C.; Gray, E.; Humphries, M.; Sycamore, N.; Barker, D.; Saunders, D.; Wallis, J.; Babbage, A.; Hammond, S.; Mashreghi-Mohammadi, M.; Barr, L.; Martin, S.; Wray, P.; Ellington, A.; Matthews, N.; Ellwood, M.; Woodmansey, R.; Clark, G.; Cooper, J.D.; Tromans, A.; Grafham, D.; Skuce, C.; Pandian, R.; Andrews, R.; Harrison, E.; Kimberley, A.; Garnett, J.; Fosker, N.; Hall, R.; Garner, P.; Kelly, D.; Bird, C.; Palmer, S.; Gehring, I.; Berger, A.; Dooley, C.M.; Ersan-Ürün, Z.; Eser, C.; Geiger, H.; Geisler, M.; Karotki, L.; Kirn, A.; Konantz, J.; Konantz, M.; Oberländer, M.; Rudolph-Geiger, S.; Teucke, M.; Lanz, C.; Raddatz, G.; Osoegawa, K.; Zhu, B.; Rapp, A.; Widaa, S.; Langford, C.; Yang, F.; Schuster, S.C.; Carter, N.P.; Harrow, J.; Ning, Z.; Herrero, J.; Searle, S.M.J.; Enright, A.; Geisler, R.; Plasterk, R.H.A.; Lee, C.; Westerfield, M.; de Jong, P.J.; Zon, L.I.; Postlethwait, J.H.; Nüsslein-Volhard, C.; Hubbard, T.J.P.; Crollius, H.R.; Rogers, J.; Stemple, D.L. The zebrafish reference genome sequence and its relationship to the human genome. Nature,  2013, 496(7446), 498-503.
 [http://dx.doi.org/10.1038/nature12111] [PMID: 23594743]

[89]
Tegelenbosch, R.A.J.; Noldus, L.P.J.J.; Richardson, M.K.; Ahmad, F. Zebrafish embryos and larvae in behavioural assays. Behaviour,  2012, 149(10-12), 1241-1281.
 [http://dx.doi.org/10.1163/1568539X-00003020]

[90]
Kunz, P.; Schenker, A.; Sähr, H.; Lehner, B.; Fellenberg, J. Optimization of the chicken chorioallantoic membrane assay as reliable in vivo model for the analysis of osteosarcoma. PLoS One,  2019, 14(4), e0215312.
 [http://dx.doi.org/10.1371/journal.pone.0215312] [PMID: 30986223]

[91]
Ekins, S.; Mestres, J.; Testa, B. in silico pharmacology for drug discovery: Methods for virtual ligand screening and profiling. Br. J. Pharmacol.,  2007, 152(1), 9-20.
 [http://dx.doi.org/10.1038/sj.bjp.0707305] [PMID: 17549047]

[92]
Fareed, M.M.; El-Esawi, M.A.; El-Ballat, E.M.; Batiha, G.E.S.; Rauf, A.; El-Demerdash, F.M.; Alhumaydhi, F.A.; Alsagaby, S.A. in silico drug screening analysis against the overexpression of PGAM1 gene in different cancer treatments. BioMed Res. Int.,  2021, 2021, 1-7.
 [http://dx.doi.org/10.1155/2021/5515692] [PMID: 34195264]

[93]
Katritch, V.; Jaakola, V.P.; Lane, J.R.; Lin, J.; IJzerman, A.P.; Yeager, M.; Kufareva, I.; Stevens, R.C.; Abagyan, R. Structure-based discovery of novel chemotypes for adenosine A(2A) receptor antagonists. J. Med. Chem.,  2010, 53(4), 1799-1809.
 [http://dx.doi.org/10.1021/jm901647p] [PMID: 20095623]

[94]
Lyu, J.; Wang, S.; Balius, T.E.; Singh, I.; Levit, A.; Moroz, Y.S.; O’Meara, M.J.; Che, T.; Algaa, E.; Tolmachova, K.; Tolmachev, A.A.; Shoichet, B.K.; Roth, B.L.; Irwin, J.J. Ultra-large library docking for discovering new chemotypes. Nature,  2019, 566(7743), 224-229.
 [http://dx.doi.org/10.1038/s41586-019-0917-9] [PMID: 30728502]

[95]
Trott, O.; Olson, A.J. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem.,  2010, 31(2), 455-461.
 [PMID: 19499576]

[96]
Huang, Y.; Xiao, D.; Burton-Freeman, B.M.; Edirisinghe, I. Chemical Changes of Bioactive Phytochemicals during Thermal Processing; Reference Module in Food Science, 2016. 
 [http://dx.doi.org/10.1016/B978-0-08-100596-5.03055-9]

[97]
Mushtaq, S.; Abbasi, B.H.; Uzair, B.; Abbasi, R. Natural products as reservoirs of novel therapeutic agents. EXCLI J.,  2018, 17, 420-451.
 [PMID: 29805348]

[98]
Elaine, M. Chapter 21 - Phenols. In: Pharmacology; Elaine M, A.CB.; Kenneth, V., Eds.; Churchill Livingstone, 2009; pp. 149-166.

[99]
Terpenes, A.E. Pharmacology,  2009, II, 167-174.

[100]
Dey, P.; Kundu, A.; Kumar, A.; Gupta, M.; Lee, B.M.; Bhakta, T. Analysis of alkaloids (indole alkaloids, isoquinoline alkaloids, tropane alkaloids); Recent Advances in Natural Products Analysis, 2020, pp. 505-567.
 [http://dx.doi.org/10.1016/B978-0-12-816455-6.00015-9]

[101]
Ain, Q.U.; Khan, H.; Mubarak, M.S.; Pervaiz, A. Plant alkaloids as antiplatelet agent: Drugs of the future in the light of recent developments. Front. Pharmacol.,  2016, 7, 292.
 [http://dx.doi.org/10.3389/fphar.2016.00292] [PMID: 27713699]

[102]
Minatel, I.O.; Borges, C.V.; Ferreira, M.I.; Gomez, H.A.G.; Chen, C-Y.O.; Lima, G.P.P. Phenolic compounds: Functional properties, impact of processing and bioavailability. In: Phenolic Compounds - Biological Activity; InTech, 2017. 

[103]
Perveen, S. introductory Chapter: Terpenes and terpenoids. In: Terpenes and Terpenoids; InTech, 2018. 
 [http://dx.doi.org/10.5772/intechopen.71175]

[104]
Yang, W.; Chen, X.; Li, Y.; Guo, S.; Wang, Z.; Yu, X. Advances in pharmacological activities of terpenoids. Nat. Prod. Commun.,  2020, 15(3), 1934578X2090355.
 [http://dx.doi.org/10.1177/1934578X20903555]

[105]
Ye, X.; Lin, M. Homoharringtonine induces apoptosis of endothelium and down-regulates VEGF expression of K562 cells. J. Zhejiang Univ. Sci.,  2004, 5(2), 230-234.
 [http://dx.doi.org/10.1631/jzus.2004.0230] [PMID: 14674038]

[106]
Chung, C.H.; Chang, C.H.; Chen, S.S.; Wang, H.H.; Yen, J.Y.; Hsiao, C.J.; Wu, N.L.; Chen, Y.L.; Huang, T.F.; Wang, P.C.; Yeh, H.I.; Wang, S.W. Butein inhibits angiogenesis of human endothelial progenitor cells via the translation dependent signaling pathway. Evid. Based Complement. Alternat. Med.,  2013, 2013, 1-10.
 [http://dx.doi.org/10.1155/2013/943187] [PMID: 23840271]

[107]
Zhang, Y.; He, L.; Meng, L.; Luo, W. Taspine isolated from Radix et Rhizoma Leonticis inhibits proliferation and migration of endothelial cells as well as chicken chorioallantoic membrane neovascularisation. Vascul. Pharmacol.,  2008, 48(2-3), 129-137.
 [http://dx.doi.org/10.1016/j.vph.2008.01.008] [PMID: 18304881]

[108]
Zhao, J.; Zhao, L.; Chen, W.; He, L.; Li, X. Taspine downregulates VEGF expression and inhibits proliferation of vascular endothelial cells through PI3 kinase and MAP kinase signaling pathways. Biomed. Pharmacother.,  2008, 62(6), 383-389.
 [http://dx.doi.org/10.1016/j.biopha.2007.07.013] [PMID: 17826025]

[109]
Guruvayoorappan, C.; Kuttan, G. Inhibition of tumor specific angiogenesis by amentoflavone. Biochemistry,  2008, 73(2), 209-218.
 [http://dx.doi.org/10.1134/S0006297908020132] [PMID: 18298378]

[110]
Bertl, E.; Bartsch, H.; Gerhäuser, C. Inhibition of angiogenesis and endothelial cell functions are novel sulforaphane-mediated mechanisms in chemoprevention. Mol. Cancer Ther.,  2006, 5(3), 575-585.
 [http://dx.doi.org/10.1158/1535-7163.MCT-05-0324] [PMID: 16546971]

[111]
Kim, J.H.; Shim, J.S.; Lee, S.K.; Kim, K.W.; Rha, S.Y.; Chung, H.C.; Kwon, H.J. Microarray-based analysis of anti-angiogenic activity of demethoxycurcumin on human umbilical vein endothelial cells: Crucial involvement of the down-regulation of matrix metalloproteinase. Jpn. J. Cancer Res.,  2002, 93(12), 1378-1385.
 [http://dx.doi.org/10.1111/j.1349-7006.2002.tb01247.x] [PMID: 12495478]

[112]
Piao, M.; Mori, D.; Satoh, T.; Sugita, Y.; Tokunaga, O. Inhibition of endothelial cell proliferation, in vitro angiogenesis, and the down-regulation of cell adhesion-related genes by genistein. Combined with a cDNA microarray analysis. Endothelium,  2006, 13(4), 249-266.
 [http://dx.doi.org/10.1080/10623320600903940] [PMID: 16990182]

[113]
Zhang, J.; Liu, Z.; Cao, W.; Chen, L.; Xiong, X.; Qin, S.; Zhang, Z.; Li, X.; Hu, C.A. Amentoflavone inhibits angiogenesis of endothelial cells and stimulates apoptosis in hypertrophic scar fibroblasts. Burns,  2014, 40(5), 922-929.
 [http://dx.doi.org/10.1016/j.burns.2013.10.012] [PMID: 24280521]

[114]
Lee, J.H.; Lee, D.H.; Lee, H.S.; Choi, J.S.; Kim, K.W.; Hong, S.S. Deguelin inhibits human hepatocellular carcinoma by antiangiogenesis and apoptosis. Oncol. Rep.,  2008, 20(1), 129-134.
 [http://dx.doi.org/10.3892/or.20.1.129] [PMID: 18575727]

