title: Valproic acid cooperates with hydralazine to augment the susceptibility             of human osteosarcoma cells to Fas- and NK cell-mediated cell death.
abstract: We investigated the effects of valproic acid (VPA), a histone deacetylase inhibitor, in combination with hydralazine, a DNA methylation inhibitor, on the expression of cell-surface Fas and MHC-class I-related chain molecules A and B (MICA and B), the ligands of NKG2D which is an activating receptor of NK cells, and on production of their soluble forms in HOS, U-2 OS and SaOS-2 human osteosarcoma cell lines. We also examined the susceptibility of these cells to Fas- and NK cell-mediated cell death. VPA did not increase the expression of Fas on the surface of osteosarcoma cells, while hydralazine did, and the combination of VPA with hydralazine increased the expression of cell-surface Fas. In contrast, the combination of VPA with hydralazine did not increase the production of soluble Fas by osteosarcoma cells. Both VPA and hydralazine increased the expression of cell-surface MICA and B in osteosarcoma cells, and their combination induced a greater increase in their expression. VPA inhibited the production of both soluble MICA and MICB by osteosarcoma cells while hydralazine produced no effect. Both VPA and hydralazine enhanced the susceptibility of osteosarcoma cells to Fas- and NK cell-mediated cell death and the combination of VPA with hydralazine further enhanced the effects. The present results suggest that combined administration of VPA and hydrazine is valuable for enhancing the therapeutic effects of immunotherapy for osteosarcomas.
authors.affiliation: Department of Pathology, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan. yamanegi@hyo-med.ac.jp
authors.forename: Koji
authors.initials: K
authors.lastname: Yamanegi
authors.forename: Junko
authors.initials: J
authors.lastname: Yamane
authors.forename: Kenta
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Nahoko
authors.initials: N
authors.lastname: Kato-Kogoe
authors.forename: Hideki
authors.initials: H
authors.lastname: Ohyama
authors.forename: Keiji
authors.initials: K
authors.lastname: Nakasho
authors.forename: Naoko
authors.initials: N
authors.lastname: Yamada
authors.forename: Masaki
authors.initials: M
authors.lastname: Hata
authors.forename: Satoru
authors.initials: S
authors.lastname: Fukunaga
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Futani
authors.forename: Haruki
authors.initials: H
authors.lastname: Okamura
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Terada
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D019175:DNA Methylation / Q000187:drug effects; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors; D004357:Drug Synergism; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006830:Hydralazine / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000276:immunology / Q000502:physiology*; D012516:Osteosarcoma; D011401:Promoter Regions, Genetic; D019139:Tumor Escape / Q000187:drug effects; D014635:Valproic Acid / Q000494:pharmacology*; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D015395:Histocompatibility Antigens Class I; D056572:Histone Deacetylase Inhibitors; C099187:MHC class I-related chain A; C098080:MICB antigen; D019014:fas Receptor; D006830:Hydralazine; D014635:Valproic Acid; D015254:DNA Modification Methylases