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Sodium valproate and Rapamycin synergistically enhance the vascular endothelial growth inhibitor-mediated cell death in human osteosarcoma and vascular endothelial cells.

Research Project

Project/Area Number 26462279
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Orthopaedic surgery
Research InstitutionHyogo Medical University

Principal Investigator

Futani Hiroyuki  兵庫医科大学, 医学部, 教授 (30248140)

Co-Investigator(Kenkyū-buntansha) 山根木 康嗣  兵庫医科大学, 医学部, 講師 (00434944)
Co-Investigator(Renkei-kenkyūsha) TERADA Nobuyuki  兵庫医科大学, 医学部, 名誉教授 (50150339)
Research Collaborator KUMANISHI Shunsuke  
Project Period (FY) 2014-04-01 – 2018-03-31
Project Status Completed (Fiscal Year 2017)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords骨肉腫 / 腫瘍新生血管抑制 / ラパマイシン標的蛋白質阻害剤 / ヒストン脱アセチル化阻害剤 / 免疫療法 / 転移 / 悪性骨腫瘍
Outline of Final Research Achievements

We investigated the effects of anti-angiogenesis by Rapamycin (mTOR) in combination with valproic acid (VPA) on human osteosarcoma cells (OS). mTOR increased vascular endothelial growth inhibitor (VEGI) and a little effect of death receptor 3 (DR3) expression. However, in combination with VPA induced further increasing effect of both VEGI and DR3 without induction of decoy receptor 3 (DcR3) on OS and human microvascular endothelial cells (HMVE). Furthermore, combination of mTOR and VPA -induced soluble VEGI in the OS culture medium markedly inhibited the vascular tube formation of HMVE. These results suggest that mTOR and HDAC inhibitor has anti-angiogenesis and anti-tumor activities that mediate soluble VEGI/DR3-induced apoptosis via both autocrine and paracrine pathways. Finally, mTOR and VPA are considered to be one of the promising strategies in the development of novel anti-neovascularization therapy on osteosarcomas.

Report

(5 results)
  • 2017 Annual Research Report   Final Research Report ( PDF )
  • 2016 Research-status Report
  • 2015 Research-status Report
  • 2014 Research-status Report
  • Research Products

    (17 results)

All 2018 2017 2016 2015

All Journal Article (8 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 8 results,  Open Access: 7 results,  Acknowledgement Compliant: 4 results) Presentation (9 results) (of which Int'l Joint Research: 3 results,  Invited: 1 results)

  • [Journal Article] A rare case of low-grade fibromyxoid sarcoma with ossification which was radiologically detected as apparent calcification and histopathologically proven.2018

    • Author(s)
      Tsuchida Y., Tsukamoto Y., Futani H., Kumanishi S., Watanabe T., Kajimoto N., Matsuo S., Yoshiya S., Hirota S.
    • Journal Title

      Human Pathology: Case Reports

      Volume: 12 Pages: 24-28

    • DOI

      10.1016/j.ehpc.2018.01.002

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The roles of a ribosomal protein S19 polymer in a mouse model of carrageenan-induced acute pleurisy.2017

    • Author(s)
      Yamanegi K, Kawakami T, Yamada N, Kumanishi S, Futani H, Nakasho K, Nishiura H.
    • Journal Title

      Immunobiology

      Volume: 222(5) Issue: 5 Pages: 738-750

    • DOI

      10.1016/j.imbio.2017.02.001

    • Related Report
      2017 Annual Research Report 2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Primary undifferentiated small round cell sarcoma of the deep abdominal wall with a novel variant of t(10;19) CIC-DUX4 gene fusion2017

    • Author(s)
      Tsukamoto Y., Futani H., Yoshiya S., Watanabe T., Kihara T., Matsuo S., and Hirota S.
    • Journal Title

      Pathol Res Pract

      Volume: 213 Issue: 10 Pages: 1315-1321

    • DOI

      10.1016/j.prp.2017.06.008

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] An unexpected skin ulcer and soft tissue necrosis after the nonconcurrent combination of proton beam therapy and pazopanib: A case of myxofibrosarcoma2017

    • Author(s)
      Uwa N., Terada T., Mohri T., Tsukamoto Y., Futani H., Demizu Y., Okimoto T., and Sakagami M.
    • Journal Title

      Auris. Nasus. Larynx.

      Volume: 44 Issue: 4 Pages: 484-488

    • DOI

      10.1016/j.anl.2016.07.016

    • Related Report
      2017 Annual Research Report 2016 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] RP S19 C-terminal peptide trimer acts as a C5a receptor antagonist2017

    • Author(s)
      Nishiura H., Kawakami T., Kawabe M., Kato-Kogoe N., Yamada N., Nakasho K., and Yamanegi K.
    • Journal Title

      Biochem. Biophys. Rep.