[115]
Li, M.; Yu, X.; Li, W.; Liu, T.; Deng, G.; Liu, W.; Liu, H.; Gao, F. Deguelin suppresses angiogenesis in human hepatocellular carcinoma by targeting HGF-c-Met pathway. Oncotarget,  2018, 9(1), 152-166.
 [http://dx.doi.org/10.18632/oncotarget.22077] [PMID: 29416603]

[116]
Liu, P.; Atkinson, S.J.; Akbareian, S.E.; Zhou, Z.; Munsterberg, A.; Robinson, S.D.; Bao, Y. Sulforaphane exerts anti-angiogenesis effects against hepatocellular carcinoma through inhibition of STAT3/HIF-1α/VEGF signalling. Sci. Rep.,  2017, 7(1), 12651.
 [http://dx.doi.org/10.1038/s41598-017-12855-w] [PMID: 28978924]

[117]
Gao, J.L.; Ji, X.; He, T.C.; Zhang, Q.; He, K.; Zhao, Y.; Chen, S.H.; Lv, G.Y. Tetrandrine suppresses cancer angiogenesis and metastasis in 4T1 tumor bearing Mice. Evid. Based Complement. Alternat. Med.,  2013, 2013, 1-12.
 [http://dx.doi.org/10.1155/2013/265061] [PMID: 23762115]

[118]
Kim, G.D. Myricetin inhibits angiogenesis by inducing apoptosis and suppressing PI3K/Akt/mTOR signaling in endothelial cells. J. Cancer Prev.,  2017, 22(4), 219-227.
 [http://dx.doi.org/10.15430/JCP.2017.22.4.219] [PMID: 29302579]

[119]
Zhou, Y.X.; Huang, Y.L. Antiangiogenic effect of celastrol on the growth of human glioma: An in vitro and in vivo study. Chin. Med. J.,  2009, 122(14), 1666-1673.
 [PMID: 19719969]

[120]
Yang, S.H.; Lin, J.K.; Chen, W.S.; Chiu, J.H. Anti-angiogenic effect of silymarin on colon cancer lovo cell line. J. Surg. Res.,  2003, 113(1), 133-138.
 [http://dx.doi.org/10.1016/S0022-4804(03)00229-4] [PMID: 12943822]

[121]
Min, J.K.; Han, K.Y.; Kim, E.C.; Kim, Y.M.; Lee, S.W.; Kim, O.H.; Kim, K.W.; Gho, Y.S.; Kwon, Y.G. Capsaicin inhibits in vitro and in vivo angiogenesis. Cancer Res.,  2004, 64(2), 644-651.
 [http://dx.doi.org/10.1158/0008-5472.CAN-03-3250] [PMID: 14744780]

[122]
Shyu, K.G.; Lin, S.; Lee, C.C.; Chen, E.; Lin, L.C.; Wang, B.W.; Tsai, S.C. Evodiamine inhibits in vitro angiogenesis: Implication for antitumorgenicity. Life Sci.,  2006, 78(19), 2234-2243.
 [http://dx.doi.org/10.1016/j.lfs.2005.09.027] [PMID: 16280136]

[123]
Song, X.; Chen, Y.; Sun, Y.; Lin, B.; Qin, Y.; Hui, H.; Li, Z.; You, Q.; Lu, N.; Guo, Q. Oroxylin A, a classical natural product, shows a novel inhibitory effect on angiogenesis induced by lipopolysaccharide. Pharmacol. Rep.,  2012, 64(5), 1189-1199.
 [http://dx.doi.org/10.1016/S1734-1140(12)70915-5] [PMID: 23238475]

[124]
Lopes, F.C.M.; Rocha, A.; Pirraco, A.; Regasini, L.O.; Silva, D.H.S.; Bolzani, V.S.; Azevedo, I.; Carlos, I.Z.; Soares, R. Anti-angiogenic effects of pterogynidine alkaloid isolated from Alchornea glandulosa. BMC Complement. Altern. Med.,  2009, 9(1), 15.
 [http://dx.doi.org/10.1186/1472-6882-9-15] [PMID: 19463163]

[125]
Liu, H.; Tang, L.; Li, X.; Li, H. Triptolide inhibits vascular endothelial growth factor‑mediated angiogenesis in human breast cancer cells. Exp. Ther. Med.,  2018, 16(2), 830-836.
 [http://dx.doi.org/10.3892/etm.2018.6200] [PMID: 30116337]

[126]
Lee, H.J.; Lee, H.J.; Magesh, V.; Nam, D.; Lee, E.O.; Ahn, K.S.; Jung, M.H.; Ahn, K.S.; Kim, D.K.; Kim, J.Y.; Kim, S.H. Shikonin, acetylshikonin, and isobutyroylshikonin inhibit VEGF-induced angiogenesis and suppress tumor growth in lewis lung carcinoma-bearing mice. Yakugaku Zasshi,  2008, 128(11), 1681-1688.
 [http://dx.doi.org/10.1248/yakushi.128.1681] [PMID: 18981704]

[127]
Xu, Y.; Xu, X.; Gao, X.; Chen, H.; Geng, L. Shikonin suppresses IL-17-induced VEGF expression via blockage of JAK2/STAT3 pathway. Int. Immunopharmacol.,  2014, 19(2), 327-333.
 [http://dx.doi.org/10.1016/j.intimp.2014.01.027] [PMID: 24521871]

[128]
Huang, H.; Chen, A.Y.; Rojanasakul, Y.; Ye, X.; Rankin, G.O.; Chen, Y.C. Dietary compounds galangin and myricetin suppress ovarian cancer cell angiogenesis. J. Funct. Foods,  2015, 15, 464-475.
 [http://dx.doi.org/10.1016/j.jff.2015.03.051] [PMID: 26113875]

[129]
Saito, K.; Matsuo, Y.; Imafuji, H.; Okubo, T.; Maeda, Y.; Sato, T.; Shamoto, T.; Tsuboi, K.; Morimoto, M.; Takahashi, H.; Ishiguro, H.; Takiguchi, S. Xanthohumol inhibits angiogenesis by suppressing nuclear factor-κB activation in pancreatic cancer. Cancer Sci.,  2018, 109(1), 132-140.
 [http://dx.doi.org/10.1111/cas.13441] [PMID: 29121426]

[130]
Park, J.H.; Park, G.M.; Kim, J.K. Zerumbone, sesquiterpene photochemical from ginger, inhibits angiogenesis. Korean J. Physiol. Pharmacol.,  2015, 19(4), 335-340.
 [http://dx.doi.org/10.4196/kjpp.2015.19.4.335] [PMID: 26170737]

[131]
Tsuboi, K.; Matsuo, Y.; Shamoto, T.; Shibata, T.; Koide, S.; Morimoto, M.; Guha, S.; Sung, B.; Aggarwal, B.B.; Takahashi, H.; Takeyama, H. Zerumbone inhibits tumor angiogenesis via NF-κB in gastric cancer. Oncol. Rep.,  2014, 31(1), 57-64.
 [http://dx.doi.org/10.3892/or.2013.2842] [PMID: 24220661]

[132]
Samad, N.A.; Abdul, A.B.; Rahman, H.S.; Rasedee, A.; Tengku Ibrahim, T.A.; Keon, Y.S. Zerumbone suppresses angiogenesis in HepG2 cells through inhibition of matrix metalloproteinase-9, vascular endothelial growth factor, and vascular endothelial growth factor receptor expressions. Pharmacogn. Mag.,  2018, 13(Suppl. 4), S731-S736.
 [PMID: 29491625]

[133]
Xu, J.Y.; Meng, Q.H.; Chong, Y.; Jiao, Y.; Zhao, L.; Rosen, E.M.; Fan, S. Sanguinarine is a novel VEGF inhibitor involved in the suppression of angiogenesis and cell migration. Mol. Clin. Oncol.,  2013, 1(2), 331-336.
 [http://dx.doi.org/10.3892/mco.2012.41] [PMID: 24649171]

[134]
Wang, N.; Wang, Z.Y.; Mo, S.L.; Loo, T.Y.; Wang, D.M.; Luo, H.B.; Yang, D.P.; Chen, Y.L.; Shen, J.G.; Chen, J.P. Ellagic acid, a phenolic compound, exerts anti-angiogenesis effects via VEGFR-2 signaling pathway in breast cancer. Breast Cancer Res. Treat.,  2012, 134(3), 943-955.
 [http://dx.doi.org/10.1007/s10549-012-1977-9] [PMID: 22350787]

[135]
Chen, Y.; Lu, N.; Ling, Y.; Gao, Y.; Wang, L.; Sun, Y.; Qi, Q.; Feng, F.; Liu, W.; Liu, W.; You, Q.; Guo, Q. Wogonoside inhibits lipopolysaccharide-induced angiogenesis in vitro and in vivo via toll-like receptor 4 signal transduction. Toxicology,  2009, 259(1-2), 10-17.
 [http://dx.doi.org/10.1016/j.tox.2009.01.010] [PMID: 19428938]

[136]
Jie, S.; Li, H.; Tian, Y.; Guo, D.; Zhu, J.; Gao, S.; Jiang, L. Berberine inhibits angiogenic potential of Hep G2 cell line through VEGF down-regulation in vitro. J. Gastroenterol. Hepatol.,  2011, 26(1), 179-185.
 [http://dx.doi.org/10.1111/j.1440-1746.2010.06389.x] [PMID: 21175812]

[137]
Xu, X.; Wu, L.; Zhou, X.; Zhou, N.; Zhuang, Q.; Yang, J.; Dai, J.; Wang, H.; Chen, S.; Mao, W. Cryptotanshinone inhibits VEGF-induced angiogenesis by targeting the VEGFR2 signaling pathway. Microvasc. Res.,  2017, 111, 25-31.
 [http://dx.doi.org/10.1016/j.mvr.2016.12.011] [PMID: 28040437]

[138]
Yuan, X.; Li, J.; Li, Y.; Deng, Z.; Zhou, L.; Long, J.; Tang, Y.; Zuo, Z.; Zhang, Y.; Xie, H. Artemisinin, a potential option to inhibit inflammation and angiogenesis in rosacea. Biomed. Pharmacother.,  2019, 117, 109181.
 [http://dx.doi.org/10.1016/j.biopha.2019.109181] [PMID: 31387196]

[139]
Kowshik, J.; Baba, A.B.; Giri, H.; Deepak Reddy, G.; Dixit, M.; Nagini, S. Astaxanthin inhibits JAK/STAT-3 signaling to abrogate cell proliferation, invasion and angiogenesis in a hamster model of oral cancer. PLoS One,  2014, 9(10), e109114.
 [http://dx.doi.org/10.1371/journal.pone.0109114] [PMID: 25296162]

