title: Inhibition of multiple pathogenic pathways by histone deacetylase inhibitor SAHA in a corneal alkali-burn injury model.
abstract: 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.
authors.affiliation: Department of Ophthalmology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, United States.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Li
authors.forename: Qinbo
authors.initials: Q
authors.lastname: Zhou
authors.forename: Jakub
authors.initials: J
authors.lastname: Hanus
authors.forename: Chastain
authors.initials: C
authors.lastname: Anderson
authors.forename: Hongmei
authors.initials: H
authors.lastname: Zhang
authors.forename: Michael
authors.initials: M
authors.lastname: Dellinger
authors.forename: Rolf
authors.initials: R
authors.lastname: Brekken
authors.forename: Shusheng
authors.initials: S
authors.lastname: Wang
mesh_terms: D000468:Alkalies; D000818:Animals; D002057:Burns, Chemical / Q000188:drug therapy* / Q000473:pathology; D003315:Cornea / Q000098:blood supply / Q000187:drug effects / Q000201:enzymology; D003316:Corneal Diseases / Q000188:drug therapy* / Q000473:pathology; D065306:Corneal Injuries; D016510:Corneal Neovascularization / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D004195:Disease Models, Animal; D005126:Eye Burns / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D042583:Lymphangiogenesis / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D000077337:Vorinostat
chemical_list: D000468:Alkalies; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat