Improvement of immunotherapy for human osteosarcoma by HDAC inhibitor

2010 Fiscal Year Final Research Report

• Project/Area Number: 21791835
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Pathobiological dentistry/Dental radiology
• Research Institution: Hyogo College of Medicine
• Principal Investigator: YAMANEGI Koji Hyogo College of Medicine, 医学部, 講師 (00434944)
• Project Period (FY): 2009 – 2010
• Keywords: 骨肉腫 / histone deacetylase inhibitor / NKG2D / NKG2D ligand

Research Abstract

We investigated the effects of valproic acid (VPA) (a histone deacetylase inhibitor) in combination with hydralazine (Hy) (a DNA methylation inhibitor) on expression of cell-surface Fas and MHC-class I-related chain molecules A and B (MICA and B), which are ligands of NKG2D, and on production of their soluble forms in HOS, U-2 OS and SaOS-2 human osteosarcoma cells. VPA showed no significant effect on expression of Fas on surface of osteosarcoma cells while Hy increased it and their combination showed the more increasing effect. VPA decreased the production of soluble Fas by osteosarcomas cells but Hy increased it and VPA reduced the increasing effect of Hy. VPA or hydralazine increased expression of cell-surface MICA and B, and their combination induced its further increase. VPA inhibited the production of soluble MICA and B in osteosarcoma cells and the inhibitory effect of VPA did not affected by Hy, which alone showed no significant effect. VPA and Hy enhanced Fas-mediated cell death and susceptibility to NK cells on osteosarcoma cells and their combination showed the more augmenting effect. These results suggest that combined administration of VPA and hydrazine may be useful for enhancing the therapeutic effect of immunotherapy for osteosarcomas.

Research Products

• [Journal Article] Sodium valproate, a histone deacetylase inhibitor, augments the expression of cell-surface NKG2D ligand, MICA and B, without increasing their soluble forms to enhance susceptibility of human osteosarcoma cells to NK cell-mediated cytotoxicity (2010)
  • Author(s): Yamanegi K, Yamane J, Kobayashi K, Kato-Kogoe N, Ohyama H, Nakasho K, Yamada N, Hata M, Nishioka T, Fukunaga S, Futani H, Okamura H, Nobuyuki Terada.
  • Journal Title: Oncol Rep. 24 Pages: 1621-1627
  • Peer Reviewed
• [Journal Article] XPC branch-point sequence mutations disrupt U2 snRNP binding resulting in abnormal pre-mRNA splicing in xeroderma pigmentosum patients (2010)
  • Author(s): Khan SG, Yamanegi K, Zheng Z-M, Boyle J, Imoto K, Oh KS, Baker CC, Gozukara E, Metin A, Kraemer KH.
  • Journal Title: Human Mutation. 31 Pages: 167-175
  • Peer Reviewed
• [Journal Article] Fibroblasts stimulated via HLA-II molecules produce prostaglandin E_2 and regulate cytokine production from helper T cells (2010)
  • Author(s): Kato-Kogoe N, Ohyama H, Nishimura F, Meguro M, Yoshizawa S, Okada Y, Nakasho K, Yamanegi K, Yamada N, Hata M, Higashi T, Terada N, Matsushita S.
  • Journal Title: Lab Invest 90 Pages: 1747-1756
  • Peer Reviewed
• [Journal Article] The involvement of IL-23 and the Th17 pathway in periodontitis (2009)
  • Author(s): Ohyama H, Kato-Kogoe N, Kuhara A, Nishimura F, Nakasho K, Yamanegi K, Yamada N, Hata M, Yamane J, Terada N.
  • Journal Title: J.Dent.Res. 88(7) Pages: 633-638
  • Peer Reviewed
• [Journal Article] Immunotherapy with interleukin-18 in combination with preoperative chemotherapy with ifosfamide effectively inhibits postoperative progression of pulmonary metastases in a mouse osteosarcoma model (2009)
  • Author(s): Yamada N, Hata M, Ohyama H, Yamanegi K, Kogoe N, Nakasho K, Futani H, Okamura H, Terada N.
  • Journal Title: Tumor Biol. 30(4) Pages: 176-184
  • Peer Reviewed
• [Journal Article] Immunohistochemical analyses of E-cadherin, β-catenin, CD44s, and CD44v6 expressions, and Ki-67 labeling index in intraductal papillary mucinous neoplasms of the pancreas and associated invasive carcinomas (2009)
  • Author(s): Okimura A, Hirano H, Nishigami T, Ueyama S, Tachibana S, Fukuda Y, Yamanegi K, Ohyama H, Terada N, Nakasho K.
  • Journal Title: Med Mol Morphol. 42 Pages: 222-229
  • Peer Reviewed
• [Presentation] ヒストン脱アセチル化阻害剤とDNAメチル化阻害剤の併用による抗腫瘍免疫細胞に対する感受性増加 (2010)
  • Author(s): 山根木康嗣、小林健太、大山秀樹、小越菜保子、秦正樹、山田直子、中正恵二、寺田信行
  • Organizer: 第99回日本病理学会総会
  • Place of Presentation: 東京
  • Year and Date: 2010-04-27
• [Presentation] ヒストン脱アセチル化阻害剤によるヒト骨肉腫細胞の免疫療法抵抗性の減弱 (2009)
  • Author(s): 山根木康嗣、山根順子、大山秀樹、小越菜保子、秦正樹、山田直子、中正恵二、寺田信行
  • Organizer: 第98回日本病理学会総会
  • Place of Presentation: 京都
  • Year and Date: 2009-05-03
• [Presentation] DNAメチル化阻害剤とヒストン脱アセチル化阻害剤の併用によるヒト骨肉腫細胞の抗腫瘍免疫細胞抵抗性の減弱 (2009)
  • Author(s): 山根順子、山根木康嗣、大山秀樹、小越菜保子、秦正樹、山田直子、中正恵二、寺田信行
  • Organizer: 第98回日本病理学会総会
  • Place of Presentation: 京都
  • Year and Date: 2009-05-03