SKLB1002, a potent inhibitor of VEGF receptor 2 signaling, inhibits endothelial angiogenic function in vitro and ocular angiogenesis in vivo

Zhang,Qiu‑Yang; Tao,Shu‑Ya; Lu,Chang; Li,Jing‑Jing; Li,Xiu‑Miao; Yao,Jin; Jiang,Qin; Yan,Biao

doi:10.3892/mmr.2020.11056

SKLB1002, a potent inhibitor of VEGF receptor 2 signaling, inhibits endothelial angiogenic function in vitro and ocular angiogenesis in vivo

Authors:
- Qiu‑Yang Zhang
- Shu‑Ya Tao
- Chang Lu
- Jing‑Jing Li
- Xiu‑Miao Li
- Jin Yao
- Qin Jiang
- Biao Yan
View Affiliations

Affiliations: The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China, The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China, Eye Institute, Eye and ENT Hospital, Shanghai Medical College, Fudan University, Shanghai 200030, P.R. China
Published online on: April 6, 2020 https://doi.org/10.3892/mmr.2020.11056
Pages: 2571-2579
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Ocular angiogenesis is a major cause of severe vision loss, which can affect several parts of the eye, including the retina, choroid and cornea. Vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors have demonstrated great potential for treating ocular angiogenesis and SKLB1002 is a potent inhibitor of VEGF receptor 2 signaling. The present study investigated the effects of SKLB1002 administration on ocular angiogenesis. SKLB1002 administration did not show obvious cytotoxicity and tissue toxicity at the tested concentrations. In an alkali‑burn corneal model, SKLB1002 administration significantly decreased the mean length and number of new corneal blood vessels. SKLB1002 administration significantly reduced endothelial cell proliferation, migration and tube formation in vitro. Mechanistically, SKLB1002 inhibited endothelial angiogenic functions by blocking the phosphorylation of ERK1/2, JNK and p38. Thus, selective inhibition of VEGFR‑2 through SKLB1002 administration is a promising therapy for ocular angiogenesis.