      Volume: 10 Pages: 70-76

    • DOI

      10.1016/j.bbrep.2016.05.006

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] A rare case of Ewing sarcoma with elevated plasma pro-gastrin-releasing peptide (proGRP) level2016

    • Author(s)
      Tsukamoto Y., Futani H., Kumanishi S., Watanabe T., Kihara T., Hirota S.
    • Journal Title

      Human Pathology: Case Reports

      Volume: 6 Pages: 13-18

    • DOI

      10.1016/j.ehpc.2015.12.001

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Chondromyxoid fibroma of the femur can not be differentiated from chondrosarcoma by 18F-FDG PET/CT, and histopathology is still the final diagnostic tool2015

    • Author(s)
      Okada T., Futani H., Kanto R., Kumanishi S., Tsukamoto Y., and Yoshiya S.
    • Journal Title

      J Clin Case Rep

      Volume: 5 Issue: 12 Pages: 1-3

    • DOI

      10.4172/2165-7920.1000661

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Sodium valproate, a histone deacetylase inhibitor, modulates the vascular endothelial growth inhibitor-mediated cell death in human osteosarcoma and vascular endothelial cells.2015

    • Author(s)
      Yamanegi K, Kawabe M, Futani H, Nishiura H, Yamada N, Kato-Kogoe N, Kishimoto H, Yoshiya S, Nakasho K.
    • Journal Title

      Int J Oncol

      Volume: 46 Issue: 5 Pages: 1994-2002

    • DOI

      10.3892/ijo.2015.2924

    • Related Report
      2014 Research-status Report
    • Peer Reviewed
  • [Presentation] Sodium valproate, a histone deacetylase inhibitor, induces 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 cytotoxicity2017

    • Author(s)
      Shunsuke Kumanishi, Koji Yamanegi, Hiroyuki Futani, Keiji Nakasho, Shinichi Yoshiya
    • Organizer
      Orthopaedic Research Society 2017 Annual Meeting
    • Place of Presentation
      Xian, China
    • Year and Date
      2017-03-19
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Sodium valproate, a histone deacetylase inhibitor, induces 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 cytotoxicity2017

    • Author(s)
      Kumanishi S., Yamanegi K., Futani H., Nakasho K., Yoshiya S.
    • Organizer
      The Orthopaedic Research Society 2017 Annual Meeting
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 高齢者発生骨肉腫の肺転移例にラジオ波焼灼術が有効であった1例2017

    • Author(s)
      中村 吉弘, 麩谷 博之, 熊西 俊介, 岩津 友大, 山田 淳平, 吉矢 晋一
    • Organizer
      第129回中部日本整形外科災害外科学会
    • Related Report
      2017 Annual Research Report
  • [Presentation] これだけは知っておきたい骨腫瘍の診断と治療2017

    • Author(s)
      麩谷博之
    • Organizer
      第30回兵庫医大整形外科開業医会学術講演会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] 鏡視下手術で腓骨近位を温存した骨巨細胞腫の4例2017

    • Author(s)
      麩谷博之、熊西俊介、川口貴之、澤井龍生、吉矢晋一
    • Organizer
      第50回日本整形外科学会骨軟部腫瘍学会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 足の内軟骨腫に対する鏡視下手術の有用性2017

    • Author(s)
      麩谷博之、熊西俊介、神頭誠、吉矢晋一
    • Organizer
      第90回日本整形外科学会学術総会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Downregulation of matrix metalloproteinase-9 mRNA by valproic acid plays a role in inhibiting the shedding of MHC class I-related molecules A and B on the surface of human osteosarcoma cells2016

    • Author(s)
      Hiroyuki Futani,Koji Yamanegi,Shunsuke Kumanishi, Keiji Nakasho,Shinichi Yoshiya
    • Organizer
      2016 International Combined Meeting of the Orthopaedic Research Societies
    • Place of Presentation
      San Diego, USA
    • Year and Date
      2016-09-21
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] 骨肉腫の免疫療法の効果増強における塩酸ヒドララジンの有用性2015

    • Author(s)
      麩谷博之,山根木康嗣,中正恵二 ,吉矢晋一
    • Organizer
      第30回日本整形外科学会基礎学術集会
    • Place of Presentation
      富山
    • Year and Date
      2015-10-22 – 2015-10-23
    • Related Report
      2014 Research-status Report
  • [Presentation] 骨肉腫の免疫療法における塩酸ヒドララジンの有用性2015

    • Author(s)
      麩谷博之、山根木康嗣、熊西俊介、中正恵二、吉矢晋一
    • Organizer
      第30回日本整形外科学会基礎学術総会
    • Place of Presentation
      富山市民プラザ、富山
    • Year and Date
      2015-10-22
    • Related Report
      2015 Research-status Report

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Published: 2014-04-04   Modified: 2019-03-29  

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