Inhibition of Multiple Pathogenic Pathways by Histone Deacetylase Inhibitor SAHA in a Corneal Alkali-Burn Injury Model
详细信息 查看全文
- 作者：Xinyu Li ; Qinbo Zhou ; Jakub Hanus ; Chastain Anderson ; Hongmei Zhang ; Michael Dellinger ; Rolf Brekken ; Shusheng Wang
- 刊名：Molecular Pharmaceutics
- 出版年：2013
- 出版时间：January 7, 2013
- 年：2013
- 卷：10
- 期：1
- 页码：307-318
- 全文大小：630K
- 年卷期：v.10,no.1(January 7, 2013)
- ISSN：1543-8392
文摘
Neovascularization (NV) in the cornea is a major cause of vision impairment and corneal blindness. Hemangiogenesis and lymphangiogenesis induced by inflammation underlie the pathogenesis of corneal NV. The current mainstay treatment, corticosteroid, treats the inflammation associated with corneal NV, but is not satisfactory due to such side effects as cataract and the increase in intraocular pressure. It is imperative to develop a novel therapy that specifically targets the hemangiogenesis, lymphangiogenesis, and inflammation pathways underlying corneal NV. Histone deacetylase inhibitors (HDACi) have been in clinical trials for cancer and other diseases. In particular, HDACi suberoylanilide hydroxamic acid (SAHA, vorinostat, Zolinza) has been approved by the FDA for the treatment of cutaneous T-cell lymphoma. The functional mechanism of SAHA in cancer and especially in corneal NV remains unclear. Here, we show that topical application of SAHA inhibits neovascularization in an alkali-burn corneal injury model. Mechanistically, SAHA inhibits corneal NV by repressing hemangiogenesis, inflammation pathways, and previously overlooked lymphangiogenesis. Topical SAHA is well tolerated on the ocular surface. In addition, the potency of SAHA in corneal NV appears to be comparable to the current steroid therapy. SAHA may possess promising therapeutic potential in alkali-burn corneal injury and other inflammatory neovascularization disorders.