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Tyrosine Kinase Inhibitor, Vatalanib, Inhibits Proliferation and Migration of Human Pterygial Fibroblasts

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Tyrosine Kinase Inhibitor, Vatalanib, Inhibits Proliferation and Migration of Human Pterygial Fibroblasts BASIC INVESTIGATION Tyrosine Kinase Inhibitor, Vatalanib, Inhibits Proliferation and Migration of Human Pterygial Fibroblasts Hong Kyu Kim, MD,* Ji-Young Choi, PhD,† Sang Min Park, PhD,‡ Chang Rae Rho, MD, PhD,§ Kyong Jin Cho, MD, PhD,¶ and Sangmee Ahn Jo, PhD‡k b significantly reduced, but there was no alteration in p53 protein Purpose: Vatalanib is a small-molecule tyrosine kinase inhibitor. levels in HPFs. We investigated the effects of vatalanib on the proliferation and migration of cultured human pterygial fibroblasts (HPFs). Conclusions: These results indicate that vatalanib significantly suppressed the proliferation and migration of HPFs by decreasing Methods: Pterygium tissues were obtained after pterygium exci- vascular endothelial growth factor and transforming growth factor-b. sion surgery and subjected to primary culture. HPFs were treated Vatalanib showed less toxicity than that of MMC. Based on these with vatalanib at various concentrations. Mitomycin C (MMC) was results, vatalanib may potentially serve as a new adjuvant treatment used as a positive control. Cell proliferation and migration assays after pterygium excision surgery. were used to investigate the effects of vatalanib. Cell death was measured using flow cytometry analysis. Western blot analysis was Key Words: tyrosine kinase inhibitor, vatalanib, mitomycin C, performed to identify signaling molecules associated with the pterygium, cell growth response to vatalanib. (Cornea 2017;36:1116–1123) Results: Vatalanib inhibited both proliferation and migration of HPFs in a dose-dependent manner. Cell proliferation was signif- m terygium is one of the most common ocular surface icantly suppressed by vatalanib (10 and 100 M) and MMC diseases. It is characterized by remodeling, proliferation, (0.004% and 0.04%) treatments. Migration assays revealed signif- P fl m angiogenesis, and in ammation of penetrating triangle- icant HPF delay when treated with vatalanib (1, 10, and 100 M) shaped fibrovascular tissue from the conjunctiva into the and MMC (0.004% and 0.04%) compared with that in a negative cornea. Pterygium is pathologically benign; however, the control. Cell death analysis showed that high concentrations of m disease recurs easily and has a tendency to invade normal vatalanib (100 M) and MMC (0.004% and 0.04%) decreased cell tissue. It has also been reported to be associated with numbers. Western blot analysis of vatalanib-treated cells showed premalignant disease, possibly because of cumulative genetic vascular endothelial growth factor and transforming growth factor- damage from chronic UV exposure.1 Causes of pterygium include UV-A exposure,2 UV-B exposure, viral infection,3 and various molecular mecha- Received for publication January 15, 2017; revision received April 16, 2017; nisms. UV-A induces urokinase-type plasminogen activator accepted April 26, 2017. Published online ahead of print June 21, 2017. fl From the *Department of Ophthalmology, Institute of Vision Research, (uPA), a central mediator of extracellular matrixes, in am- 2 College of Medicine, Yonsei University, Seoul, South Korea; †Department matory processes, and angiogenesis. UV-B causes cellular of Pharmacology and Medicinal Toxicology Research Center, Hypoxia- DNA damage through 2 distinct mechanisms: direct photo- related Disease Research Center, Inha University School of Medicine, toxic effects on cellular DNA and generation of reactive ‡ Incheon, South Korea; Department of Nanobiomedical Science and BK21 oxygen species.4 A variety of oncogenic viruses have been PLUS NBM Global Research Center for Regenerative Medicine, Dankook fi University, Cheonan-si, South Korea; §Department of Ophthalmology and identi ed in pterygium tissues (eg, human papillomavirus, Visual Science, Daejeon St. Mary’s Hospital, College of Medicine, The cytomegalovirus, and herpes simplex virus), which inactivate Catholic University of Korea, Seoul, Republic of Korea; ¶Department of p53 and lead to chromosomal instability.3 Several additional Ophthalmology, College of Medicine, Dankook University, Cheonan-si, factors play a role in the pathogenesis of pterygium, South Korea; and kDepartment of Pharmacy, College of Pharmacy, – Dankook University, Cheonan-si, South Korea. including epigenetic factors, cell proliferation related fac- Supported by grants by the Korea Health Technology R&D Project, tors, inflammatory mediators, growth factors, extracellular Ministry of Health & Welfare, Republic of Korea (HI12C0003), and matrix modulators, angiogenic and lymphangiogenic factors, the National Research Foundation of Korea (NRF) grant funded by immunologic