Evaluation of effect of nilotinib in an experimental corneal neovascularization model

Year 2022, , 431 - 437, 22.10.2022

Hakan Yıldırım , Mehmet Balbaba , Murat Erdağ , Mehmet Canleblebici , Ali Dal , Nevin İlhan , Yesari Eröksüz , Sabiha Güngör Kobat

https://doi.org/10.38053/acmj.1175479

Abstract

Aim: This study aims to investigate the neovascularization-inhibiting effect of topical nilotinib and to determine the effective dose of nilotinib.
Material and Method: In this study, 42 healthy Wistar albino rats were randomly divided into six groups. The left corneas of all rats except group 1 were cauterized with silver nitrate. Group 1 was the healthy control, with no corneal vascularization, which did not receive any treatment; Group 2 (sham) did not receive treatment, only topical DMSO; Groups 3, 4, and 5 received topical nilotinib at doses of 10, 20, and 40 μM three times a day, respectively; Group 6 received 5 mg/dL topical bevacizumab three times for a day for seven days. On the 8th day, photographs of the corneas were taken, and the percentage of corneal neovascularization area was calculated. Following all rats being killed via anesthesia, the corneas were removed to determine the levels of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) ELISA and corneal immune staining.
Results: Other than Group 3, the percentage of neovascular corneal area was lower in the treatment groups compared to Group 2 (p<0.05). The intensity of VEGF and PDGF immune staining was also lower in the treatment groups. The treatment groups showed no significant differences compared to Group 1, except Group 3. The VEGF ELISA levels were statistically significantly lower in the treatment groups compared to Group 2 (p<0.05), with the exception of Group 3. The PDGF ELISA levels were statistically significantly lower in the treatment groups compared to Group 2 (p<0.05), and the Group 4 PDGF levels were statistically the lowest among the treatment groups.
Conclusion: Nilotinib was as effective as bevacizumab in the regression of corneal neovascularization. We observed that nilotinib was effective at doses of 20 μM and more.