[140]
Luo, W.; Wang, X.; Zheng, L.; Zhan, Y.; Zhang, D.; Zhang, J.; Zhang, Y. Brucine suppresses colon cancer cells growth via mediating KDR signalling pathway. J. Cell. Mol. Med.,  2013, 17(10), 1316-1324.
 [http://dx.doi.org/10.1111/jcmm.12108] [PMID: 23905676]

[141]
Lin, C.M.; Shyu, K.G.; Wang, B.W.; Chang, H.; Chen, Y.H.; Chiu, J.H. Chrysin suppresses IL-6-induced angiogenesis via down-regulation of JAK1/STAT3 and VEGF: An in vitro and in ovo approach. J. Agric. Food Chem.,  2010, 58(11), 7082-7087.
 [http://dx.doi.org/10.1021/jf100421w] [PMID: 20443595]

[142]
Omi, K.; Matsuo, Y.; Ueda, G.; Aoyama, Y.; Kato, T.; Hayashi, Y.; Imafuji, H.; Saito, K.; Tsuboi, K.; Morimoto, M.; Ogawa, R.; Takahashi, H.; Takiguchi, S. Escin inhibits angiogenesis by suppressing interleukin‑8 and vascular endothelial growth factor production by blocking nuclear factor‑κB activation in pancreatic cancer cell lines. Oncol. Rep.,  2021, 45(5), 55.
 [http://dx.doi.org/10.3892/or.2021.8006] [PMID: 33760162]

[143]
Shi, L.; Yang, F.; Luo, F.; Liu, Y.; Zhang, F.; Zou, M.; Liu, Q. Evodiamine exerts anti-tumor effects against hepatocellular carcinoma through inhibiting β-catenin-mediated angiogenesis. Tumour Biol.,  2016, 37(9), 12791-12803.
 [http://dx.doi.org/10.1007/s13277-016-5251-3] [PMID: 27449032]

[144]
Bhat, T.A.; Nambiar, D.; Pal, A.; Agarwal, R.; Singh, R.P. Fisetin inhibits various attributes of angiogenesis in vitro and in vivo--implications for angioprevention. Carcinogenesis,  2012, 33(2), 385-393.
 [http://dx.doi.org/10.1093/carcin/bgr282] [PMID: 22139440]

[145]
Chen, D.; Li, D.; Xu, X.; Qiu, S.; Luo, S.; Qiu, E.; Rong, Z.; Zhang, J.; Zheng, D. Galangin inhibits epithelial-mesenchymal transition and angiogenesis by downregulating CD44 in glioma. J. Cancer,  2019, 10(19), 4499-4508.
 [http://dx.doi.org/10.7150/jca.31487] [PMID: 31528214]

[146]
Lu, Y.; Jiang, F.; Jiang, H.; Wu, K.; Zheng, X.; Cai, Y.; Katakowski, M.; Chopp, M.; To, S.S.T. Gallic acid suppresses cell viability, proliferation, invasion and angiogenesis in human glioma cells. Eur. J. Pharmacol.,  2010, 641(2-3), 102-107.
 [http://dx.doi.org/10.1016/j.ejphar.2010.05.043] [PMID: 20553913]

[147]
Zhao, B.; Hu, M. Gallic acid reduces cell viability, proliferation, invasion and angiogenesis in human cervical cancer cells. Oncol. Lett.,  2013, 6(6), 1749-1755.
 [http://dx.doi.org/10.3892/ol.2013.1632] [PMID: 24843386]

[148]
Su, S.J.; Yeh, T.M.; Chuang, W.J.; Ho, C.L.; Chang, K.L.; Cheng, H.L.; Liu, H.S.; Cheng, H.L.; Hsu, P.Y.; Chow, N.H. The novel targets for anti-angiogenesis of genistein on human cancer cells. Biochem. Pharmacol.,  2005, 69(2), 307-318.
 [http://dx.doi.org/10.1016/j.bcp.2004.09.025] [PMID: 15627483]

[149]
Wittig, C.; Scheuer, C.; Parakenings, J.; Menger, M.D.; Laschke, M.W. Geraniol suppresses angiogenesis by downregulating vascular endothelial growth factor (VEGF)/VEGFR-2 signaling. PLoS One,  2015, 10(7), e0131946.
 [http://dx.doi.org/10.1371/journal.pone.0131946] [PMID: 26154255]

[150]
Tsai, Y.M.; Yang, C.J.; Hsu, Y.L.; Wu, L.Y.; Tsai, Y.C.; Hung, J.Y.; Lien, C.T.; Huang, M.S.; Kuo, P.L. Glabridin inhibits migration, invasion, and angiogenesis of human non-small cell lung cancer A549 cells by inhibiting the FAK/rho signaling pathway. Integr. Cancer Ther.,  2011, 10(4), 341-349.
 [http://dx.doi.org/10.1177/1534735410384860] [PMID: 21059620]

[151]
Kim, K.J.; Choi, J.S.; Kim, K.W.; Jeong, J.W. The anti-angiogenic activities of glycyrrhizic acid in tumor progression. Phytother. Res.,  2013, 27(6), 841-846.
 [http://dx.doi.org/10.1002/ptr.4800] [PMID: 22899320]

[152]
Lee, E.O.; Lee, H.J.; Hwang, H.S.; Ahn, K.S.; Chae, C.; Kang, K.S.; Lu, J.; Kim, S.H. Potent inhibition of Lewis lung cancer growth by heyneanol A from the roots of Vitis amurensis through apoptotic and anti-angiogenic activities. Carcinogenesis,  2006, 27(10), 2059-2069.
 [http://dx.doi.org/10.1093/carcin/bgl055] [PMID: 16675471]

[153]
He, L.; Wu, Y.; Lin, L.; Wang, J.; Wu, Y.; Chen, Y.; Yi, Z.; Liu, M.; Pang, X. Hispidulin, a small flavonoid molecule, suppresses the angiogenesis and growth of human pancreatic cancer by targeting vascular endothelial growth factor receptor 2-mediated PI3K/Akt/mTOR signaling pathway. Cancer Sci.,  2011, 102(1), 219-225.
 [http://dx.doi.org/10.1111/j.1349-7006.2010.01778.x] [PMID: 21087351]

[154]
Bai, X.; Cerimele, F.; Ushio-Fukai, M.; Waqas, M.; Campbell, P.M.; Govindarajan, B.; Der, C.J.; Battle, T.; Frank, D.A.; Ye, K.; Murad, E.; Dubiel, W.; Soff, G.; Arbiser, J.L. Honokiol, a small molecular weight natural product, inhibits angiogenesis in vitro and tumor growth in vivo. J. Biol. Chem.,  2003, 278(37), 35501-35507.
 [http://dx.doi.org/10.1074/jbc.M302967200] [PMID: 12816951]

[155]
Zhu, W.; Fu, A.; Hu, J.; Wang, T.; Luo, Y.; Peng, M.; Ma, Y.; Wei, Y.; Chen, L. 5-Formylhonokiol exerts anti-angiogenesis activity via inactivating the ERK signaling pathway. Exp. Mol. Med.,  2011, 43(3), 146-152.
 [http://dx.doi.org/10.3858/emm.2011.43.3.017] [PMID: 21297378]

[156]
Sun, Z.J.; Chen, G.; Zhang, W.; Hu, X.; Huang, C.F.; Wang, Y.F.; Jia, J.; Zhao, Y.F. Mammalian target of rapamycin pathway promotes tumor-induced angiogenesis in adenoid cystic carcinoma: Its suppression by isoliquiritigenin through dual activation of c-Jun NH2-terminal kinase and inhibition of extracellular signal-regulated kinase. J. Pharmacol. Exp. Ther.,  2010, 334(2), 500-512.
 [http://dx.doi.org/10.1124/jpet.110.167692] [PMID: 20484154]

[157]
Wang, Z.; Wang, N.; Han, S.; Wang, D.; Mo, S.; Yu, L.; Huang, H.; Tsui, K.; Shen, J.; Chen, J. Dietary compound isoliquiritigenin inhibits breast cancer neoangiogenesis via VEGF/VEGFR-2 signaling pathway. PLoS One,  2013, 8(7), e68566.
 [http://dx.doi.org/10.1371/journal.pone.0068566] [PMID: 23861918]

[158]
Liang, F.; Han, Y.; Gao, H.; Xin, S.; Chen, S.; Wang, N.; Qin, W.; Zhong, H.; Lin, S.; Yao, X.; Li, S. Kaempferol identified by zebrafish assay and fine fractionations strategy from dysosma versipellis inhibits angiogenesis through VEGF and FGF pathways. Sci. Rep.,  2015, 5(1), 14468.
 [http://dx.doi.org/10.1038/srep14468] [PMID: 26446489]

[159]
Chin, H.K.; Horng, C.T.; Liu, Y.S.; Lu, C.C.; Su, C.Y.; Chen, P.S.; Chiu, H.Y.; Tsai, F.J.; Shieh, P.C.; Yang, J.S. Kaempferol inhibits angiogenic ability by targeting VEGF receptor-2 and downregulating the PI3K/AKT, MEK and ERK pathways in VEGF-stimulated human umbilical vein endothelial cells. Oncol. Rep.,  2018, 39(5), 2351-2357.
 [http://dx.doi.org/10.3892/or.2018.6312] [PMID: 29565448]

[160]
Kim, Y.H.; Shin, E.K.; Kim, D.H.; Lee, H.H.; Park, J.H.Y.; Kim, J.K. Antiangiogenic effect of licochalcone A. Biochem. Pharmacol.,  2010, 80(8), 1152-1159.
 [http://dx.doi.org/10.1016/j.bcp.2010.07.006] [PMID: 20637733]

[161]
Kangsamaksin, T.; Chaithongyot, S.; Wootthichairangsan, C.; Hanchaina, R.; Tangshewinsirikul, C.; Svasti, J. Lupeol and stigmasterol suppress tumor angiogenesis and inhibit cholangiocarcinoma growth in mice via downregulation of tumor necrosis factor-α. PLoS One,  2017, 12(12), e0189628.
 [http://dx.doi.org/10.1371/journal.pone.0189628] [PMID: 29232409]

[162]
Li, X.; Chen, M.; Lei, X.; Huang, M.; Ye, W.; Zhang, R.; Zhang, D. Luteolin inhibits angiogenesis by blocking Gas6/Axl signaling pathway. Int. J. Oncol.,  2017, 51(2), 677-685.
 [http://dx.doi.org/10.3892/ijo.2017.4041] [PMID: 28627676]

