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Tamara J. Granner, Shawn C. Maloney, Sebastian Di Cesare, Tiago Briccoli, Cristina Miyamoto, Miguel N. Burnier, Jr.; The Combination of Bevacizumab and 3,4 Dihydroxyphenyl Ethanol Reduces Angiogenin in Retinal Pigment Epithelial Cells. Invest. Ophthalmol. Vis. Sci. 2012;53(14):437. doi: https://doi.org/.
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Choroidal neovascularization is the hallmark of the wet form of Age-Related Macular Degeneration (AMD) and is currently the target of multiple anti-angiogenic pharmacotherapies. The current study evaluated if 3,4 Dihydroxyphenyl Ethanol (DPE) reduces secretion of pro-angiogenic cytokines from a human retinal pigment epithelial cell line (ARPE-19). Moreover, additional anti-angiogenic effects of DPE in combination with bevacizumab were evaluated.
ARPE-19 cells were cultured for 24 hours under normoxic conditions or with a hypoxia-mimicking agent (100μM cobalt chloride [CoCl2]). After 24 hours, all media was removed and replaced with one of the following serum-free conditions: Control media, DPE (100μM), bevacizumab (0.25mg/ml), or combination of DPE (100μM) and bevacizumab (0.25mg/ml). Media was harvested after 24 hours for sandwich ELISA-based angiogenesis arrays. The secretion of the following ten pro-angiogenic cytokines was measured: Angiogenin, ANG2, EGF, bFGF, HB-EGF, PDGF-BB, Leptin, PIGF, HGF, and VEGF-A. Statistical significance was evaluated using a Student’s t-test with p<0.05 as a cutoff for significance.
Of the ten cytokines assayed, three (Angiogenin, ANG2, and VEGF-A) were secreted by ARPE-19 cells under normoxia and all three were significantly increased under CoCl2-simulated hypoxia. HB-EGF and PIGF were not secreted under normoxia, but secretion was induced under simulated hypoxia. Following treatment with DPE, levels of Angiogenin and VEGF-A significantly decreased under normoxia while all five detectable cytokines significantly decreased under simulated hypoxia compared to the control. The combination of bevacizumab with DPE significantly reduced secretion of Angiogenin and ANG2 under normoxia. Angiogenin was significantly down-regulated by the combination under simulated hypoxia compared to bevacizumab alone.
This study demonstrated that DPE significantly reduced the secretion of multiple pro-angiogenic cytokines to varying degrees under normoxia and simulated hypoxia. Further, the combination of DPE and bevacizumab proved to be a more effective approach to reduce Angiogenin than bevacizumab alone. Therefore the combination of DPE and bevacizumab may represent a valuable therapeutic option for the wet form of AMD.
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