May 2008
Volume 49, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2008
Anti-Angiogenesis Efficacy of the Novel NF-B and Oxidative Stress Inhibitor, OT-551
Author Affiliations & Notes
  • S. A. Mousa
    Pharmaceutical Research Institute, Albany College of Pharmacy, Albany, New York
  • E. Dier
    Pharmaceutical Research Institute, Albany College of Pharmacy, Albany, New York
  • T. Kannanayakal
    R & D, Othera Pharmaceuticals, Exton, Pennsylvania
  • G. Patil
    R & D, Othera Pharmaceuticals, Exton, Pennsylvania
  • Footnotes
    Commercial Relationships  S.A. Mousa, Consultant to Othera Pharmaceuticals, C; E. Dier, None; T. Kannanayakal, Employee of Othera Pharmaceuticals, E; G. Patil, Employee of Othera Pharmaceuticals, E.
  • Footnotes
    Support  Recipient of Othera Pharmaceutical grant
Investigative Ophthalmology & Visual Science May 2008, Vol.49, 4590. doi:https://doi.org/
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      S. A. Mousa, E. Dier, T. Kannanayakal, G. Patil; Anti-Angiogenesis Efficacy of the Novel NF-B and Oxidative Stress Inhibitor, OT-551. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4590. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : Recent reports have suggested the importance of mediators in addition to vascular endothelial growth factor (VEGF) in ocular angiogenesis-associated disorder. Hence, the purpose of this investigation was to evaluate the anti-angiogenesis efficacy of OT-551, a small molecule that inhibits nuclear factor-ΚB (NF-ΚB) and oxidative stress pathways, on angiogenesis in the chick chorioallantoic membrane (CAM) model as well as its efficacy on NF-ΚB associated pro-inflammatory pathways.

Methods: : OT-551 was tested for inhibition of various pro-angiogenesis stimuli, including oxidative stress (H2O2, lipid hydroperoxide), basic fibroblast growth factor (bFGF), VEGF, angiotensin II, bradykinin, and lipopolysaccharide (LPS). OT-551 was also tested in combination with bevacizumab or ranibizumab in inhibiting VEGF-induced angiogenesis in the CAM model. Additionally, NF-ΚB activation and oxidative stress pathways were evaluated using microarray, RT-PCR, Western blots, gel shift, and membrane lipid peroxidation assays ; LPS-induced, NF-ΚB-dependent upregulation of chemokines and cytokines was determined in vitro in human blood as well as in vivo in a mouse model treated with different doses OT-551.

Results: : OT-551 effectively inhibited angiogenesis-induced by various stimuli in CAM model. Furthermore, enhanced anti-angiogenesis efficacy was demonstrated when OT-551 was utilized in combination with bevacizumab or ranibizumab in inhibiting VEGF-induced angiogenesis in the CAM model. OT-551 demonstrated effective inhibition of LPS-induced NF-ΚB activation, nuclear translocation of p50/p65, degradation of IKBα, without any effect on nuclear p50/p65 DNA binding. OT-551 effectively inhibited LPS-mediated TNF-α production in vitro by human blood cells with an IC50 of 9.2 µM. Similarly in mice, in a dose-dependent manner, OT-551 effectively inhibited up-regulation of chemokines and cytokines, without any effect on basal/constitutive levels of cytokines(e.g. TNF-α). Additionally, OT-551 inhibited membrane lipid peroxidation (80-90% inhibition at 1.0 -3.0 µM). Microarray results demonstrated effective inhibition of NADH oxidase in the human monocytic cell line.

Conclusions: : These results indicated a broad spectrum of anti-angiogenesis efficacy of OT-551 against various mediators. The compound enhanced the anti-angiogenesis efficacy of bevacizumab and ranibizumab. These properties of OT-551 are likely related to its ability to inhibit NF-ΚB activation and cellular oxidative stress pathways.

Keywords: inflammation • growth factors/growth factor receptors • antioxidants 
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