Therapeutic Potential of an Orally Available Dual Small-Molecule Modulator of Wnt and P53 Pathways in Neovascular Age-Related Macular Degeneration
39 Pages Posted: 28 Nov 2018More...
Background: Neovascular age-related macular degeneration is a common cause of irreversible vision loss in the elderly. Anti-vascular endothelial growth factor has been effective in treating pathological ocular neovascularization, but it has limitations including the need for repeated intraocular injections for the maintenance of therapeutic effects in most patients and poor or non-response to this agent in some patients.
Methods: In vitro cellular studies were conducted using retinal pigment epithelial cell lines (ARPE-19 and hTERT-RPE1), human umbilical vein endothelial cells, and HUVSMCs. In vivo efficacy of ilimaquinone was tested in laser-induced choroidal neovascularization mouse models.
Findings: Ilimaquinone, 4,9-friedodrimane-type sesquiterpenoid isolated from marine sponge, repressed the expression of angiogenic/inflammatory factors and restored the expression of E-cadherin in retinal pigment epithelial cells by inhibiting the Wnt/b-catenin pathway. In addition, it selectively inhibited proliferation and tube formation of human umbilical vein endothelial cells by activating the p53 pathway. Intravitreal, intraperitoneal, and oral administration of ilimaquinone significantly reduced abnormal vascular leakage in mice with laser-induced choroidal neovascularization without affecting established, mature blood vessels in the adult mouse retina.
Interpretation: Our findings demonstrate that ilimaquinone functions through regulation of p53 and Wnt/b-catenin pathways with conceivable advantages over existing cytokine-targeted anti-angiogenic therapies.
Funding Statement: This work was supported by the Fundamental Technology Program (2012M3A9B2028335, 2017R1A2A2A05001340) through the National Research Foundation of Korea (NRF) funded by the Korean Government.
Declaration of Interests: The authors have declared that no competing interest exists.
Ethics Approval Statement: All experimental procedures and animal care were conducted following guidelines and approvals of the Animal Care Committee of Konkuk University (KU15104).
Keywords: neovascular age-related macular degeneration, Ilimaquinone, Wnt/b-catenin pathway, p53 pathway
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