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 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.Kim JH, 2008, J PHARMACOL EXP THER, V324, P643, DOI 10.1124/jpet.107.132720KIM JH, 2008, J CELL MOL MEDKim JH, 2007, BIOCHEM BIOPH RES CO, V362, P848, DOI 10.1016/j.bbrc.2007.08.100Kim DH, 2007, BIOCHEM BIOPH RES CO, V356, P233, DOI 10.1016/j.bbrc.2007.02.126Min JK, 2007, BLOOD, V109, P1495, DOI 10.1182/blood-2006-06-029298Mann BS, 2007, ONCOLOGIST, V12, P1247, DOI 10.1634/theoncologist.12-10-1247CHEN J, 2007, ANGIOGENESIS, V10, P133, DOI 10.1007/s10456-007-9066-0Folkman J, 2006, ANNU REV MED, V57, P1, DOI 10.1146/annutev.med.57.121304.131306Parker M, 2006, J BIOSOC SCI, V38, P117, DOI 10.1017/S0021932005001136Adamis AP, 2005, RETINA-J RET VIT DIS, V25, P111Sasakawa Y, 2003, BIOCHEM PHARMACOL, V66, P897, DOI 10.1016/S0006-2952(03)00411-8Haggarty SJ, 2003, P NATL ACAD SCI USA, V100, P4389, DOI 10.1073/pnas.0430973100Zhang Y, 2003, EMBO J, V22, P1168Matsuyama A, 2002, EMBO J, V21, P6820Deroanne CF, 2002, ONCOGENE, V21, P427Kim MS, 2001, NAT MED, V7, P437Han JW, 2000, CANCER RES, V60, P6068Xiao HY, 1999, J CELL BIOCHEM, V73, P291Archer SY, 1998, P NATL ACAD SCI USA, V95, P6791Grunstein M, 1997, NATURE, V389, P349Hassig CA, 1997, CELL, V89, P341Risau W, 1997, NATURE, V386, P671Pierce EA, 1996, ARCH OPHTHALMOL-CHIC, V114, P1219Richon VM, 1996, P NATL ACAD SCI USA, V93, P5705Taunton J, 1996, SCIENCE, V272, P408AIELLO LP, 1994, NEW ENGL J MED, V331, P1480SMITH LEH, 1994, INVEST OPHTH VIS SCI, V35, P101HAWKINS BS, 1991, ARCH OPHTHALMOL-CHIC, V109, P1109MILLER H, 1986, INVEST OPHTH VIS SCI, V27, P1644ROTH AM, 1977, AM J OPHTHALMOL, V84, P636