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Enhancement mechanisms of cell growth suppression by bisphosphonates in cancer microenvironment

Research Project

Project/Area Number 16K08423
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Medical pharmacy
Research InstitutionKyoto Pharmaceutical University

Principal Investigator

NISHIGUCHI KOHSHI  京都薬科大学, 薬学部, 教授 (80379437)

Co-Investigator(Kenkyū-buntansha) 辻本 雅之  京都薬科大学, 薬学部, 講師 (90372739)
峯垣 哲也  京都薬科大学, 薬学部, 助教 (10549306)
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords食道がん / がん微小環境 / 低酸素 / ビスホスホネート / 微小環境 / 食道癌 / ビスホスホネート系薬物 / コレステロール合成 / 治療標的
Outline of Final Research Achievements

Tumour hypoxia is a major obstacle in cancer therapy that leads to poor prognosis. Therefore, the development of cancer treatments that are effective
in hypoxia is necessary. Bisphosphonates (BPs), which are used to treat bone disease, are cytotoxic to several cancer cells in normoxia.
In hypoxia, cell growth inhibition by BPs and via zoledronate-induced apoptosis was higher in hypoxia than that in normoxia. Furthermore, geranylgeraniol completely inhibited the growth inhibitory effects of zoledronate. Additionally, the mRNA and protein levels of HMG-CoA reductase significantly decreased in hypoxia. Moreover, simvastatin potentiated the growth inhibitory effect of zoledronate.The cytotoxicity of BPs is potentiated in hypoxia, through the loss of HMG-CoA reductase function. BPs may be effective against cancer in normoxia and hypoxia.

Academic Significance and Societal Importance of the Research Achievements

本研究成果は、既存の化学療法に全く奏功しない、あるいは高い治療効果を望めない食道がん患者に対して、代替えとなる治療法あるいは治療薬の選択肢を広げるとともに、食道がんに対する新規治療標的を見出し得るという点で極めて重要な基礎的知見である。また、食道がんの治療成績向上のみならず、治療薬候補に乏しい食道がんの新規治療薬の開発に対して有益な情報を付与することから社会的意義は非常に大きいものと考えられる。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (5 results)

All 2019 2018 2017 2016

All Journal Article (1 results) (of which Peer Reviewed: 1 results) Presentation (4 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] Augmentation of the cytotoxic effects of nitrogen-containing bisphosphonates in hypoxia2018

    • Author(s)
      Tetsuya Minegaki, Saya Koiki, Yutaro Douke, Chihiro Yamane, Ai Suzuki, Misato Mori, Masayuki Tsujimoto, and Kohshi Nishiguchi
    • Journal Title

      Journal of Pharmacy and Pharmacology

      Volume: 印刷中

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Presentation] ヒト食道癌細胞株の低酸素環境下におけるビスホスホネートに対する感受性増強機序の解明2019

    • Author(s)
      楠斐未、峯垣哲也、池上歩花、奥田博允、藤井啓子、眞弓万里奈、北山純花、原祢幸汰、葛本貴大、米田朋美、辻本雅之、西口工司
    • Organizer
      日本薬学会第139年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 低酸素下におけるビスホスホネート系薬物の細胞毒性増強とそのメカニズムの解明2017

    • Author(s)
      峯垣哲也、戀木沙耶、道家雄太郎、山根千尋、鈴木 藍、森 美里、辻本雅之、西口工司
    • Organizer
      日本薬学会 第137年会
    • Place of Presentation
      仙台
    • Year and Date
      2017-03-24
    • Related Report
      2016 Research-status Report
  • [Presentation] Hypoxia Potentiates the Cytotoxic Effects of Nitrogen-Containing Bisphosphonates in Human Esophageal Cancer Cell Line.2016

    • Author(s)
      Kohshi Nishiguchi, Tetsuya Minegaki, Saya Koiki, Yutaro Doke, Chihiro Yamane, Ai Suzuki, Misato Mori, Masayuki Tsujimoto
    • Organizer
      2016 AAPS Annual Meeting and Exposition
    • Place of Presentation
      Denver, Colorado, USA
    • Year and Date
      2016-11-13
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] 低酸素下でのビスホスホネート系薬剤による細胞毒性の増強におけるメバロン酸経路の関与2016

    • Author(s)
      戀木沙耶、峯垣哲也、道家雄太郎、山根千尋、鈴木 藍、森 美里、辻本雅之、西口工司
    • Organizer
      医療薬学フォーラム2016 第24回クリニカルファーマシーシンポジウム
    • Place of Presentation
      滋賀県大津市
    • Year and Date
      2016-06-25
    • Related Report
      2016 Research-status Report

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Published: 2016-04-21   Modified: 2020-03-30  

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