Valproic Acid Inhibits Angiogenesis in Vitro and in Vivo

Abstract

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 Ϯ 5%, migration by 86 Ϯ 11%, and tube formation by 82 Ϯ 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.

Modulation of angiogenesis by dithiolethione‐modified NSAIDs and valproic acid

“…Activity of valproate in the zebrafish model is consistent with earlier published reports of its inhibition of vessel development in the chicken chorioallantoic membrane and in mice (Michaelis et al, 2004;Zgouras et al, 2004), and thereby validates the zebrafish model as a screening tool for angiogenesis inhibitors. The endothelial inhibition results and the tumor explant studies argue that both S-NSAIDs and S-valproate are angiogenesis inhibitors, with the primary antiangiogenic effects most likely residing in the dithiolthione moieties.…”

“…These responses were maximal at 10 and/or 100 mM. The Hsp27 response to valproate is consistent with its reported antiangiogenic activity (Michaelis et al, 2004) and the intersomitic vessel defects in valproate-treated zebrafish embryos.…”

Histone Deacetylase Inhibitors for Cancer Therapy

“…40 VPA selectively induced the degradation of HDAC2 in vitro and in vivo. 41,42 Phenylacetate (PA), a well studied member of the short-chain fatty acids, is a metabolite of phenylbutyrate (PB) that arrests cells in G 1 by inducing the expression of p21 WAF1/CIP1 . PA can penetrate the central nervous system and when tested in solid tumors showed anti-tumor effects mediated by histone acetylation.…”

Biological Screening of Novel Derivatives of Valproic Acid for Anticancer and Antiangiogenic Properties

“…The pivotal role of angiogenesis in tumor progression and metastasis has urged researchers to test newly developed angiogenesis inhibitors in a broad variety of animal tumor growth models. The short chain fatty acid valproic acid (VPA) and VPA-analogs have been reported as an affective anticancer molecules by inducing differentiation, inhibiting proliferation, increasing apoptosis, and immunogenicity and by decreasing metastatic and angiogenetic potential (Regan, 1985;Kawagoe et al, 2002;Michaelis et al, 2004;Blaheta et al, 2005;Rocchi et al, 2005;Kaiser et al, 2006;Rezacova et al, 2006;Kostrouchova Kostrouch, 2007). Valproic acid is emerging as a potential anticancer drug and may also serve as a powerful molecular tool for targeting of pathways that regulate the behavior of cancer cells (Kostrouchova Kostrouch 2007).…”

“…Beside an effective epileptic drug VPA also inhibits angiogenesis both in vitro and in vivo (Michaelis et al, 2004;Zgouras et al, 2004;Farooq et al, 2008;Kitazoe et al, 2009;Osuka et al, 2012). Being a smaller in size and remarkable therapeutic potential, several synthetic compounds have been designed as structural derivatives of VPA with improved bioactivities.…”