June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Small molecule inhibition of ferrochelatase blocks ocular angiogenesis in vitro and ex vivo
Author Affiliations & Notes
  • Trupti Shetty
    Pharmacology, Indiana University, Indianapolis, Indiana, United States
  • Sheik Pran Babu Sardar Pasha
    Opthalmology, Indiana University, Indianapolis, Indiana, United States
  • Rania S. Sulaiman
    Opthalmology, Indiana University, Indianapolis, Indiana, United States
  • Halesha Dhurvigere Basavarajappa
    Biochemistry & Molecular Biology, Indiana University, Indianapolis, Indiana, United States
  • Kamakshi Sishtla
    Opthalmology, Indiana University, Indianapolis, Indiana, United States
  • Christian Briggs
    Opthalmology, Indiana University, Indianapolis, Indiana, United States
  • Timothy William Corson
    Opthalmology, Indiana University, Indianapolis, Indiana, United States
  • Footnotes
    Commercial Relationships   Trupti Shetty, None; Sheik Pran Babu Sardar Pasha, None; Rania Sulaiman, None; Halesha Basavarajappa, Indiana University (P); Kamakshi Sishtla, None; Christian Briggs, None; Timothy Corson, Indiana University (P)
  • Footnotes
    Support  NIH R01EY025641, Research to Prevent Blindness, Inc.
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 4066. doi:
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      Trupti Shetty, Sheik Pran Babu Sardar Pasha, Rania S. Sulaiman, Halesha Dhurvigere Basavarajappa, Kamakshi Sishtla, Christian Briggs, Timothy William Corson; Small molecule inhibition of ferrochelatase blocks ocular angiogenesis in vitro and ex vivo. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4066.

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

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Abstract

Purpose : Pathologic neovascularization is a factor in many blinding eye diseases. We previously identified an enzyme of heme biosynthesis, ferrochelatase, as playing a role in mediating ocular angiogenesis. Knockdown of this enzyme decreases angiogenic properties of human retinal endothelial cells. Interestingly, an FDA-approved antifungal drug, griseofulvin, inhibits ferrochelatase as an off-target effect and has similar antiangiogenic effects to ferrochelatase inhibition in the laser-induced choroidal neovascularization mouse model. Here, we aim to explore the effects of griseofulvin and its active metabolite on retinal and choroidal neovascularization using ocular endothelial cells and ex vivo sprouting assays.

Methods : We tested griseofulvin and its ferrochelatase-inhibiting metabolite N-methylprotoporphyrin (NMPP) on Rhesus macaque choroidal endothelial cells (RF/6A cells) in proliferation, apoptosis, scratch-wound healing, and tube formation assays. Griseofulvin was also examined for any effects on ocular non-endothelial cell types, human retinal pigment epithelial (ARPE-19), retinoblastoma (Y79) and uveal melanoma (92.1) cells. We further performed an ex vivo murine angiogenesis assay, testing the effects of griseofulvin on endothelial sprouting of retinal fragments ex vivo isolated from 4-5 week old C57BL/6 mice.

Results : Griseofulvin and NMPP both decreased proliferation of RF/6A cells, without inducing apoptosis (GI50 = 77 μM and 49 μM, respectively). This antiproliferative effect was reversible in a washout experiment. These compounds also blocked migration and tube formation of RF/6A cells. Griseofulvin had no antiproliferative effect on other ocular non-endothelial cell types. Importantly, 20 μM and 40 μM griseofulvin profoundly inhibited endothelial sprouting of retinal explants ex vivo by nearly 80% compared to the vehicle control.

Conclusions : Griseofulvin has promising therapeutic effects on both retinal and choroidal angiogenesis without toxicity at effective doses in vitro. We postulate that griseofulvin could be repurposed as a therapeutic drug to treat aberrant neovascularization in ocular diseases.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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