Valproic acid inhibits tumor angiogenesis in mice transplanted with Kasumi-1 leukemia cells

Abstract

Histone deacetylase (HDAC) inhibitors have been reported to inhibit tumor angiogenesis via the downregulation of angiogenic factors. Our previous in vitro studies demonstrated that valproic acid (VPA) exerted antitumor effects on Kasumi-1 cells, which are human acute myeloid leukemia cells with an 8;21 chromosome translocation. In the present study, the effects of VPA on tumor angiogenesis were investigated in mice transplanted with Kasumi-1 cells. Semi-quantitative reverse transcription-polymerase chain reaction, western blotting and immunohistochemistry were used to detect the expression of vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR2) and basic fibroblast growth factor (bFGF). The tumor microvessel density was measured following staining with an anti-CD34 antibody. Chromatin immunoprecipitation was used to study the effect of VPA-induced histone hyperacetylation on VEGF transcription. An intraperitoneal injection of VPA inhibited tumor growth and angiogenesis in mice transplanted with Kasumi-1 cells. The mRNA and protein expression of VEGF, VEGFR2 and bFGF were inhibited by VPA treatment. In addition, VPA downregulated HDAC, increased histone H3 acetylation and enhanced the accumulation of hyperacetylated histone H3 on the VEGF promoters. The findings of the present study indicate that VPA, an HDAC inhibitor, exerts an antileukemic effect through an anti-angiogenesis mechanism. In conclusion, the mechanism underlying VPA-induced anti-angiogenesis is associated with the suppression of angiogenic factors and their receptors. VPA may increase the accumulation of acetylated histones on the VEGF promoters, which possibly contributes to the regulation of angiogenic factors.

The progress of angiogenic factors in the development of leukemias

“…Ginsenoside Rg3 has been not only used in antiangiogenic therapy of solid tumors, but also exhibits an anti-leukemia effect in part due to its anti-angiogenic activity via inhibiting PI3K/Akt and ERK1/2 pathways, which act to regulate expression of HIF-1α and VEGF (30). Histone deacetylase (HDAC) inhibitors have been reported to inhibit tumor angiogenesis via downregulation of angiogenic factors (31). The mechanism underlying VPA induced antiangiogenesis is associated with suppression of VEGF and its receptors (31).…”

“…Histone deacetylase (HDAC) inhibitors have been reported to inhibit tumor angiogenesis via downregulation of angiogenic factors (31). The mechanism underlying VPA induced antiangiogenesis is associated with suppression of VEGF and its receptors (31). Furthermore, the combined use of histone deacetylase inhibitor VPA, all-trans retinoic acid (ATRA), and deoxyribonucleic acid polymerase-α inhibitor cytarabine (Ara-C) is now considered for disease-stabilizing treatment of AML, which was related to antiproliferative effects, and modulation of release of angiogenic mediator of endothelial helix-loop-helix leucine zipper transcription factor can be attributed to c-myc (41).…”

Effects of Histone Deacetylase Inhibitor (Valproic Acid) on the Expression of Hypoxia-inducible Factor-1 Alpha in Human Retinal Müller Cells

“…One of the HDAC inhibitors is valproic acid (VPA), which has been widely used for the treatment of epilepsy [ 25 ]. Several studies have shown that VPA also inhibits tumor angiogenesis through suppression of angiogenic factors such as VEGF [ 26 27 ]. While HDACIs have been widely used in cancer treatment, these agents have yet to be applied to the treatment of ophthalmic disease [ 28 29 30 ].…”

Roles of Histone Deacetylases and Inhibitors in Anticancer Therapy

“…The inhibitors of HDACs render cancer cells more sensitive to immunotherapy, increasing the expression of antigens present in the tumor and thus acting as immunomodulators [ 192 ]. The anticancer activity of HDACis comprises different molecular and physiological events such as the inhibition of the vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS) and TGFβ1 [ 193 , 194 , 195 ]. The apoptosis of tumor cells induced by HDACis is associated with their ability to selectively regulate proapoptotic pathways [ 196 ], which does not occur in normal cells [ 197 ].…”