title: 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.
authors.affiliation: Affiliated Hospital of Chengde Medical College, Chengde, Hebei 067000, P.R. China.
authors.forename: Zhi-Hua
authors.initials: ZH
authors.lastname: Zhang
authors.affiliation: Affiliated Hospital of Chengde Medical College, Chengde, Hebei 067000, P.R. China.
authors.forename: Chang-Lai
authors.initials: CL
authors.lastname: Hao
authors.affiliation: The First Hospital of Shijiazhuang City, Shijiazhuang, Hebei 050000, P.R. China.
authors.forename: Peng
authors.initials: P
authors.lastname: Liu
authors.affiliation: Chinese PLA 89 Hospital, Weifang, Shandong 261000, P.R. China.
authors.forename: Xia
authors.initials: X
authors.lastname: Tian
authors.affiliation: Affiliated Hospital of Chengde Medical College, Chengde, Hebei 067000, P.R. China.
authors.forename: Li-Hong
authors.initials: LH
authors.lastname: Wang
authors.affiliation: Affiliated Hospital of Chengde Medical College, Chengde, Hebei 067000, P.R. China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Affiliated Hospital of Chengde Medical College, Chengde, Hebei 067000, P.R. China.
authors.forename: Cui-Min
authors.initials: CM
authors.lastname: Zhu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D040262:Receptors, Vascular Endothelial Growth Factor / Q000096:biosynthesis; D014635:Valproic Acid / Q000008:administration & dosage*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D023041:Xenograft Model Antitumor Assays
chemical_list: D056572:Histone Deacetylase Inhibitors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D014635:Valproic Acid; D040262:Receptors, Vascular Endothelial Growth Factor