title: Sodium valproate, a histone deacetylase inhibitor, modulates the vascular endothelial growth inhibitor-mediated cell death in human osteosarcoma and vascular endothelial cells.
abstract: The level of vascular endothelial growth inhibitor (VEGI) has been reported to be negatively associated with neovascularization in malignant tumors. The soluble form of VEGI is a potent anti-angiogenic factor due to its effects in inhibiting endothelial cell proliferation. This inhibition is mediated by death receptor 3 (DR3), which contains a death domain in its cytoplasmic tail capable of inducing apoptosis that can be subsequently blocked by decoy receptor 3 (DcR3). We investigated the effects of sodium valproate (VPA) and trichostatin A (TSA), histone deacetylase inhibitors, on the expression of VEGI and its related receptors in human osteosarcoma (OS) cell lines and human microvascular endothelial (HMVE) cells. Consequently, treatment with VPA and TSA increased the VEGI and DR3 expression levels without inducing DcR3 production in the OS cell lines. In contrast, the effect on the HMVE cells was limited, with no evidence of growth inhibition or an increase in the DR3 and DcR3 expression. However, VPA-induced soluble VEGI in the OS cell culture medium markedly inhibited the vascular tube formation of HMVE cells, while VEGI overexpression resulted in enhanced OS cell death. Taken together, the HDAC inhibitor has anti-angiogenesis and antitumor activities that mediate soluble VEGI/DR3-induced apoptosis via both autocrine and paracrine pathways. This study indicates that the HDAC inhibitor may be exploited as a therapeutic strategy modulating the soluble VEGI/DR3 pathway in osteosarcoma patients.
authors.affiliation: Department of Pathology, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Yamanegi
authors.affiliation: Department of Pathology, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Mutsuki
authors.initials: M
authors.lastname: Kawabe
authors.affiliation: Department of Orthopedic Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Futani
authors.affiliation: Department of Pathology, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishiura
authors.affiliation: Department of Pathology, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Yamada
authors.affiliation: Department of Pathology, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Nahoko
authors.initials: N
authors.lastname: Kato-Kogoe
authors.affiliation: Department of Oral and Maxillofacial Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Kishimoto
authors.affiliation: Department of Orthopedic Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Yoshiya
authors.affiliation: Department of Pathology, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Nakasho
mesh_terms: D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006801:Humans; D006877:Hydroxamic Acids / Q000627:therapeutic use; D012516:Osteosarcoma / Q000378:metabolism / Q000473:pathology*; D060888:Real-Time Polymerase Chain Reaction; D053323:Receptors, Tumor Necrosis Factor, Member 6b / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014635:Valproic Acid / Q000627:therapeutic use*
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D053323:Receptors, Tumor Necrosis Factor, Member 6b; C117026:TNFSF15 protein, human; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15; C012589:trichostatin A; D014635:Valproic Acid