[163]
Zhang, X.; Hou, G.; Liu, A.; Xu, H.; Guan, Y.; Wu, Y.; Deng, J.; Cao, X. Matrine inhibits the development and progression of ovarian cancer by repressing cancer associated phosphorylation signaling pathways. Cell Death Dis.,  2019, 10(10), 770.
 [http://dx.doi.org/10.1038/s41419-019-2013-3] [PMID: 31601793]

[164]
Yue, M.; Zeng, N.; Xia, Y.; Wei, Z.; Dai, Y. Morin exerts anti-arthritic effects by attenuating synovial angiogenesis via activation of peroxisome proliferator activated receptor-γ. Mol. Nutr. Food Res.,  2018, 62(21), 1800202.
 [http://dx.doi.org/10.1002/mnfr.201800202] [PMID: 30160015]

[165]
Zhou, Z.; Mao, W.; Li, Y.; Qi, C.; He, Y. Myricetin inhibits breast tumor growth and angiogenesis by regulating VEGF/VEGFR2 and p38MAPK signaling pathways. Anat. Rec.,  2019, 302(12), 2186-2192.
 [http://dx.doi.org/10.1002/ar.24222] [PMID: 31266091]

[166]
Babykutty, S.; S, P.P.; J, N.R.; Kumar, M.A.; Nair, M.S.; Srinivas, P.; Gopala, S. Nimbolide retards tumor cell migration, invasion, and angiogenesis by downregulating MMP-2/9 expression via inhibiting ERK1/2 and reducing DNA-binding activity of NF-κB in colon cancer cells. Mol. Carcinog.,  2012, 51(6), 475-490.
 [http://dx.doi.org/10.1002/mc.20812] [PMID: 21678498]

[167]
Pratheeshkumar, P.; Kuttan, G. Nomilin inhibits tumor-specific angiogenesis by downregulating VEGF, NO and proinflammatory cytokine profile and also by inhibiting the activation of MMP-2 and MMP-9. Eur. J. Pharmacol.,  2011, 668(3), 450-458.
 [http://dx.doi.org/10.1016/j.ejphar.2011.07.029] [PMID: 21839074]

[168]
Li, X.; Fan, S.; Pan, X.; Xiaokaiti, Y.; Duan, J.; Shi, Y.; Pan, Y.; Tie, L.; Wang, X.; Li, Y.; Li, X. Nordihydroguaiaretic acid impairs prostate cancer cell migration and tumor metastasis by suppressing neuropilin 1. Oncotarget,  2016, 7(52), 86225-86238.
 [http://dx.doi.org/10.18632/oncotarget.13368] [PMID: 27863391]

[169]
Newcomb, E.W.; Lukyanov, Y.; Schnee, T.; Ali, M.A.; Lan, L.; Zagzag, D. Noscapine inhibits hypoxia-mediated HIF-1alpha expression andangiogenesis in vitro: A novel function for an old drug. Int. J. Oncol.,  2006, 28(5), 1121-1130.
 [PMID: 16596228]

[170]
Sohn, K.H.; Lee, H.Y.; Chung, H.Y.; Young, H.S.; Yi, S.Y.; Kim, K.W. Anti-angiogenic activity of triterpene acids. Cancer Lett.,  1995, 94(2), 213-218.
 [http://dx.doi.org/10.1016/0304-3835(95)03856-R] [PMID: 7543366]

[171]
Li, L.; Lin, J.; Sun, G.; Wei, L.; Shen, A.; Zhang, M.; Peng, J. Oleanolic acid inhibits colorectal cancer angiogenesis in vivo and in vitro via  suppression of STAT3 and Hedgehog pathways. Mol. Med. Rep.,  2016, 13(6), 5276-5282.
 [http://dx.doi.org/10.3892/mmr.2016.5171] [PMID: 27108756]

[172]
Lai, S.L.; Cheah, S.C.; Wong, P.F.; Noor, S.M.; Mustafa, M.R. in vitro and in vivo anti-angiogenic activities of panduratin A. PLoS One,  2012, 7(5), e38103.
 [http://dx.doi.org/10.1371/journal.pone.0038103] [PMID: 22666456]

[173]
Hsiao, Y.H.; Hsieh, M.J.; Yang, S.F.; Chen, S.P.; Tsai, W.C.; Chen, P.N. Phloretin suppresses metastasis by targeting protease and inhibits cancer stemness and angiogenesis in human cervical cancer cells. Phytomedicine,  2019, 62, 152964.
 [http://dx.doi.org/10.1016/j.phymed.2019.152964] [PMID: 31153059]

[174]
Liu, Y.; Chang, Y.; Yang, C.; Sang, Z.; Yang, T.; Ang, W.; Ye, W.; Wei, Y.; Gong, C.; Luo, Y. Biodegradable nanoassemblies of piperlongumine display enhanced anti-angiogenesis and anti-tumor activities. Nanoscale,  2014, 6(8), 4325-4337.
 [http://dx.doi.org/10.1039/C3NR06599E] [PMID: 24622772]

[175]
Yu, Y.; Cai, W.; Pei, C.; Shao, Y. Rhamnazin, a novel inhibitor of VEGFR2 signaling with potent antiangiogenic activity and antitumor efficacy. Biochem. Biophys. Res. Commun.,  2015, 458(4), 913-919.
 [http://dx.doi.org/10.1016/j.bbrc.2015.02.059] [PMID: 25704088]

[176]
Huang, S.; Zheng, R. Rosmarinic acid inhibits angiogenesis and its mechanism of action in vitro. Cancer Lett.,  2006, 239(2), 271-280.
 [http://dx.doi.org/10.1016/j.canlet.2005.08.025] [PMID: 16239062]

[177]
Kim, J.H.; Lee, B.J.; Kim, J.H.; Yu, Y.S.; Kim, M.Y.; Kim, K.W. Rosmarinic acid suppresses retinal neovascularization via cell cycle arrest with increase of p21WAF1 expression. Eur. J. Pharmacol.,  2009, 615(1-3), 150-154.
 [http://dx.doi.org/10.1016/j.ejphar.2009.05.015] [PMID: 19470386]

[178]
Eun, J.P.; Koh, G.Y. Suppression of angiogenesis by the plant alkaloid, sanguinarine. Biochem. Biophys. Res. Commun.,  2004, 317(2), 618-624.
 [http://dx.doi.org/10.1016/j.bbrc.2004.03.077] [PMID: 15063803]

[179]
Liu, C.; He, L.; Wang, J.; Wang, Q.; Sun, C.; Li, Y.; Jia, K.; Wang, J.; Xu, T.; Ming, R.; Wang, Q.; Lin, N. Anti-angiogenic effect of shikonin in rheumatoid arthritis by downregulating PI3K/AKT and MAPKs signaling pathways. J. Ethnopharmacol.,  2020, 260, 113039.
 [http://dx.doi.org/10.1016/j.jep.2020.113039] [PMID: 32497675]

[180]
Kok, T.W.; Yue, P.Y.K.; Mak, N.K.; Fan, T.P.D.; Liu, L.; Wong, R.N.S. The anti-angiogenic effect of sinomenine. Angiogenesis,  2005, 8(1), 3-12.
 [http://dx.doi.org/10.1007/s10456-005-2892-z] [PMID: 16132613]

[181]
Xie, T.; Ren, H.Y.; Lin, H.Q.; Mao, J.P.; Zhu, T.; Wang, S.D.; Ye, Z.M. Sinomenine prevents metastasis of human osteosarcoma cells via S phase arrest and suppression of tumor-related neovascularization and osteolysis through the CXCR4-STAT3 pathway. Int. J. Oncol.,  2016, 48(5), 2098-2112.
 [http://dx.doi.org/10.3892/ijo.2016.3416] [PMID: 26983669]

[182]
Nizamutdinova, I.T.; Lee, G.W.; Lee, J.S.; Cho, M.K.; Son, K.H.; Jeon, S.J.; Kang, S.S.; Kim, Y.S.; Lee, J.H.; Seo, H.G.; Chang, K.C.; Kim, H.J. Tanshinone I suppresses growth and invasion of human breast cancer cells, MDA-MB-231, through regulation of adhesion molecules. Carcinogenesis,  2008, 29(10), 1885-1892.
 [http://dx.doi.org/10.1093/carcin/bgn151] [PMID: 18586687]

[183]
Wang, Y.; Li, J.X.; Wang, Y.Q.; Miao, Z.H. Tanshinone I inhibits tumor angiogenesis by reducing STAT3 phosphorylation at TYR705 and hypoxia-induced HIF-1α accumulation in both endothelial and tumor cells. Oncotarget,  2015, 6(18), 16031-16042.
 [http://dx.doi.org/10.18632/oncotarget.3648] [PMID: 26202747]

[184]
Sui, H.; Zhao, J.; Zhou, L.; Wen, H.; Deng, W.; Li, C.; Ji, Q.; Liu, X.; Feng, Y.; Chai, N.; Zhang, Q.; Cai, J.; Li, Q. Tanshinone IIA inhibits β-catenin/VEGF-mediated angiogenesis by targeting TGF-β1 in normoxic and HIF-1α in hypoxic microenvironments in human colorectal cancer. Cancer Lett.,  2017, 403, 86-97.
 [http://dx.doi.org/10.1016/j.canlet.2017.05.013] [PMID: 28602978]

[185]
Lee, H.P.; Liu, Y.C.; Chen, P.C.; Tai, H.C.; Li, T.M.; Fong, Y.C.; Chang, C.S.; Wu, M.H.; Chiu, L.P.; Wang, C.J.; Chen, Y.H.; Wu, Y.J.; Tang, C.H.; Wang, S.W. Tanshinone IIA inhibits angiogenesis in human endothelial progenitor cells in vitro and in vivo. Oncotarget,  2017, 8(65), 109217-109227.
 [http://dx.doi.org/10.18632/oncotarget.22649] [PMID: 29312602]

[186]
Wei, S.; Fukuhara, H.; Chen, G.; Kawada, C.; Kurabayashi, A.; Furihata, M.; Inoue, K.; Shuin, T. Terrestrosin D, a steroidal saponin from Tribulus terrestris L., inhibits growth and angiogenesis of human prostate cancer in vitro and in vivo. Pathobiology,  2014, 81(3), 123-132.
 [http://dx.doi.org/10.1159/000357622] [PMID: 24642631]

[187]
Chen, Y.; Chen, J.C.; Tseng, S.H. Tetrandrine suppresses tumor growth and angiogenesis of gliomas in rats. Int. J. Cancer,  2009, 124(10), 2260-2269.
 [http://dx.doi.org/10.1002/ijc.24208] [PMID: 19165864]

