Journal
MOLECULAR PHARMACEUTICS
Volume 6, Issue 2, Pages 513-519Publisher
AMER CHEMICAL SOC
DOI: 10.1021/mp800178b
Keywords
Anti-angiogenesis; choroidal neovascularization; histone deacetylase inhibitor; N-hydroxy-7-(2-naphthylthio) heptanomide; retinal neovascularization
Funding
- National R&D Prooram for Cancer Control. Ministry of Health Welfare [0620360-1]
- Basic Research Program of the Korea Science & Engineering Foundation [R01-2004-000-10212-0]
- Bio-Signal Analysis Technology Innovation Program [M1064501001-06n4501-00110]
- Ministry of Science and Technology (MOST)
- Korea Science and Engineering Foundation (KOSEF)
- Brain Korea 21 Project, Republic of Korea
- National Research Foundation of Korea [R01-2004-000-10212-0] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Histone deacetylase (HDAC) is a key enzyme regulating gene expression, including angiogenic cytokine expression. We have previously identified a novel synthetic HDAC inhibitor, known as N-hydroxy-7-(2-naphthylthio) heptanomide (HNHA), with antitumor properties. Here, we investigated the antiangiogenic properties of this small synthetic molecule both in vitro and in vivo. HNHA inhibited nuclear HDAC enzyme activity in human umbilical endothelial cells (HUVECs), an effect accompanied by histone hyperacetylation, p21 upregulation, and cell cycle arrest. HNHA also inhibited vascular endothelial growth factor-induced tube formation and migration of HUVECs, in the absence of any detectable cellular toxicity. Intravitreous injection of HNHA into mice inhibited retinal neovascularization associated with oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV), as determined through fluorescence angiography and vessel counting. Retinas from HNHA-treated animals had a normal histological appearance without any detectable increase in terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeliing-positive cells, showing that this compound did not induce retinal toxicity. These findings indicate that HNHA has direct antiangiogenic effects and may be an effective strategy for inhibiting the pathological retinal and choroidal neovascularization underlying blinding eye diseases.
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