View Figures

View References

1	Ellenberg D, Azar DT, Hallak JA, Tobaigy F, Han KY, Jain S, Zhou Z and Chang JH: Novel aspects of corneal angiogenic and lymphangiogenic privilege. Prog Retin Eye Res. 29:208–248. 2010. View Article : Google Scholar : PubMed/NCBI
2	Zhang SX and Ma JX: Ocular neovascularization: Implication of endogenous angiogenic inhibitors and potential therapy. Prog Retin Eye Res. 26:1–37. 2007. View Article : Google Scholar : PubMed/NCBI
3	Qazi Y, Wong G, Monson B, Stringham J and Ambati BK: Corneal transparency: Genesis, maintenance and dysfunction. Brain Res Bull. 81:198–210. 2010. View Article : Google Scholar : PubMed/NCBI
4	Fu YC and Xin ZM: Inhibited corneal neovascularization in rabbits following corneal alkali burn by double-target interference for VEGF and HIF-1α. Biosci Rep. 39(pii): BSR201805522019. View Article : Google Scholar : PubMed/NCBI
5	Qazi Y, Maddula S and Ambati BK: Mediators of ocular angiogenesis. J Genet. 88:495–515. 2009. View Article : Google Scholar : PubMed/NCBI
6	Maddula S, Davis DK, Maddula S, Burrow MK and Ambati BK: Horizons in therapy for corneal angiogenesis. Ophthalmology. 118:591–599. 2011. View Article : Google Scholar : PubMed/NCBI
7	Sene A, Chin-Yee D and Apte RS: Seeing through VEGF: Innate and adaptive immunity in pathological angiogenesis in the eye. Trends Mol Med. 21:43–51. 2015. View Article : Google Scholar : PubMed/NCBI
8	Roshandel D, Eslani M, Baradaran-Rafii A, Cheung AY, Kurji K, Jabbehdari S, Maiz A, Jalali S, Djalilian AR and Holland EJ: Current and emerging therapies for corneal neovascularization. Ocul Surf. 16:398–414. 2018. View Article : Google Scholar : PubMed/NCBI
9	Bock F, Maruyama K, Regenfuss B, Hos D, Steven P, Heindl LM and Cursiefen C: Novel anti(lymph)angiogenic treatment strategies for corneal and ocular surface diseases. Prog Retin Eye Res. 34:89–124. 2013. View Article : Google Scholar : PubMed/NCBI
10	Poulaki V, Mitsiades N, Kruse FE, Radetzky S, Iliaki E, Kirchhof B and Joussen AM: Activin a in the regulation of corneal neovascularization and vascular endothelial growth factor expression. Am J Pathol. 164:1293–1302. 2004. View Article : Google Scholar : PubMed/NCBI
11	Apte RS, Chen DS and Ferrara N: VEGF in signaling and disease: Beyond discovery and development. Cell. 176:1248–1264. 2019. View Article : Google Scholar : PubMed/NCBI
12	Eilken HM and Adams RH: Dynamics of endothelial cell behavior in sprouting angiogenesis. Curr Opin Cell Biol. 22:617–625. 2010. View Article : Google Scholar : PubMed/NCBI
13	Hoeben A, Landuyt B, Highley MS, Wildiers H, Van Oosterom AT and De Bruijn EA: Vascular endothelial growth factor and angiogenesis. Pharmacol Rev. 56:549–580. 2004. View Article : Google Scholar : PubMed/NCBI
14	Ferrara N, Gerber HP and LeCouter J: The biology of VEGF and its receptors. Nat Med. 9:669–676. 2003. View Article : Google Scholar : PubMed/NCBI
15	Varricchi G, Loffredo S, Galdiero MR and Marone G, Cristinziano L, Granata F and Marone G: Innate effector cells in angiogenesis and lymphangiogenesis. Curr Opin Immunol. 53:152–160. 2018. View Article : Google Scholar : PubMed/NCBI
16	Shen G, Li Y, Du T, Shi G, Dai L, Chen X, Zheng R, Li W, Su X, Zhang S, et al: SKLB1002, a novel inhibitor of VEGF receptor 2 signaling, induces vascular normalization to improve systemically administered chemotherapy efficacy. Neoplasma. 59:486–493. 2012. View Article : Google Scholar : PubMed/NCBI
17	Li WW, Chen JJ, Zheng RL, Zhang WQ, Cao ZX, Yang LL, Qing XY, Zhou LX, Yang L, Yu LD, et al: Taking quinazoline as a general support-Nog to design potent and selective kinase inhibitors: application to FMS-like tyrosine kinase 3. Chem Med Chem. 5:513–516. 2010. View Article : Google Scholar : PubMed/NCBI
18	Zhang S, Cao Z, Tian H, Shen G, Ma Y, Xie H, Liu Y, Zhao C, Deng S, Yang Y, et al: SKLB1002, a novel potent inhibitor of VEGF receptor 2 signaling, inhibits angiogenesis and tumor growth in vivo. Clin Cancer Res. 17:4439–4450. 2011. View Article : Google Scholar : PubMed/NCBI
19	Bignami F, Lorusso A, Rama P and Ferrari G: Growth inhibition of formed corneal neovascularization following Fosaprepitant treatment. Acta Ophthalmol. 95:e641–e648. 2017. View Article : Google Scholar : PubMed/NCBI
20	Skobe M and Dana R: Blocking the path of lymphatic vessels. Nat Med. 15:993–994. 2009. View Article : Google Scholar : PubMed/NCBI
21	Tolentino MJ: Current molecular understanding and future treatment strategies for pathologic ocular neovascularization. Curr Mol Med. 9:973–981. 2009. View Article : Google Scholar : PubMed/NCBI
22	Liu S, Romano V, Steger B, Kaye SB, Hamill KJ and Willoughby CE: Gene-based antiangiogenic applications for corneal neovascularization. Surv Ophthalmol. 63:193–213. 2018. View Article : Google Scholar : PubMed/NCBI
23	Zhong W, Montana M, Santosa SM, Isjwara ID, Huang YH, Han KY, O'Neil C, Wang A, Cortina MS, de la Cruz J, et al: Angiogenesis and lymphangiogenesis in corneal transplantation-A review. Surv Ophthalmol. 63:453–479. 2018. View Article : Google Scholar : PubMed/NCBI