[188]
Xiao, W.; Jiang, Y.; Men, Q.; Yuan, L.; Huang, Z.; Liu, T.; Li, W.; Liu, X. Tetrandrine induces G1/S cell cycle arrest through the ROS/Akt pathway in EOMA cells and inhibits angiogenesis in vivo. Int. J. Oncol.,  2015, 46(1), 360-368.
 [http://dx.doi.org/10.3892/ijo.2014.2735] [PMID: 25355542]

[189]
Gao, Y.; Rankin, G.O.; Tu, Y.; Chen, Y.C. Theaflavin-3, 3′-digallate decreases human ovarian carcinoma OVCAR-3 cell-induced angiogenesis via Akt and Notch-1 pathways, not via MAPK pathways. Int. J. Oncol.,  2016, 48(1), 281-292.
 [http://dx.doi.org/10.3892/ijo.2015.3257] [PMID: 26648098]

[190]
Xu, X.; Tian, L.; Zhang, Z. RETRACTED ARTICLE: Triptolide inhibits angiogenesis in microvascular endothelial cells through regulation of miR-92a. J. Physiol. Biochem.,  2019, 75(4), 573-583.
 [http://dx.doi.org/10.1007/s13105-019-00707-2] [PMID: 31691162]

[191]
Mohan, R.; Hammers, H.; Bargagna-mohan, P.; Zhan, X.; Herbstritt, C.; Ruiz, A.; Zhang, L.; Hanson, A.; Conner, B.; Rougas, J.; Pribluda, V. Withaferin A is a potent inhibitor of angiogenesis. Angiogenesis,  2004, 7(2), 115-122.
 [http://dx.doi.org/10.1007/s10456-004-1026-3] [PMID: 15516832]

[192]
Fu, R.; Chen, Y.; Wang, X.P.; An, T.; Tao, L.; Zhou, Y.X.; Huang, Y.J.; Chen, B.A.; Li, Z.Y.; You, Q.D.; Guo, Q.L.; Wu, Z.Q. Wogonin inhibits multiple myeloma-stimulated angiogenesis via c-Myc/VHL/HIF-1α signaling axis. Oncotarget,  2016, 7(5), 5715-5727.
 [http://dx.doi.org/10.18632/oncotarget.6796] [PMID: 26735336]

[193]
Huang, Y.; Zhao, K.; Hu, Y.; Zhou, Y.; Luo, X.; Li, X.; Wei, L.; Li, Z.; You, Q.; Guo, Q.; Lu, N. Wogonoside inhibits angiogenesis in breast cancer via suppressing Wnt/β-catenin pathway. Mol. Carcinog.,  2016, 55(11), 1598-1612.
 [http://dx.doi.org/10.1002/mc.22412] [PMID: 26387984]

[194]
Lin, B.; Zhao, K.; Yang, D.; Bai, D.; Liao, Y.; Zhou, Y.; Yu, Z.; Yu, X.; Guo, Q.; Lu, N. Wogonoside impedes the progression of acute myeloid leukemia through inhibiting bone marrow angiogenesis. J. Cell. Physiol.,  2019, 234(2), 1913-1924.
 [http://dx.doi.org/10.1002/jcp.27067] [PMID: 30105796]

[195]
Yan, Y.; Yao, L.; Sun, H.; Pang, S.; Kong, X.; Zhao, S.; Xu, S. Effects of wogonoside on invasion and migration of lung cancer A549 cells and angiogenesis in xenograft tumors of nude mice. J. Thorac. Dis.,  2020, 12(4), 1552-1560.
 [http://dx.doi.org/10.21037/jtd-20-1555] [PMID: 32395292]

[196]
Negrão, R.; Costa, R.; Duarte, D.; Gomes, T.T.; Azevedo, I.; Soares, R. Different effects of catechin on angiogenesis and inflammation depending on VEGF levels. J. Nutr. Biochem.,  2013, 24(2), 435-444.
 [http://dx.doi.org/10.1016/j.jnutbio.2011.12.011] [PMID: 22704779]

[197]
Tabana, Y.M.; Hassan, L.E.A.; Ahamed, M.B.K.; Dahham, S.S.; Iqbal, M.A.; Saeed, M.A.A.; Khan, M.S.S.; Sandai, D.; Majid, A.S.A.; Oon, C.E.; Majid, A.M.S.A. Scopoletin, an active principle of tree tobacco (Nicotiana glauca) inhibits human tumor vascularization in xenograft models and modulates ERK1, VEGF-A, and FGF-2 in computer model. Microvasc. Res.,  2016, 107, 17-33.
 [http://dx.doi.org/10.1016/j.mvr.2016.04.009] [PMID: 27133199]

[198]
Luo, H.; Rankin, G.O.; Liu, L.; Daddysman, M.K.; Jiang, B.H.; Chen, Y.C. Kaempferol inhibits angiogenesis and VEGF expression through both HIF dependent and independent pathways in human ovarian cancer cells. Nutr. Cancer,  2009, 61(4), 554-563.
 [http://dx.doi.org/10.1080/01635580802666281] [PMID: 19838928]

[199]
Li, B.; Tong, T.; Ren, N.; Rankin, G.O.; Rojanasakul, Y.; Tu, Y.; Chen, Y.C. Theasaponin E1 inhibits platinum-resistant ovarian cancer cells through activating apoptosis and suppressing angiogenesis. Molecules,  2021, 26(6), 1681.
 [http://dx.doi.org/10.3390/molecules26061681] [PMID: 33802884]

[200]
Ma, J.; Zhang, Y.; Li, R.; Ye, J.; Li, H.; Zhang, Y.; Ma, Z.; Li, J.; Zhong, X.; Yang, X. Tetrandrine suppresses human glioma growth by inhibiting cell survival, proliferation and tumour angiogenesis through attenuating STAT3 phosphorylation. Eur. J. Pharmacol.,  2015, 764, 228-239.
 [http://dx.doi.org/10.1016/j.ejphar.2015.06.017] [PMID: 26086859]

[201]
Tarallo, V.; Lepore, L.; Marcellini, M.; Dal Piaz, F.; Tudisco, L.; Ponticelli, S.; Lund, F.W.; Roepstorff, P.; Orlandi, A.; Pisano, C.; De Tommasi, N.; De Falco, S. The biflavonoid amentoflavone inhibits neovascularization preventing the activity of proangiogenic vascular endothelial growth factors. J. Biol. Chem.,  2011, 286(22), 19641-19651.
 [http://dx.doi.org/10.1074/jbc.M110.186239] [PMID: 21471210]

[202]
Lin, C.M.; Chang, H.; Li, S.Y.; Wu, I.H.; Chiu, J.H. Chrysin inhibits lipopolysaccharide-induced angiogenesis via down-regulation of VEGF/VEGFR-2(KDR) and IL-6/IL-6R pathways. Planta Med.,  2006, 72(8), 708-714.
 [http://dx.doi.org/10.1055/s-2006-931602] [PMID: 16732516]

[203]
Shah, B.B.; Baksi, R.; Chaudagar, K.K.; Nivsarkar, M.; Mehta, A.A. Anti-leukemic and anti-angiogenic effects of D -Limonene on K562-implanted C57BL/6 mice and the chick chorioallantoic membrane model. Animal Model. Exp. Med.,  2018, 1(4), 328-333.
 [http://dx.doi.org/10.1002/ame2.12039] [PMID: 30891583]

[204]
Liao, Z.H.; Zhu, H.Q.; Chen, Y.Y.; Chen, R.L.; Fu, L.X.; Li, L.; Zhou, H.; Zhou, J.L.; Liang, G. The epigallocatechin gallate derivative Y6 inhibits human hepatocellular carcinoma by inhibiting angiogenesis in MAPK/ERK1/2 and PI3K/AKT/HIF-1α/VEGF dependent pathways. J. Ethnopharmacol.,  2020, 259, 112852.
 [http://dx.doi.org/10.1016/j.jep.2020.112852] [PMID: 32278759]

[205]
Jhanji, V.; Liu, H.; Law, K.; Lee, V.Y.W.; Huang, S.F.; Pang, C.P.; Yam, G.H.F. Isoliquiritigenin from licorice root suppressed neovascularisation in experimental ocular angiogenesis models. Br. J. Ophthalmol.,  2011, 95(9), 1309-1315.
 [http://dx.doi.org/10.1136/bjophthalmol-2011-300110] [PMID: 21719569]

[206]
Ambasta, R.K.; Jha, S.K.; Kumar, D.; Sharma, R.; Jha, N.K.; Kumar, P. Comparative study of anti-angiogenic activities of luteolin, lectin and lupeol biomolecules. J. Transl. Med.,  2015, 13(1), 307.
 [http://dx.doi.org/10.1186/s12967-015-0665-z] [PMID: 26385094]

[207]
Mousa, S.S.; Mousa, S.S.; Mousa, S.A. Effect of resveratrol on angiogenesis and platelet/fibrin-accelerated tumor growth in the chick chorioallantoic membrane model. Nutr. Cancer,  2005, 52(1), 59-65.
 [http://dx.doi.org/10.1207/s15327914nc5201_8] [PMID: 16091005]

[208]
Thirusangu, P.; Vigneshwaran, V.; Vijay Avin, B.R.; Rakesh, H.; Vikas, H.M.; Prabhakar, B.T. Scutellarein antagonizes the tumorigenesis by modulating cytokine VEGF mediated neoangiogenesis and DFF-40 actuated nucleosomal degradation. Biochem. Biophys. Res. Commun.,  2017, 484(1), 85-92.
 [http://dx.doi.org/10.1016/j.bbrc.2017.01.067] [PMID: 28104392]

[209]
Tung, Y.T.; Chen, H.L.; Tsai, H.C.; Yang, S.H.; Chang, Y.C.; Chen, C.M. Therapeutic potential of andrographolide isolated from the leaves of andrographis paniculata nees for treating lung adenocarcinomas. Evid. Based Complement. Alternat. Med.,  2013, 2013, 1-8.
 [http://dx.doi.org/10.1155/2013/305898] [PMID: 23997793]

[210]
Li, P.; Zhang, M.; Ma, W.; Sun, X.; Jin, F. Effects of brucine on vascular endothelial growth factor expression and microvessel density in a nude mouse model of bone metastasis due to breast cancer. Chin. J. Integr. Med.,  2012, 18(8), 605-609.
 [http://dx.doi.org/10.1007/s11655-012-1184-x] [PMID: 22855035]

[211]
Moon, D.O.; Choi, Y.H.; Moon, S.K.; Kim, W.J.; Kim, G.Y. Butein suppresses the expression of nuclear factor-kappa B-mediated matrix metalloproteinase-9 and vascular endothelial growth factor in prostate cancer cells. Toxicol. in vitro,  2010, 24(7), 1927-1934.
 [http://dx.doi.org/10.1016/j.tiv.2010.08.002] [PMID: 20696233]

