Modulation of Bevacizumab-Induced Toxicity for Cultured Human Corneal Fibroblasts

Kim, Eung Kweon; Kang, Sang Won; Kim, Ji Yeon; Min, Kyung; Kim, Tae Im

doi:10.1167/iovs.12-11287

Cited by 5 publications

(4 citation statements)

References 33 publications

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“…16 Lactate dehydrogenase (LDH) activity increased at 1.0, 1.5, and 2.0 mg/mL of bevacizumab treatment, but LDH activity after ranibizumab treatment did not increase at concentrations up to 2.0 mg/mL. In the present study, aflibercept had no adverse effects on cell viability at 1.0 and 2.0 mg/mL, at which concentrations bevacizumab and ranibizumab treatment resulted in decreased cell viability.…”

Section: Discussioncontrasting

confidence: 43%

Differential Effects of Bevacizumab, Ranibizumab, and Aflibercept on the Viability and Wound Healing of Corneal Epithelial Cells

Kang

Choi

Rho

2016

Journal of Ocular Pharmacology and Therapeutics

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Purpose: This study compared the effects of 3 antivascular endothelial growth factor (VEGF) agents (bevacizumab, ranibizumab, and aflibercept) on corneal epithelial cell viability and wound healing using human corneal epithelial cells (HCECs). Methods: To determine the cytotoxic effects of anti-VEGF agents on HCECs, HCEC viability was determined at various concentrations of these agents. An in vitro migration assay was used to investigate the migration of HCECs treated with 3 anti-VEGF agents. The protein level of extracellular signal-regulated kinase was used to evaluate the effect of anti-VEGF treatment on cell proliferation. The protein levels of p38 mitogen-activated protein kinase (MAPK) were analyzed by Western blotting to investigate cell migration. Results: After 24 or 48 h of exposure, aflibercept treatment showed no apparent effect on cell viability; however, bevacizumab and ranibizumab treatment decreased cell viability at high concentrations (1 and 2 mg/ mL). A migration assay showed that HCEC migration was different among the 3 anti-VEGF treatment groups. Bevacizumab significantly delayed HCEC migration. Western blotting showed that bevacizumab treatment decreased the expression levels of phosphorylated p38 MAPK. Conclusions: Bevacizumab, the most widely used and investigated anti-VEGF agent, decreased epithelial cell migration and viability. Anti-VEGF agents other than bevacizumab might therefore be better for treating corneal neovascularization complicated with epithelial defects.

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Section: Discussioncontrasting

confidence: 43%

Differential Effects of Bevacizumab, Ranibizumab, and Aflibercept on the Viability and Wound Healing of Corneal Epithelial Cells

Kang

Choi

Rho

2016

Journal of Ocular Pharmacology and Therapeutics

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“…Regarding corneal endothelial cells, while Bevacizumab causes no toxicity, a significant dose dependent reduction of their proliferation is observed [35]. While there are conflicting reports linking Bevacizumab cytotoxicity to corneal fibroblasts [18,36], it was shown that there were neither cytotoxic nor anti-proliferative effects on an immortalized human corneal epithelial cell line [18] while histological assessment showed no significant impact in mouse corneal epithelium [32]. Our data confirm the latter observation in primary human limbal epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

Bevacizumab Induces Upregulation of Keratin 3 and VEGFA in Human Limbal Epithelial Cells in Vitro

Notara

Lentzsch

Clahsen

et al. 2019

JCM

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Topical application of vascular endothelial growth factor A (VEGFA) inhibitors including Bevacizumab is used for antiangiogenic therapy at the ocular surface. While clinical studies have suggested that this approach is well-tolerated, the effect of the drug on limbal epithelial stem cells has not been studied. In this study, the effect of Bevacizumab on phenotype and functionality of putative limbal epithelial stem cells (SC) was investigated. The effect of Bevacizumab on human limbal epithelial cells was assessed in terms of metabolic activity and scratch wound closure. The different treatment groups featured no difference in proliferation and colony forming efficiency (CFE) of limbal epithelial cells or their putative SC marker expression. A significant delay in scratch closure of all the Bevacizumab-treated groups was detected at 4 h. RNA and protein quantification indicated a dose-responsive increase of keratin 3. VEGFA RNA expression also increased while VEGFC and D as well as VEGFR1, 2 and 3 were unchanged. This study highlights previously unknown effects of Bevacizumab on cultured putative limbal epithelial SC: a dose-related increase of keratin 3, an increase in VEGFA as well as a delay in scratch wound closure. These in vitro data should be considered when using Bevacizumab in the context of limbal epithelial SC transplantation.

