RT Journal Article
SR Electronic
T1 Valproic Acid Inhibits Angiogenesis in Vitro and in Vivo
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 520
OP 527
DO 10.1124/mol.65.3.520
VO 65
IS 3
A1 Martin Michaelis
A1 U. Ruth Michaelis
A1 Ingrid Fleming
A1 Tatyana Suhan
A1 Jaroslav Cinatl
A1 Roman A. Blaheta
A1 Katrin Hoffmann
A1 Rouslan Kotchetkov
A1 Rudi Busse
A1 Heinz Nau
A1 Jindrich Cinatl, Jr.
YR 2004
UL http://molpharm.aspetjournals.org/content/65/3/520.abstract
AB Valproic acid (VPA) is a widely used antiepileptic agent that is undergoing clinical evaluation for anticancer therapy. We assessed the effects of VPA on angiogenesis in vitro and in vivo. In human umbilical vein endothelial cells, therapeutically relevant concentrations of VPA (0.25 to 1 mM) inhibited proliferation, migration, and tube formation. VPA 1 mM inhibited endothelial cell proliferation by 51 ± 5%, migration by 86 ± 11%, and tube formation by 82 ± 3%. These changes were preceded by the hyperacetylation of histone H4, indicating the inhibition of histone deacetylase (HDAC), and a decreased expression of the endothelial nitric-oxide synthase (eNOS). The inhibition of endothelial cell tube formation by VPA was prevented by addition of the nitric oxide donor (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA NONOate). The anticonvulsive active VPA derivative 2-ethyl-4-methylpentanoic acid, which does not inhibit HDAC, did not affect endothelial cell proliferation, tube formation, or eNOS expression. VPA was also found to inhibit angiogenesis in vivo in the chicken chorioallantoic membrane assay and in a Matrigel plug assay in mice. Embryos from VPA-treated mice showed disturbed vessel formation. These results indicate that therapeutic plasma levels of VPA inhibit angiogenesis by a mechanism involving a decrease in eNOS expression preceded by HDAC inhibition.