24	Nominato LF, Dias AC, Dias LC, Fantucci MZ, Mendes da Silva LEC, Murashima AA and Rocha EM: Prevention of corneal neovascularization by adenovirus encoding human vascular endothelial growth factor soluble receptor (s-VEGFR1) in lacrimal gland. Invest Ophthalmol Vis Sci. 59:6036–6044. 2018. View Article : Google Scholar : PubMed/NCBI
25	Lee JE, Kim KL, Kim D, Yeo Y, Han H, Kim MG, Kim SH, Kim H, Jeong JH and Suh W: Apatinib-loaded nanoparticles suppress vascular endothelial growth factor-induced angiogenesis and experimental corneal neovascularization. Int J Nanomedicine. 12:4813–4822. 2017. View Article : Google Scholar : PubMed/NCBI
26	Chang JH, Garg NK, Lunde E, Han KY, Jain S and Azar DT: Corneal neovascularization: An anti-VEGF therapy review. Surv Ophthalmol. 57:415–429. 2012. View Article : Google Scholar : PubMed/NCBI
27	Friedman M, Azrad-Lebovitz T, Morzaev D, Zahavi A, Marianayagam NJ, Nicholson JD, Brookman M, Michowiz S, Hochhauser E and Goldenberg-Cohen N: Protective effect of TLR4 ablation against corneal neovascularization following chemical burn in a mouse model. Curr Eye Res. 44:505–513. 2019. View Article : Google Scholar : PubMed/NCBI
28	van Wijngaarden P, Coster DJ and Williams KA: Inhibitors of ocular neovascularization: Promises and potential problems. JAMA. 293:1509–1513. 2005. View Article : Google Scholar : PubMed/NCBI
29	Menzel-Severing J: Emerging techniques to treat corneal neovascularisation. Eye (Lond). 26:2–12. 2012. View Article : Google Scholar : PubMed/NCBI
30	Chang CY, Wang MC, Miyagawa T, Chen ZY, Lin FH, Chen KH, Liu GS and Tseng CL: Preparation of arginine-glycine-aspartic acid-modified biopolymeric nanoparticles containing epigalloccatechin-3-gallate for targeting vascular endothelial cells to inhibit corneal neovascularization. Int J Nanomedicine. 12:279–294. 2017. View Article : Google Scholar : PubMed/NCBI
31	Urtti A: Challenges and obstacles of ocular pharmacokinetics and drug delivery. Adv Drug Deliv Rev. 58:1131–1135. 2006. View Article : Google Scholar : PubMed/NCBI
32	Kisielewska J, Ligeza J and Klein A: The effect of tyrosine kinase inhibitors, tyrphostins: AG1024 and SU1498, on autocrine growth of prostate cancer cells (DU145). Folia Histochem Cytobiol. 46:185–191. 2008. View Article : Google Scholar : PubMed/NCBI
33	De Bock K, Georgiadou M and Carmeliet P: Role of endothelial cell metabolism in vessel sprouting. Cell Metab. 18:634–647. 2013. View Article : Google Scholar : PubMed/NCBI
34	Siemerink MJ, Augustin AJ and Schlingemann RO: Mechanisms of ocular angiogenesis and its molecular mediators. Dev Ophthalmol. 46:4–20. 2010. View Article : Google Scholar : PubMed/NCBI
35	Eelen G, de Zeeuw P, Simons M and Carmeliet P: Endothelial cell metabolism in normal and diseased vasculature. Circ Res. 116:1231–1244. 2015. View Article : Google Scholar : PubMed/NCBI
36	Shi W, Liu J, Li M, Gao H and Wang T: Expression of MMP, HPSE, and FAP in stroma promoted corneal neovascularization induced by different etiological factors. Curr Eye Res. 35:967–977. 2010. View Article : Google Scholar : PubMed/NCBI
37	Adams RH and Alitalo K: Molecular regulation of angiogenesis and lymphangiogenesis. Nat Rev Mol Cell Biol. 8:464–478. 2007. View Article : Google Scholar : PubMed/NCBI
38	Olsson AK, Dimberg A, Kreuger J and Claesson-Welsh L: VEGF receptor signalling-in control of vascular function. Nat Rev Mol Cell Biol. 7:359–371. 2006. View Article : Google Scholar : PubMed/NCBI
39	Cross MJ and Claesson-Welsh L: FGF and VEGF function in angiogenesis: Signalling pathways, biological responses and therapeutic inhibition. Trends Pharmacol Sci. 22:201–207. 2001. View Article : Google Scholar : PubMed/NCBI
40	Cargnello M and Roux PP: Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev. 75:50–83. 2011. View Article : Google Scholar : PubMed/NCBI
41	Arthur JS and Ley SC: Mitogen-activated protein kinases in innate immunity. Nat Rev Immunol. 13:679–692. 2013. View Article : Google Scholar : PubMed/NCBI
42	Simons M, Gordon E and Claesson-Welsh L: Mechanisms and regulation of endothelial VEGF receptor signalling. Nat Rev Mol Cell Biol. 17:611–625. 2016. View Article : Google Scholar : PubMed/NCBI
43	del Barco Barrantes I and Nebreda AR: Roles of p38 MAPKs in invasion and metastasis. Biochem Soc Trans. 40:79–84. 2012. View Article : Google Scholar : PubMed/NCBI
44	Penn JS, Madan A, Caldwell RB, Bartoli M, Caldwell RW and Hartnett ME: Vascular endothelial growth factor in eye disease. Prog Retin Eye Res. 27:331–371. 2008. View Article : Google Scholar : PubMed/NCBI
45	Sehgal V and Ram PT: Network Motifs in JNK Signaling. Genes Cancer. 4:409–413. 2013. View Article : Google Scholar : PubMed/NCBI
46	Kim EK and Choi EJ: Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta. 1802:396–405. 2010. View Article : Google Scholar : PubMed/NCBI