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“…However, only few studies have investigated the toxic effects of anti‐VEGF on retinal cells and very limited information is available on corneal cells (Hosny et al, ; Iriyama, Chen, Tamaki, & Yanagi, ; E.K. Kim et al, ; Thaler et al, ). Our study has addressed the hypothesis that intraocular administration of anti‐VEGF drugs might affect the survival of corneal endothelium by interfering with the NGF pathways.…”

Section: Discussionmentioning

confidence: 99%

“…In vitro VEGF inhibition induces cytotoxic effects on corneal fibroblast and epithelium (E.K. Kim, Kang, Kim, Min, & Kim, 2013;Yoeruek et al, 2007). Moreover, in vivo studies show a detrimental treatment on several corneal features, such as healing and innervation (Dong, Di, Zhang, Zhou, & Shi, 2017; T.I.…”

Section: Introductionmentioning

confidence: 99%

In vivo antivascular endothelial growth factor treatment induces corneal endothelium apoptosis in rabbits through changes in p75NTR–proNGF pathway

Gharbiya

Sacchetti

Rosso

et al. 2018

Journal Cellular Physiology

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Intravitreal injection (IVT) of antivascular endothelial growth factor (anti-VEGF) agents is widely used for the treatment of retinal vascular diseases. Recently, the injection of anti-VEGF agents in the ocular anterior chamber has been proposed for the treatment of neovascular glaucoma and potential side effects on the corneal structures have been investigated with contrasting results. Increasing evidence has demonstrated that VEGF inhibition is associated with cellular apoptotic changes and that this effect may be mediated by alterations in nerve growth factor (NGF) pathway. In this study, we demonstrated that anterior chamber injection (IC), but not IVT injection of two different anti-VEGF agents, aflibercept and ranibizumab, affects rabbit corneal endothelium in terms of survival and apoptosis and is associated with changes in endothelial expression of NGF precursor (proNGF) and p75 neurotrophin receptor (p75NTR) receptor. We observed an increase in corneal endothelial cell incorporation of trypan blue and expression of cleaved-caspase 3 (c-Casp3), p75NTR, and RhoA after IC injection of both anti-VEGF drugs when compared with the vehicle. Our results showed that apoptosis induction by aflibercept was more pronounced when compared with that of ranibizumab. Aflibercept also mediated a significant increase in endothelial expression of proNGF when compared with the vehicle. In line with these data, IC administration of both anti-VEGF agents induced the activation of apoptotic signals in endothelial cells, including an increase in c-Casp3, decrease in Bad Ser 112 phosphorylation, and unbalance of AKT phosphorylation. These results demonstrated that administration of anti-VEGF in the anterior chamber of rabbit affects endothelial cell survival by inducing apoptosis through alteration of NGF pathway.

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Modulation of Bevacizumab-Induced Toxicity for Cultured Human Corneal Fibroblasts

Abstract: Citation: Kim EK, Kang SW, Kim JY, Min K, Kim T. Modulation of bevacizumab-induced toxicity for cultured human corneal fibroblasts. Invest Ophthalmol Vis Sci. 2013;54:3922-3931.

Cited by 5 publications

References 33 publications

Differential Effects of Bevacizumab, Ranibizumab, and Aflibercept on the Viability and Wound Healing of Corneal Epithelial Cells

Differential Effects of Bevacizumab, Ranibizumab, and Aflibercept on the Viability and Wound Healing of Corneal Epithelial Cells

Bevacizumab Induces Upregulation of Keratin 3 and VEGFA in Human Limbal Epithelial Cells in Vitro

In vivo antivascular endothelial growth factor treatment induces corneal endothelium apoptosis in rabbits through changes in p75NTR–proNGF pathway

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