N-hydroxy-7-(2-naphthylthio) heptanomide inhibits retinal and choroidal angiogenesis.
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 labeling-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.
Kim
Jeong Hun
JH
Chemical Genomics Laboratory, Department of Biotechnology, College of Life Science & Biotechnology, Yonsei University, Seoul 120-749, Korea.
Kim
Jin Hyoung
JH
Oh
Meeyeon
M
Yu
Young Suk
YS
Kim
Kyu-Won
KW
Kwon
Ho Jeong
HJ
D000818:Animals; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D020256:Choroidal Neovascularization / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005451:Fluorescein Angiography; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D009281:Naphthalenes / Q000494:pharmacology*; D015861:Retinal Neovascularization / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C520433:N-hydroxy-7-(2-naphthylthio)heptanamide; D009281:Naphthalenes; D006655:Histone Deacetylases