Keywords

Corneal neovascularization, nilotinib, bevacizumab, VEGF, PDGF

References

• Cortina MS, Azar DT: Corneal angiogenesis. In: Immunology, Inflammation and Diseases of the Eye. Darlene A. Dartt (eds) 2011; pp 401–08.
• Nicholas MP, Mysore N. Corneal neovascularization. Exp Eye Res 2021; 202: 108363.
• Yang J, Luo L, Oh Y, et al. Sunitinib malate-loaded biodegradable microspheres for the prevention of corneal neovascularization in rats. J Control Release 2020; 327: 456–66.
• Timke C, Zieher H, Roth A, et al. Combination of vascular endothelial growth factor receptor/platelet-derived growth factor receptor inhibition markedly improves radiation tumor therapy. Clin Cancer Res 2008; 4: 2210–9.
• Han YS, Lee JE, Jung JW. Inhibitory effects of bevacizumab on angiogenesis and corneal neovascularization. Graefes Arch Clin Exp Ophthalmol 2009; 247: 541–8.
• Kramer I LH. Bevacizumab, a humanized anti-angiogenic monoclonal antibody for the treatment of colorectal cancer. J Clin Pharm Ther 2009; 32: 1–14.
• Avery RL. Regression of retinal and iris neovascularization after intravitreal bevacizumab (Avastin) treatment. Retina 2006; 26: 352–4.
• Avery RL, Pieramici DJ, Rabena MD, Castellarin AA, Nasir MA, Giust MJ. Intravitreal bevacizumab (Avastin) for neo-vascular age-related macular degeneration. Ophthalmology 2006; 113: 363–72.
• Bock F, König Y, Kruse F, Baier M, Cursiefen C. Bevacizumab (Avastin) eye drops inhibit corneal neovascularization. Graefes Arch Clin Exp Ophthalmol 2008: 246: 281–4.
• Bock F, Onderka J, Dietrich T, et al. Bevacizumab as apotent inhibitor of inflammatory corneal angiogenesis and lymphangiogenesis. Invest Ophthalmol Vis Sci 2007; 48: 545–52.
• DeStafeno JJ, Kim T. Topical bevacizumab therapy for corneal neovascularization. Arch Opth 2007; 125: 834-6.
• Kim TI, Kim SW, Kim S, Kim T, Kim EK. Inhibition of experimental corneal neovascularization by using subconjunctival injection of bevacizumab (Avastin). Cornea 2008; 27: 349–52.
• Manzano RP, Peyman GA, Khan P, et al. Inhibition of experimental corneal neovascularisation by bevacizumab (Avastin). Br J Ophthalmol 2007; 91: 804–7.
• Papathanassiou M, Theodossiadis PG, Liarakos VS, Rouvas A, Giamareloos-Bourboulis EJ, Vergados IA. Inhibition of corneal neovascularization by subconjunctival bevacizumab in an animal model. Am J Ophthalmol 2008; 145: 424–31.
• Hadzijusufovic E, Albrecht-Schgoer K, Huber K, et al. Nilotinib-induced vasculopathy: Identification of vascular endothelial cells as a primary target site. Leukemia 2017; 31: 388–97.
• Rhee CK, Lee SH, Yoon HK, et al. Effect of nilotinib on bleomycin-induced acute lung injury and pulmonary fibrosis in mice. Respiration 2011; 82: 273–87.
• Gordon JK, Martyanoc V, Magro C, et al. Nilotinib (TasignaTM) in the treatment of early diffuse systemic sclerosis: An open-label, pilot clinical trial. Arthritis Res Ther 2015; 17: 1–14.
• Liu Y, Wang Z, Kwong SQ, et al. Inhibition of PDGF, TGF-β, and Abl signaling and reduction of liver fibrosis by the small molecule Bcr-Abl tyrosine kinase antagonist Nilotinib. J Hepatol 2011; 55: 612–25.
• Shi S, Peng F, Zheng Q, et al. Micelle-solubilized axitinib for ocular administration in anti-neovascularization. International journal of pharmaceutics 2019; 560: 19-26.
• Yildirim H, Aydemir O, Balbaba M, Özercan İH, İlhan N. Comparison of the effect of topical bevacizumab and sorafenib in experimental corneal neovascularization. Cutaneous and ocular toxicology 2020; 39: 223-8.
• Lowry OH, Rosenbrough NJ, Farr AL, Randall RJ. Protein measurements with the folin fenol reagent. J Biol Chem 1951; 193: 265-75.
• Bachmann BO, Bock F, Wiegand SJ, et al. Promotion of graft survival by vascular endothelial growth factor a neutralization after high-risk corneal transplantation. Arch Ophthalmol 2008; 126: 71-7.
• Lee P, Wang CC, Adamis A. Ocular neovascularization: an epidemiologic review. Surv Ophthalmol 1998; 43: 245-69.
• Nicholas MP, Mysore N. Corneal neovascularization, Experimental Eye Research 2021; 202: 108363.
