Fc Receptor Inhibition Reduces Susceptibility to Oxidative Stress in Human RPE Cells Treated with Bevacizumab, but not Aflibercept
Background/Aims: VEGF-A is induced by oxidative stress, and functions as a survival factor for various cell types, including retinal pigment epithelial (RPE) cells. Anti-vascular endothelial growth factor (VEGF) drugs like aflibercept and bevacizumab have shown to be most effective in treating neova...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Cell Physiol Biochem Press GmbH & Co KG
2016-02-01
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| Series: | Cellular Physiology and Biochemistry |
| Subjects: | |
| Online Access: | http://www.karger.com/Article/FullText/443030 |
| _version_ | 1818110340668325888 |
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| author | Mahdy Ranjbar Max Philipp Brinkmann Dorinja Zapf Yoko Miura Martin Rudolf Salvatore Grisanti |
| author_facet | Mahdy Ranjbar Max Philipp Brinkmann Dorinja Zapf Yoko Miura Martin Rudolf Salvatore Grisanti |
| author_sort | Mahdy Ranjbar |
| collection | DOAJ |
| description | Background/Aims: VEGF-A is induced by oxidative stress, and functions as a survival factor for various cell types, including retinal pigment epithelial (RPE) cells. Anti-vascular endothelial growth factor (VEGF) drugs like aflibercept and bevacizumab have shown to be most effective in treating neovascular age-related macular degeneration (AMD), however uptake of the drugs might lead to interference with cell physiology. Herein, we evaluated the significance of the Fc receptor (FcR) within this context and moreover explored the impact of VEGF inhibition under normal conditions as well as under oxidative stress, in terms of potential adverse effects. Methods: ARPE-19 (human RPE) cells were treated with aflibercept and bevacizumab in presence or absence of H2O2 as oxidative stress stimulus. After 24h cells were evaluated for drug uptake, VEGF-A expression and secretion, levels of intracellular reactive oxygen species (ROS) as well as cell proliferation. Experiments were repeated with cells being pre-incubated with an FcR inhibitor prior to drug application. Results: Both drugs inhibited extracellular levels of VEGF-A and were taken up into the RPE, resulting in significantly reduced intracellular levels of VEGF-A. When oxidative stress was applied, intracellular ROS levels in cells treated with both drugs rose, and cell proliferation was reduced. Prior incubation with the FcR inhibitor lessened the uptake of bevacizumab, but not aflibercept into RPE cells, and simultaneously enhanced cell survival under oxidative stress conditions. Conclusions: Our results indicate that uptake and accumulation of aflibercept and bevacizumab within RPE cells affect the intracellular VEGF-A metabolism negatively, leading to a biologically relevant reduced cell survival under oxidative stress. The FcR plays a substantial role in the uptake of bevacizumab, but not aflibercept, which allows an enhanced RPE cell survival through FcR blockage in an environment dominated by oxidative stress, as clinically significant for various inflammatory retinal disorders. |
| first_indexed | 2024-12-11T02:45:36Z |
| format | Article |
| id | doaj.art-f20342178bf04bbb961036e24be7e46b |
| institution | Directory Open Access Journal |
| issn | 1015-8987 1421-9778 |
| language | English |
| last_indexed | 2024-12-11T02:45:36Z |
| publishDate | 2016-02-01 |
| publisher | Cell Physiol Biochem Press GmbH & Co KG |
| record_format | Article |
| series | Cellular Physiology and Biochemistry |
| spelling | doaj.art-f20342178bf04bbb961036e24be7e46b2022-12-22T01:23:28ZengCell Physiol Biochem Press GmbH & Co KGCellular Physiology and Biochemistry1015-89871421-97782016-02-0138273774710.1159/000443030443030Fc Receptor Inhibition Reduces Susceptibility to Oxidative Stress in Human RPE Cells Treated with Bevacizumab, but not AfliberceptMahdy RanjbarMax Philipp BrinkmannDorinja ZapfYoko MiuraMartin RudolfSalvatore GrisantiBackground/Aims: VEGF-A is induced by oxidative stress, and functions as a survival factor for various cell types, including retinal pigment epithelial (RPE) cells. Anti-vascular endothelial growth factor (VEGF) drugs like aflibercept and bevacizumab have shown to be most effective in treating neovascular age-related macular degeneration (AMD), however uptake of the drugs might lead to interference with cell physiology. Herein, we evaluated the significance of the Fc receptor (FcR) within this context and moreover explored the impact of VEGF inhibition under normal conditions as well as under oxidative stress, in terms of potential adverse effects. Methods: ARPE-19 (human RPE) cells were treated with aflibercept and bevacizumab in presence or absence of H2O2 as oxidative stress stimulus. After 24h cells were evaluated for drug uptake, VEGF-A expression and secretion, levels of intracellular reactive oxygen species (ROS) as well as cell proliferation. Experiments were repeated with cells being pre-incubated with an FcR inhibitor prior to drug application. Results: Both drugs inhibited extracellular levels of VEGF-A and were taken up into the RPE, resulting in significantly reduced intracellular levels of VEGF-A. When oxidative stress was applied, intracellular ROS levels in cells treated with both drugs rose, and cell proliferation was reduced. Prior incubation with the FcR inhibitor lessened the uptake of bevacizumab, but not aflibercept into RPE cells, and simultaneously enhanced cell survival under oxidative stress conditions. Conclusions: Our results indicate that uptake and accumulation of aflibercept and bevacizumab within RPE cells affect the intracellular VEGF-A metabolism negatively, leading to a biologically relevant reduced cell survival under oxidative stress. The FcR plays a substantial role in the uptake of bevacizumab, but not aflibercept, which allows an enhanced RPE cell survival through FcR blockage in an environment dominated by oxidative stress, as clinically significant for various inflammatory retinal disorders.http://www.karger.com/Article/FullText/443030VEGF-AAfliberceptBevacizumabFcROxidative stressROS |
| spellingShingle | Mahdy Ranjbar Max Philipp Brinkmann Dorinja Zapf Yoko Miura Martin Rudolf Salvatore Grisanti Fc Receptor Inhibition Reduces Susceptibility to Oxidative Stress in Human RPE Cells Treated with Bevacizumab, but not Aflibercept Cellular Physiology and Biochemistry VEGF-A Aflibercept Bevacizumab FcR Oxidative stress ROS |
| title | Fc Receptor Inhibition Reduces Susceptibility to Oxidative Stress in Human RPE Cells Treated with Bevacizumab, but not Aflibercept |
| title_full | Fc Receptor Inhibition Reduces Susceptibility to Oxidative Stress in Human RPE Cells Treated with Bevacizumab, but not Aflibercept |
| title_fullStr | Fc Receptor Inhibition Reduces Susceptibility to Oxidative Stress in Human RPE Cells Treated with Bevacizumab, but not Aflibercept |
| title_full_unstemmed | Fc Receptor Inhibition Reduces Susceptibility to Oxidative Stress in Human RPE Cells Treated with Bevacizumab, but not Aflibercept |
| title_short | Fc Receptor Inhibition Reduces Susceptibility to Oxidative Stress in Human RPE Cells Treated with Bevacizumab, but not Aflibercept |
| title_sort | fc receptor inhibition reduces susceptibility to oxidative stress in human rpe cells treated with bevacizumab but not aflibercept |
| topic | VEGF-A Aflibercept Bevacizumab FcR Oxidative stress ROS |
| url | http://www.karger.com/Article/FullText/443030 |
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