mechanisms, epithelial–mesenchymal transi- the Korean government (NRF 2014R1A2A2A005564 and NRF- tion, and alterations in cholesterol metabolism.4 2016R1C1B2016649). The authors have no conflicts of interest to disclose. Surgical excision is a standard treatment for symp- K. J. Cho and S. A. Jo contributed equally to this article and should be tomatic pterygium, although the condition frequently regarded as co-corresponding authors. (24%–89%) recurs after treatment.5,6 Adjunctive surgical Reprints: Kyong Jin Cho, MD, PhD, Department of Ophthalmology, procedures and adjuvant therapies are used to decrease the Dankook University Hospital, College of Medicine, Dankook University, #119 Dandae-ro, Dongnam-gu, Cheonan-si, Chungcheongnam-do, risk of recurrence. Conjunctival autografts and amniotic Republic of Korea, 31116 (e-mail: [email protected]). membrane grafts have been implemented as adjunctive Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. surgical techniques. Adjunctive pharmaceutical treatments 1116 | www.corneajrnl.com Cornea Volume 36, Number 9, September 2017 Copyright Ó 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Cornea Volume 36, Number 9, September 2017 Inhibitory Effect of Vatalanib in HPFs include mitomycin C (MMC), subconjunctival bevacizu- Korea) solution and passaged for subcultures with 1:4 split. mab,7 bevacizumab eye drops,8,9 cyclosporine,10 pirfeni- Cells at 4 to 6 passages were used for further experiments. done,11 and 5-fluorouracil.12,13 Proliferative factors related to pterygium development include basic fibroblast growth factor (bFGF), vascular Characterization of Cultured endothelial growth factor (VEGF), platelet-derived growth Pterygial Fibroblasts factor (PDGF), heparin-binding EGF, c-myc, and uPA.2,14–17 Immunofluorescence staining was performed to char- The VEGF family members (eg, VEGF and PDGF) are acterize the cultured human pterygial fibroblasts (HPFs). activated by binding to tyrosine receptors on cellular The cells were fixed with 10% neutral-buffered formalin membranes. Vatalanib is a tyrosine kinase inhibitor (TKI) (BBC Biochemical, Mount Vernon, WA) for 30 minutes at that suppresses receptor-mediated signaling. It was well room temperature (RT), then washed with washing buffer tolerated without toxicities (eg, hypertension, proteinuria, [1· PBS (Biosesang, Seongnam, Korea), 0.3% Triton X-100 nausea, diarrhea, and fatigue) in patients with advanced (Sigma-Aldrich)] 5 times (5 min per wash). The cells were colorectal cancer in a phase I study, and its biological activity then incubated with blocking solution [1· PBS, 0.3% Triton was maintained.18,19 To our knowledge, few studies have X-100, 2% bovine serum albumin (BSA) (Cellect; MP investigated the effects of TKIs on pterygial fibroblasts. Biomedicals, Santa Ana, CA), 2% goat serum (Vector The objective of this study was therefore to elucidate Laboratories, Burlingame, CA)] for 1 hour at RT. Cells the effects of vatalanib on proliferation and migration of were then incubated with antibodies against cytokeratin-13, pterygial fibroblasts and to identify the molecular mechanism vimentin, and alpha-smooth muscle actin (a-SMA) over- underlying any observed effects. night at 4°C (Table 1). After washing with PBS, cells were incubated with fluorescein isothiocyanate–conjugated sec- ondary antibodies for 1 hour at RT. The washed cells were mountedwithVectashieldmountingmediumwithDAPI MATERIALS AND METHODS (Vector Laboratories, Burlingame, CA) and stored in a dark Study Subjects place. Prepared cells were monitored at ·200 magnification Discarded pterygium tissue was obtained from patients using a fluorescent microscope (Observer Z1, Carl Zeiss, who underwent clinically indicated pterygium excision with Oberkochen, Germany). conjunctival autograft surgery. Written informed consent was obtained; the research was performed in accordance with the Declaration of Helsinki. The study was reviewed and Cell Number Counting approved by the Institutional Review Board of Dankook HPFs were seeded in 12-well culture plates at a density University Hospital (Cheonan, South Korea) on February 23, of 15,000 cells per well. After 24 hours, cells were treated m 2015 (code: 2015-02-023). with vatalanib (0, 1, 10, or 100 M) or MMC (0.004 or 0.04%). At 0, 6, 12, 24, and 36 hours, the cells were trypsinized and inactivated with 50% fetal bovine serum. After centrifugation at 300g for 5 minutes, the cell pellet was Isolation and Primary Culture of resuspended in growth media containing 0.1% Trypan blue to Pterygial Fibroblasts detect dead cells and loaded into a hemocytometer. The cell Excised pterygium specimens were stored in 1.5-mL number was counted under microscopy. tubes containing Dulbecco Modified Eagle Medium (DMEM/ F12; Welgene, Gyeongsan, Korea); the samples were placed on ice and transferred to our laboratory within an hour. Cell Proliferation
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