• Zheng M, Deshpande S, Lee S, Ferrara N, Rouse BT. Contribution of vascular endothelial growth factor in the neovascularization process during the pathogenesis of herpetic stromal keratitis. J Virol 2001; 75: 9828–35.
• Philipp W, Speicher L, Humpel C. Expression of vascular endothelial growth factor and ıts receptors in ınflamed and vascularized human corneas. Invest Ophthalmol Vis Sci 2000; 41: 2514–22.
• Amano S, Rohan R, Kuroki M, Tolentino M, Adamis AP. Requirement for vascular endothelial growth factor in wound and inflammation-related corneal neovascularization. Invest Ophthalmol Vis Sci 1998; 31: 18–22.
• Penn JS, Madan A, Caldwell RB, Bartoli M, Caldwell RW, Hartnett ME. Vascular endothelial growth factor in eye disease. Prog Retin Eye Res 2008; 27: 331–71.
• Jo N, Mailhos C, Ju M, et al. Inhibition of platelet-derived growth factor B signaling enhances the efficacy of antivascular endothelial growth factor therapy in multiple models of ocular neovascularization. Am JPathol 2006; 168: 2036–53.
• Roskoski JR R. Sunitinib: a VEGF and PDGF receptor protein kinase and angiogenesis inhibitor. Biochemical and Biophysical Research Communications 2007; 356: 323-8.
• Dastjerdi MH, Al-Arfaj KM, Nallasamy N, et al. Topical bevacizumab in the treatment of corneal neovascularization: results of a prospective, open-label, noncomparative study. Arch Ophthalmol 2009; 127: 381–9.
• Habot-Wilner Z, Barequet IS, Ivanir Y. Moisseiev J, Rosner M. The inhibitory effect of different concentrations of topical bevacizumab on corneal neovascularization. Acta Ophthalmol 2010; 88: 862–7.
• Koenig Y, Bock F, Horn F, Kurse F, Straub K, Cursiefen C. Short and long-term safety profile and efficacy of topical bevacizumab (Avastin®) eye drops against corneal neovascularization. Graefes Arch Clin Exp Ophthalmol 2009; 247: 1375–82.
• Dastjerdi MH, Sadrai Z, Saban DR, Zhang Q, Dana R. Corneal penetration of topical and subconjunctival bevacizumab. Invest Ophthalmol Vis Sci 2011; 52: 8718-23.
• Perez-Santonja JJ, Campos-Mollo E, Lledo-Riquelme M, Javaloy J, Alio JL. Inhibition of corneal neovascularization by topical bevacizumab (anti-VEGF) and Sunitinib (anti-VEGF and anti-PDGF) in an animal model. Am J Ophthalmol 2010; 150: 519–28.
• Kang JW, Jeong JH, Moon NJ. The anti-fibrotic effect of nilotinib on Tenon’s capsule fibroblasts in vitro. J Korean Ophthalmological Society 2018; 59: 49-555.
• Heine A, Held SAE, Bringmann A, Holderried TAW, Brossart P. Immunomodulatory effects of anti-angiogenic drugs. Leukemia 2011; 25: 899–905.
• Gacche RN, Meshram RJ. Targeting tumor micro-environment for design and development of novel anti-angiogenic agents arresting tumor growth. Progress in Biophysics and Molecular Biology 2013; 113: 333-54.
• van Steensel L, Paridaens D, Schrijver B, et al. Imatinib mesylate and AMN107 inhibit PDGF-signaling in orbital fibroblasts: a potential treatment for Graves’ ophthalmopathy. Invest Ophthalmol Vis Sci 2009; 50: 3091-8.
• Baek YY, Sung B, Choi JS, et al. In vivo efficacy of ımatinib mesylate, a tyrosine kinase ınhibitor, in the treatment of chemically ınduced dry eye in animal models. Translational Vision Science & Technology 2021;10: 14.
• Onder HI, Erdurmus M, Bucak YY, Simavli H, Oktay M, Kukner AS. Inhibitory effects of regorafenib, a multiple tyrosine kinase inhibitor, on corneal neovascularization. Int J Ophthalmol 2014; 7: 220-5.
• Gong Y, Wu GH, Zhang LY, Zhang Z, Laio YH, Liu XT. Effect of nintedanib thermo-sensitive hydrogel on neovascularization in alkali burn rat model. Int J Ophthalmol 2020; 13: 879-85.
• Sahan B, Ciftci F, Eyuboglu S, Yaba A, Yilmaz B, Yalvac BI. Comparison of the effects of dovitinib and bevacizumab on reducing neovascularization in an experimental rat corneal neovascularization model. Cornea 2019; 38: 1161-8.
• Cakmak H, Gokmen E, Bozkurt G, Kocaturk T, Ergin K. Effects of sunitinib and bevacizumab on VEGF and miRNA levels on corneal neovascularization, Cutaneous Ocular Toxicol 2018; 37: 191-5.