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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 2018

See all articles by Younglim Son

Younglim Son

Kookmin University

Daehan Lim

Konkuk University

Seoyoung Park

Kookmin University

Im-Sook Song

Kyungpook National University

Joo-Hyun Kim

Kookmin University

Sora Shin

Kookmin University

Hoik Jang

Konkuk University

Kwang-Hyeon Liu

Kyungpook National University

Yuseok O

Chungnam National University

Gyu-Yong Song

Chungnam National University

MinKyun Na

Chungnam National University - College of Pharmacy

Hyewon Chung

Konkuk University - Department of Ophthalmology

Sangtaek Oh

Kookmin University - Department of Bio and Fermentation Convergence Technology

More...

Abstract

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

Suggested Citation

Son, Younglim and Lim, Daehan and Park, Seoyoung and Song, Im-Sook and Kim, Joo-Hyun and Shin, Sora and Jang, Hoik and Liu, Kwang-Hyeon and O, Yuseok and Song, Gyu-Yong and Na, MinKyun and Chung, Hyewon and Oh, Sangtaek, Therapeutic Potential of an Orally Available Dual Small-Molecule Modulator of Wnt and P53 Pathways in Neovascular Age-Related Macular Degeneration (November 22, 2018). Available at SSRN: https://ssrn.com/abstract=3289783 or http://dx.doi.org/10.2139/ssrn.3289783

Younglim Son

Kookmin University

Chongnung-dong, Songbuk-gu
Seoul, 136-702
Korea, Republic of (South Korea)

Daehan Lim

Konkuk University

Seoul 143-701, Korea
120 Neungdong-ro, Gwangjin-gu
Seoul 143-701, 143-701
Korea, Republic of (South Korea)

Seoyoung Park

Kookmin University

Chongnung-dong, Songbuk-gu
Seoul, 136-702
Korea, Republic of (South Korea)

Im-Sook Song

Kyungpook National University

Korea, Republic of (South Korea)

Joo-Hyun Kim

Kookmin University

Chongnung-dong, Songbuk-gu
Seoul, 136-702
Korea, Republic of (South Korea)

Sora Shin

Kookmin University

Chongnung-dong, Songbuk-gu
Seoul, 136-702
Korea, Republic of (South Korea)

Hoik Jang

Konkuk University

Seoul 143-701, Korea
120 Neungdong-ro, Gwangjin-gu
Seoul 143-701, 143-701
Korea, Republic of (South Korea)

Kwang-Hyeon Liu

Kyungpook National University

Korea, Republic of (South Korea)

Yuseok O

Chungnam National University

Daejon, 34134
Korea, Republic of (South Korea)

Gyu-Yong Song

Chungnam National University

Daejon, 34134
Korea, Republic of (South Korea)

MinKyun Na

Chungnam National University - College of Pharmacy ( email )

Daejon, 34134
Korea, Republic of (South Korea)

Hyewon Chung

Konkuk University - Department of Ophthalmology ( email )

Seoul 143-701, Korea
120 Neungdong-ro, Gwangjin-gu
Seoul 143-701, 143-701
Korea, Republic of (South Korea)

Sangtaek Oh (Contact Author)

Kookmin University - Department of Bio and Fermentation Convergence Technology ( email )

Chongnung-dong, Songbuk-gu
Seoul, 136-702
Korea, Republic of (South Korea)

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