[212]
Oršolić, N.; Kunštić, M.; Kukolj, M.; Gračan, R.; Nemrava, J. Oxidative stress, polarization of macrophages and tumour angiogenesis: Efficacy of caffeic acid. Chem. Biol. Interact.,  2016, 256, 111-124.
 [http://dx.doi.org/10.1016/j.cbi.2016.06.027] [PMID: 27378625]

[213]
Bao, M.; Cao, Z.; Yu, D.; Fu, S.; Zhang, G.; Yang, P.; Pan, Y.; Yang, B.; Han, H.; Zhou, Q. Columbamine suppresses the proliferation and neovascularization of metastatic osteosarcoma U2OS cells with low cytotoxicity. Toxicol. Lett.,  2012, 215(3), 174-180.
 [http://dx.doi.org/10.1016/j.toxlet.2012.10.015] [PMID: 23124089]

[214]
Yoysungnoen, P.; Wirachwong, P.; Changtam, C.; Suksamrarn, A.; Patumraj, S. Anti-cancer and anti-angiogenic effects of curcumin and tetrahydrocurcumin on implanted hepatocellular carcinoma in nude mice. World J. Gastroenterol.,  2008, 14(13), 2003-2009.
 [http://dx.doi.org/10.3748/wjg.14.2003] [PMID: 18395899]

[215]
Liu, W.; Meng, M.; Zhang, B.; Du, L.; Pan, Y.; Yang, P.; Gu, Z.; Zhou, Q.; Cao, Z. Dehydroeffusol effectively inhibits human gastric cancer cell-mediated vasculogenic mimicry with low toxicity. Toxicol. Appl. Pharmacol.,  2015, 287(2), 98-110.
 [http://dx.doi.org/10.1016/j.taap.2015.05.003] [PMID: 25982451]

[216]
Kim, M.H.; Jeong, Y.J.; Cho, H.J.; Hoe, H.S.; Park, K.K.; Park, Y.Y.; Choi, Y.H.; Kim, C.H.; Chang, H.W.; Park, Y.J.; Chung, I.K.; Chang, Y.C. Delphinidin inhibits angiogenesis through the suppression of HIF-1α and VEGF expression in A549 lung cancer cells. Oncol. Rep.,  2017, 37(2), 777-784.
 [http://dx.doi.org/10.3892/or.2016.5296] [PMID: 27959445]

[217]
Xu, H.; Becker, C.M.; Lui, W.T.; Chu, C.Y.; Davis, T.N.; Kung, A.L.; Birsner, A.E.; D’Amato, R.J.; Wai Man, G.C.; Wang, C.C. Green tea epigallocatechin-3-gallate inhibits angiogenesis and suppresses vascular endothelial growth factor C/vascular endothelial growth factor receptor 2 expression and signaling in experimental endometriosis in vivo. Fertil. Steril.,  2011, 96(4), 1021.e1-1028.e1.
 [http://dx.doi.org/10.1016/j.fertnstert.2011.07.008] [PMID: 21821246]

[218]
Wang, C.C.; Xu, H.; Man, G.C.W.; Zhang, T.; Chu, K.O.; Chu, C.Y.; Cheng, J.T.Y.; Li, G.; He, Y.X.; Qin, L.; Lau, T.S.; Kwong, J.; Chan, T.H. Prodrug of green tea epigallocatechin-3-gallate (Pro-EGCG) as a potent anti-angiogenesis agent for endometriosis in mice. Angiogenesis,  2013, 16(1), 59-69.
 [http://dx.doi.org/10.1007/s10456-012-9299-4] [PMID: 22948799]

[219]
Zeng, D.; Zhou, P.; Jiang, R.; Li, X.; Huang, S.; Li, D.; Li, G.; Li, L.; Zhao, S.; Hu, L.; Ran, J.; Chen, D.; Wang, Y.; Li, J. Evodiamine inhibits vasculogenic mimicry in HCT116 cells by suppressing hypoxia-inducible factor 1-alpha-mediated angiogenesis. Anticancer Drugs,  2021, 32(3), 314-322.
 [http://dx.doi.org/10.1097/CAD.0000000000001030] [PMID: 33394687]

[220]
Tang, Y.C.; Zhang, Y.; Zhou, J.; Zhi, Q.; Wu, M.Y.; Gong, F.R.; Shen, M.; Liu, L.; Tao, M.; Shen, B.; Gu, D.M.; Yu, J.; Xu, M.D.; Gao, Y.; Li, W. Ginsenoside Rg3 targets cancer stem cells and tumor angiogenesis to inhibit colorectal cancer progression in vivo. Int. J. Oncol.,  2018, 52(1), 127-138.
 [PMID: 29115601]

[221]
Hu, S.; Zhu, Y.; Xia, X.; Xu, X.; Chen, F.; Miao, X.; Chen, X. Ginsenoside Rg3 prolongs survival of the orthotopic hepatocellular carcinoma model by inducing apoptosis and inhibiting angiogenesis. Anal. Cell. Pathol.,  2019, 2019, 1-7.
 [http://dx.doi.org/10.1155/2019/3815786] [PMID: 31534898]

[222]
Xiong, J.; Li, J.; Yang, Q.; Wang, J.; Su, T.; Zhou, S. Gossypol has anti-cancer effects by dual-targeting MDM2 and VEGF in human breast cancer. Breast Cancer Res.,  2017, 19(1), 27.
 [http://dx.doi.org/10.1186/s13058-017-0818-5] [PMID: 28274247]

[223]
Li, S.; Priceman, S.J.; Xin, H.; Zhang, W.; Deng, J.; Liu, Y.; Huang, J.; Zhu, W.; Chen, M.; Hu, W.; Deng, X.; Zhang, J.; Yu, H.; He, G. Icaritin inhibits JAK/STAT3 signaling and growth of renal cell carcinoma. PLoS One,  2013, 8(12), e81657.
 [http://dx.doi.org/10.1371/journal.pone.0081657] [PMID: 24324713]

[224]
Liu, R.; Cao, Z.; Pan, Y.; Zhang, G.; Yang, P.; Guo, P.; Zhou, Q. Jatrorrhizine hydrochloride inhibits the proliferation and neovascularization of C8161 metastatic melanoma cells. Anticancer Drugs,  2013, 24(7), 667-676.
 [http://dx.doi.org/10.1097/CAD.0b013e328361ab28] [PMID: 23695011]

[225]
Park, S.; Kwon, S.; Lim, S.; Kim, J.K.; Lee, K.; Park, J. Licoricidin, an active compound in the hexane/ethanol extract of glycyrrhiza uralensis, inhibits lung metastasis of 4T1 murine mammary carcinoma cells. Int. J. Mol. Sci.,  2016, 17(6), 934.
 [http://dx.doi.org/10.3390/ijms17060934] [PMID: 27314329]

[226]
Dai, Y.; Zheng, H.; Liu, Z.; Wang, Y.; Hu, W. The flavonoid luteolin suppresses infantile hemangioma by targeting FZD6 in the Wnt pathway. Invest. New Drugs,  2021, 39(3), 775-784.
 [http://dx.doi.org/10.1007/s10637-020-01052-8] [PMID: 33411210]

[227]
Sivaramakrishnan, V.; Niranjali Devaraj, S. Morin regulates the expression of NF-κB-p65, COX-2 and matrix metalloproteinases in diethylnitrosamine induced rat hepatocellular carcinoma. Chem. Biol. Interact.,  2009, 180(3), 353-359.
 [http://dx.doi.org/10.1016/j.cbi.2009.02.004] [PMID: 19539802]

[228]
Jung, S.K.; Lee, K.W.; Byun, S.; Lee, E.J.; Kim, J.E.; Bode, A.M.; Dong, Z.; Lee, H.J. Myricetin inhibits UVB-induced angiogenesis by regulating PI-3 kinase in vivo. Carcinogenesis,  2010, 31(5), 911-917.
 [http://dx.doi.org/10.1093/carcin/bgp221] [PMID: 20008033]

[229]
Zhang, C.; Bian, M.; Chen, X.; Jin, H.; Zhao, S.; Yang, X.; Shao, J.; Chen, A.; Guo, Q.; Zhang, F.; Zheng, S. Oroxylin A prevents angiogenesis of LSECs in liver fibrosis via inhibition of YAP/HIF-1α signaling. J. Cell. Biochem.,  2018, 119(2), 2258-2268.
 [http://dx.doi.org/10.1002/jcb.26388] [PMID: 28857294]

[230]
Butt, N.A.; Kumar, A.; Dhar, S.; Rimando, A.M.; Akhtar, I.; Hancock, J.C.; Lage, J.M.; Pound, C.R.; Lewin, J.R.; Gomez, C.R.; Levenson, A.S. Targeting MTA 1/HIF -1 α signaling by pterostilbene in combination with histone deacetylase inhibitor attenuates prostate cancer progression. Cancer Med.,  2017, 6(11), 2673-2685.
 [http://dx.doi.org/10.1002/cam4.1209] [PMID: 29024573]

[231]
Zhao, X.; Wang, Q.; Yang, S.; Chen, C.; Li, X.; Liu, J.; Zou, Z.; Cai, D. Quercetin inhibits angiogenesis by targeting calcineurin in the xenograft model of human breast cancer. Eur. J. Pharmacol.,  2016, 781, 60-68.
 [http://dx.doi.org/10.1016/j.ejphar.2016.03.063] [PMID: 27041643]

[232]
De Stefano, I.; Raspaglio, G.; Zannoni, G.F.; Travaglia, D.; Prisco, M.G.; Mosca, M.; Ferlini, C.; Scambia, G.; Gallo, D. Antiproliferative and antiangiogenic effects of the benzophenanthridine alkaloid sanguinarine in melanoma. Biochem. Pharmacol.,  2009, 78(11), 1374-1381.
 [http://dx.doi.org/10.1016/j.bcp.2009.07.011] [PMID: 19643088]

[233]
Feng, Z.; Yang, T.; Hou, X.; Wu, H.; Feng, J.; Ou, B.; Cai, S.; Li, J.; Mei, Z. Sinomenine mitigates collagen-induced arthritis mice by inhibiting angiogenesis. Biomed. Pharmacother.,  2019, 113, 108759.
 [http://dx.doi.org/10.1016/j.biopha.2019.108759] [PMID: 30856539]

[234]
Huang, S.T.; Huang, C.C.; Huang, W.L.; Lin, T.K.; Liao, P.L.; Wang, P.W.; Liou, C.W.; Chuang, J.H. Tanshinone IIA induces intrinsic apoptosis in osteosarcoma cells both in vivo and in vitro associated with mitochondrial dysfunction. Sci. Rep.,  2017, 7(1), 40382.
 [http://dx.doi.org/10.1038/srep40382] [PMID: 28106052]

[235]
Zhou, J.; Jiang, Y.Y.; Wang, X.X.; Wang, H.P.; Chen, H.; Wu, Y.C.; Wang, L.; Pu, X.; Yue, G.Z.; Zhang, L. Tanshinone IIA suppresses ovarian cancer growth through inhibiting malignant properties and angiogenesis. Ann. Transl. Med.,  2020, 8(20), 1295.
 [http://dx.doi.org/10.21037/atm-20-5741] [PMID: 33209875]

[236]
Lamoke, F.; Labazi, M.; Montemari, A.; Parisi, G.; Varano, M.; Bartoli, M. Trans-Chalcone prevents VEGF expression and retinal neovascularization in the ischemic retina. Exp. Eye Res.,  2011, 93(4), 350-354.
 [http://dx.doi.org/10.1016/j.exer.2011.02.007] [PMID: 21354136]

[237]
Huang, Y.; Zhou, Y.; Fan, Y.; Zhou, D. Celastrol inhibits the growth of human glioma xenografts in nude mice through suppressing VEGFR expression. Cancer Lett.,  2008, 264(1), 101-106.
 [http://dx.doi.org/10.1016/j.canlet.2008.01.043] [PMID: 18343027]

[238]
Lamalice, L.; Houle, F.; Jourdan, G.; Huot, J. Phosphorylation of tyrosine 1214 on VEGFR2 is required for VEGF-induced activation of Cdc42 upstream of SAPK2/p38. Oncogene,  2004, 23(2), 434-445.
 [http://dx.doi.org/10.1038/sj.onc.1207034] [PMID: 14724572]

[239]
Bhise, N.S.; Shmueli, R.B.; Sunshine, J.C.; Tzeng, S.Y.; Green, J.J. Drug delivery strategies for therapeutic angiogenesis and antiangiogenesis. Expert Opin. Drug Deliv.,  2011, 8(4), 485-504.
 [http://dx.doi.org/10.1517/17425247.2011.558082] [PMID: 21338327]

[240]
Shiojima, I.; Walsh, K. Role of Akt signaling in vascular homeostasis and angiogenesis. Circ. Res.,  2002, 90(12), 1243-1250.
 [http://dx.doi.org/10.1161/01.RES.0000022200.71892.9F] [PMID: 12089061]

[241]
Tavora, B.; Batista, S.; Reynolds, L.E.; Jadeja, S.; Robinson, S.; Kostourou, V.; Hart, I.; Fruttiger, M.; Parsons, M.; Hodivala-Dilke, K.M. Endothelial FAK is required for tumour angiogenesis. EMBO Mol. Med.,  2016, 8(10), 1229.
 [http://dx.doi.org/10.15252/emmm.201606907] [PMID: 27702771]

[242]
McLaughlin, A.P.; De Vries, G.W. Role of PLCγ and Ca 2+ in VEGF- and FGF-induced choroidal endothelial cell proliferation. Am. J. Physiol. Cell Physiol.,  2001, 281(5), C1448-C1456.
 [http://dx.doi.org/10.1152/ajpcell.2001.281.5.C1448] [PMID: 11600407]

[243]
Zhang, J.; Gao, B.; Zhang, W.; Qian, Z.; Xiang, Y. Monitoring antiangiogenesis of bevacizumab in zebrafish. Drug Des. Devel. Ther.,  2018, 12, 2423-2430.
 [http://dx.doi.org/10.2147/DDDT.S166330] [PMID: 30122900]

[244]
Kim, B.R.; Jeon, Y.K.; Nam, M.J. A mechanism of apigenin-induced apoptosis is potentially related to anti-angiogenesis and anti-migration in human hepatocellular carcinoma cells. Food Chem. Toxicol.,  2011, 49(7), 1626-1632.
 [http://dx.doi.org/10.1016/j.fct.2011.04.015] [PMID: 21515330]

[245]
Lee, H.; Lee, J.H.; Jung, K.H.; Hong, S.S. Deguelin promotes apoptosis and inhibits angiogenesis of gastric cancer. Oncol. Rep.,  2010, 24(4), 957-963.
 [PMID: 20811676]

[246]
Tang, M.; Bian, W.; Cheng, L.; Zhang, L.; Jin, R.; Wang, W.; Zhang, Y. Ginsenoside Rg3 inhibits keloid fibroblast proliferation, angiogenesis and collagen synthesis in vitro via the TGF‑β/Smad and ERK signaling pathways. Int. J. Mol. Med.,  2018, 41(3), 1487-1499.
 [http://dx.doi.org/10.3892/ijmm.2018.3362] [PMID: 29328420]

[247]
Noh, S.; Choi, E.; Hwang, C.H.; Jung, J.H.; Kim, S.H.; Kim, B. Dietary compounds for targeting prostate cancer. Nutrients,  2019, 11(10), 2401.
 [http://dx.doi.org/10.3390/nu11102401] [PMID: 31597327]

[248]
Cao, W.; Hu, C.; Wu, L.; Xu, L.; Jiang, W. Rosmarinic acid inhibits inflammation and angiogenesis of hepatocellular carcinoma by suppression of NF-κB signaling in H22 tumor-bearing mice. J. Pharmacol. Sci.,  2016, 132(2), 131-137.
 [http://dx.doi.org/10.1016/j.jphs.2016.09.003] [PMID: 27707649]

[249]
Song, W.; Zhao, X.; Xu, J.; Zhang, H. Quercetin inhibits angiogenesis-mediated human retinoblastoma growth by targeting vascular endothelial growth factor receptor. Oncol. Lett.,  2017, 14(3), 3343-3348.
 [http://dx.doi.org/10.3892/ol.2017.6623] [PMID: 28927086]

[250]
Kim, S.; Oh, S.J.; Lee, J.; Han, J.; Jeon, M.; Jung, T.; Lee, S.K.; Bae, S.Y.; Kim, J.; Gil, W.H.; Kim, S.W.; Lee, J.E.; Nam, S.J. Berberine suppresses TPA-induced fibronectin expression through the inhibition of VEGF secretion in breast cancer cells. Cell. Physiol. Biochem.,  2013, 32(5), 1541-1550.
 [http://dx.doi.org/10.1159/000356591] [PMID: 24335179]

[251]
Zhang, Z.; Li, C.; Tan, Q.; Xie, C.; Yang, Y.; Zhan, W.; Han, F.; Sharma, H.S.; Sharma, A. Curcumin suppresses tumor growth and angiogenesis in human glioma cells through modulation of vascular endothelial growth factor/angiopoietin-2/thrombospondin-1 signaling. CNS Neurol. Disord. Drug Targets,  2017, 16(3), 346-350.
 [http://dx.doi.org/10.2174/1871527315666160902144513] [PMID: 27592626]

[252]
Yu, X.; Zhu, J.; Mi, M.; Chen, W.; Pan, Q.; Wei, M. Anti-angiogenic genistein inhibits VEGF-induced endothelial cell activation by decreasing PTK activity and MAPK activation. Med. Oncol.,  2012, 29(1), 349-357.
 [http://dx.doi.org/10.1007/s12032-010-9770-2] [PMID: 21132400]

[253]
Monteiro, R.; Calhau, C.; Silva, A.O.; Pinheiro-Silva, S.; Guerreiro, S.; Gärtner, F.; Azevedo, I.; Soares, R. Xanthohumol inhibits inflammatory factor production and angiogenesis in breast cancer xenografts. J. Cell. Biochem.,  2008, 104(5), 1699-1707.
 [http://dx.doi.org/10.1002/jcb.21738] [PMID: 18348194]

[254]
Li, X.; Lu, Q.; Xie, W.; Wang, Y.; Wang, G. Anti-tumor effects of triptolide on angiogenesis and cell apoptosis in osteosarcoma cells by inducing autophagy via repressing Wnt/β-Catenin signaling. Biochem. Biophys. Res. Commun.,  2018, 496(2), 443-449.
 [http://dx.doi.org/10.1016/j.bbrc.2018.01.052] [PMID: 29330051]

[255]
Khazaei, M.R.; Nasr-Esfahani, M.H.; Chobsaz, F.; Khazaei, M. Noscapine inhibiting the growth and angiogenesis of human eutopic endometrium of endometriosis patients through expression of apoptotic genes and nitric oxide reduction in three-dimensional culture model. Iran. J. Pharm. Res.,  2019, 18(2), 836-845.
 [PMID: 31531066]

[256]
Ziyad, S.; Iruela-Arispe, M.L. Molecular mechanisms of tumor angiogenesis. Genes Cancer,  2011, 2(12), 1085-1096.
 [http://dx.doi.org/10.1177/1947601911432334] [PMID: 22866200]

[257]
Minet, E.; Michel, G.; Remacle, J.; Michiels, C. Role of HIF-1 as a transcription factor involved in embryonic development, cancer progression and apoptosis. Int. J. Mol. Med.,  2000, 5(3), 253-259.
 [http://dx.doi.org/10.3892/ijmm.5.3.253] [PMID: 10677565]

[258]
Krock, B.L.; Skuli, N.; Simon, M.C. Hypoxia-induced angiogenesis: Good and evil. Genes Cancer,  2011, 2(12), 1117-1133.
 [http://dx.doi.org/10.1177/1947601911423654] [PMID: 22866203]

[259]
Waltenberger, J.; Mayr, U.; Pentz, S.; Hombach, V. Functional upregulation of the vascular endothelial growth factor receptor KDR by hypoxia. Circulation,  1996, 94(7), 1647-1654.
 [http://dx.doi.org/10.1161/01.CIR.94.7.1647] [PMID: 8840857]

[260]
Maisonpierre, P.C.; Suri, C.; Jones, P.F.; Bartunkova, S.; Wiegand, S.J.; Radziejewski, C.; Compton, D.; McClain, J.; Aldrich, T.H.; Papadopoulos, N.; Daly, T.J.; Davis, S.; Sato, T.N.; Yancopoulos, G.D. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science,  1997, 277(5322), 55-60.
 [http://dx.doi.org/10.1126/science.277.5322.55] [PMID: 9204896]

[261]
Yuan, H.T.; Khankin, E.V.; Karumanchi, S.A.; Parikh, S.M. Angiopoietin 2 is a partial agonist/antagonist of Tie2 signaling in the endothelium. Mol. Cell. Biol.,  2009, 29(8), 2011-2022.
 [http://dx.doi.org/10.1128/MCB.01472-08] [PMID: 19223473]

[262]
Joussen, A.M.; Ricci, F.; Paris, L.P.; Korn, C.; Quezada-Ruiz, C.; Zarbin, M. Angiopoietin/Tie2 signalling and its role in retinal and choroidal vascular diseases: A review of preclinical data. Eye,  2021, 35(5), 1305-1316.
 [http://dx.doi.org/10.1038/s41433-020-01377-x] [PMID: 33564135]

[263]
Huang, H.; Bhat, A.; Woodnutt, G.; Lappe, R. Targeting the ANGPT–TIE2 pathway in malignancy. Nat. Rev. Cancer,  2010, 10(8), 575-585.
 [http://dx.doi.org/10.1038/nrc2894] [PMID: 20651738]

[264]
Oliner, J.; Min, H.; Leal, J.; Yu, D.; Rao, S.; You, E.; Tang, X.; Kim, H.; Meyer, S.; Han, S.J.; Hawkins, N.; Rosenfeld, R.; Davy, E.; Graham, K.; Jacobsen, F.; Stevenson, S.; Ho, J.; Chen, Q.; Hartmann, T.; Michaels, M.; Kelley, M.; Li, L.; Sitney, K.; Martin, F.; Sun, J.R.; Zhang, N.; Lu, J.; Estrada, J.; Kumar, R.; Coxon, A.; Kaufman, S.; Pretorius, J.; Scully, S.; Cattley, R.; Payton, M.; Coats, S.; Nguyen, L.; Desilva, B.; Ndifor, A.; Hayward, I.; Radinsky, R.; Boone, T.; Kendall, R. Suppression of angiogenesis and tumor growth by selective inhibition of angiopoietin-2. Cancer Cell,  2004, 6(5), 507-516.
 [http://dx.doi.org/10.1016/j.ccr.2004.09.030] [PMID: 15542434]

[265]
Zegeye, M.M.; Lindkvist, M.; Fälker, K.; Kumawat, A.K.; Paramel, G.; Grenegård, M.; Sirsjö, A.; Ljungberg, L.U. Activation of the JAK/STAT3 and PI3K/AKT pathways are crucial for IL-6 trans-signaling-mediated pro-inflammatory response in human vascular endothelial cells. Cell Commun. Signal.,  2018, 16(1), 55.
 [http://dx.doi.org/10.1186/s12964-018-0268-4] [PMID: 30185178]

[266]
Masjedi, A.; Hashemi, V.; Hojjat-Farsangi, M.; Ghalamfarsa, G.; Azizi, G.; Yousefi, M.; Jadidi-Niaragh, F. The significant role of interleukin-6 and its signaling pathway in the immunopathogenesis and treatment of breast cancer. Biomed. Pharmacother.,  2018, 108, 1415-1424.
 [http://dx.doi.org/10.1016/j.biopha.2018.09.177] [PMID: 30372844]

[267]
Seghezzi, G.; Patel, S.; Ren, C.J.; Gualandris, A.; Pintucci, G.; Robbins, E.S.; Shapiro, R.L.; Galloway, A.C.; Rifkin, D.B.; Mignatti, P. Fibroblast growth factor-2 (FGF-2) induces vascular endothelial growth factor (VEGF) expression in the endothelial cells of forming capillaries: An autocrine mechanism contributing to angiogenesis. J. Cell Biol.,  1998, 141(7), 1659-1673.
 [http://dx.doi.org/10.1083/jcb.141.7.1659] [PMID: 9647657]

[268]
Rundhaug, J.E. Matrix metalloproteinases and angiogenesis. J. Cell. Mol. Med.,  2005, 9(2), 267-285.
 [http://dx.doi.org/10.1111/j.1582-4934.2005.tb00355.x] [PMID: 15963249]

[269]
Arnold, L.; Enders, J.; Thomas, S. Activated HGF-c-Met axis in head and neck cancer. Cancer,  2017, 9(12), 169.
 [http://dx.doi.org/10.3390/cancers9120169] [PMID: 29231907]

[270]
You, W.K.; McDonald, D.M. The hepatocyte growth factor/c-Met signaling pathway as a therapeutic target to inhibit angiogenesis. BMB Rep.,  2008, 41(12), 833-839.
 [http://dx.doi.org/10.5483/BMBRep.2008.41.12.833] [PMID: 19123972]

[271]
Fajardo, L.F.; Kwan, H.H.; Kowalski, J.; Prionas, S.D.; Allison, A.C. Dual role of tumor necrosis factor-alpha in angiogenesis. Am. J. Pathol.,  1992, 140(3), 539-544.
 [PMID: 1372154]

[272]
Fràter-Schröder, M.; Risau, W.; Hallmann, R.; Gautschi, P.; Böhlen, P. Tumor necrosis factor type alpha, a potent inhibitor of endothelial cell growth in vitro, is angiogenic in vivo. Proc. Natl. Acad. Sci.,  1987, 84(15), 5277-5281.
 [http://dx.doi.org/10.1073/pnas.84.15.5277] [PMID: 2440047]

[273]
Pepper, M.S.; Vassalli, J.D.; Orci, L.; Montesano, R. Biphasic effect of transforming growth factor-beta 1 on in vitro angiogenesis. Exp. Cell Res.,  1993, 204(2), 356-363.
 [http://dx.doi.org/10.1006/excr.1993.1043] [PMID: 7679998]

[274]
Berse, B.; Hunt, J.A.; Diegel, R.J.; Morganelli, P.; Yeo, K.T.; Brown, F.; Fava, R.A. Hypoxia augments cytokine (transforming growth factor-beta (TGF-β) and IL-1)-induced vascular endothelial growth factor secretion by human synovial fibroblasts. Clin. Exp. Immunol.,  2001, 115(1), 176-182.
 [http://dx.doi.org/10.1046/j.1365-2249.1999.00775.x] [PMID: 9933439]

[275]
Lee, J.G.; Kay, E.P. NF-κB is the transcription factor for FGF-2 that causes endothelial mesenchymal transformation in cornea. Invest. Ophthalmol. Vis. Sci.,  2012, 53(3), 1530-1538.
 [http://dx.doi.org/10.1167/iovs.11-9102] [PMID: 22323467]

[276]
Jagielska, J.; Kapopara, P.R.; Salguero, G.; Scherr, M.; Schütt, H.; Grote, K.; Schieffer, B.; Bavendiek, U. Interleukin-1 assembles a proangiogenic signaling module consisting of caveolin-1, tumor necrosis factor receptor-associated factor 6, p38-mitogen-activated protein kinase (MAPK), and MAPK-activated protein kinase 2 in endothelial cells. Arterioscler. Thromb. Vasc. Biol.,  2012, 32(5), 1280-1288.
 [http://dx.doi.org/10.1161/ATVBAHA.111.243477] [PMID: 22345171]

[277]
Vestweber, D. VE-Cadherin. Arterioscler. Thromb. Vasc. Biol.,  2008, 28(2), 223-232.
 [http://dx.doi.org/10.1161/ATVBAHA.107.158014] [PMID: 18162609]

[278]
Derycke, L.; Morbidelli, L.; Ziche, M.; De Wever, O.; Bracke, M.; Van Aken, E. Soluble N-cadherin fragment promotes angiogenesis. Clin. Exp. Metastasis,  2006, 23(3-4), 187-201.
 [http://dx.doi.org/10.1007/s10585-006-9029-7] [PMID: 17028923]

[279]
Olsen, J.J.; Pohl, S.O.; Deshmukh, A.; Visweswaran, M.; Ward, N.C.; Arfuso, F.; Agostino, M.; Dharmarajan, A. The role of Wnt signalling in angiogenesis. Clin. Biochem. Rev.,  2017, 38(3), 131-142.
 [PMID: 29332977]

[280]
Srinivasan, R.; Zabuawala, T.; Huang, H.; Zhang, J.; Gulati, P.; Fernandez, S.; Karlo, J.C.; Landreth, G.E.; Leone, G.; Ostrowski, M.C. Erk1 and Erk2 regulate endothelial cell proliferation and migration during mouse embryonic angiogenesis. PLoS One,  2009, 4(12), e8283.
 [http://dx.doi.org/10.1371/journal.pone.0008283] [PMID: 20011539]

[281]
Chen, Z.; Han, Z.C. STAT3: A critical transcription activator in angiogenesis. Med. Res. Rev.,  2008, 28(2), 185-200.
 [http://dx.doi.org/10.1002/med.20101] [PMID: 17457812]

[282]
Xue, C.; Xie, J.; Zhao, D.; Lin, S.; Zhou, T.; Shi, S.; Shao, X.; Lin, Y.; Zhu, B.; Cai, X. The JAK/STAT3 signalling pathway regulated angiogenesis in an endothelial cell/adipose-derived stromal cell co-culture, 3D gel model. Cell Prolif.,  2017, 50(1), e12307.
 [http://dx.doi.org/10.1111/cpr.12307] [PMID: 27667148]

[283]
Ma, J.; Zhang, L.; Han, W.; Shen, T.; Ma, C.; Liu, Y.; Nie, X.; Liu, M.; Ran, Y.; Zhu, D. Activation of JNK/c-Jun is required for the proliferation, survival, and angiogenesis induced by EET in pulmonary artery endothelial cells. J. Lipid Res.,  2012, 53(6), 1093-1105.
 [http://dx.doi.org/10.1194/jlr.M024398] [PMID: 22493087]

[284]
National Library of Medicine, National Center for Biotechnology Information.  Available from:https://pubchem.ncbi.nlm.nih.gov/compound/452548

[285]
FDA: FDA-Approved Drugs.  Available from:https://www.accessdata.fda.gov/scripts/cder/daf
Rights & Permissions Print Cite
Article Metrics
30
3
Journal Information
For Authors
For Editors
For Reviewers
Explore Articles
Open Access
Open Access Articles
For Visitors
DOI https://dx.doi.org/10.2174/0115680266264349231016094456	Print ISSN 1568-0266
Publisher Name Bentham Science Publisher	Online ISSN 1873-4294
Current Topics in Medicinal Chemistry

Phytochemicals Showing Antiangiogenic Effect in Pre-clinical Models and their Potential as an Alternative to Existing Therapeutics

Abstract

Graphical Abstract

Adaptogens—History and Future Perspectives

AlphaFold in Medicinal Chemistry: Opportunities and Challenges

Artificial intelligence for Natural Products Discovery and Development

Challenges, Consequences and Possible Treatments of Anticancer Drug Discovery ll

Current Topics in Medicinal Chemistry

Phytochemicals Showing Antiangiogenic Effect in Pre-clinical Models and their Potential as an Alternative to Existing Therapeutics

Abstract

Graphical Abstract

Call for Papers in Thematic Issues

Adaptogens—History and Future Perspectives

AlphaFold in Medicinal Chemistry: Opportunities and Challenges

Artificial intelligence for Natural Products Discovery and Development

Challenges, Consequences and Possible Treatments of Anticancer Drug Discovery ll

Related Journals

Related Books

Related Articles
