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Elucidation of the mechanism of drug-induced lethal cardiac myopathy; participation of autophagic process and the rab, intracellular membrane transport system

Research Project

Project/Area Number 18K06885
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 48030:Pharmacology-related
Research InstitutionTohoku University

Principal Investigator

SATO TAKEYA  東北大学, 医学系研究科, 准教授 (10312696)

Co-Investigator(Kenkyū-buntansha) 戸田 法子  東北大学, 医学系研究科, 非常勤講師 (50375052)
斎藤 将樹  東北大学, 医学系研究科, 助教 (50400271)
野村 亮介  東北大学, 大学病院, 助教 (90400358)
Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywordsオートファジー / 薬物 / 抗ガン剤 / 薬物障害 / Rab / SNARE / ミトコンドリア / LC3B / 薬剤誘発性心筋症
Outline of Final Research Achievements

Doxorubicin is an effective anticancer drug against various cancers. However, it shows lethal toxicity to the heart, and the molecular mechanism remains unclear. In this study, we found that doxorubicin inhibited autophagy and investigated its molecular mechanism. We found that doxorubicin activated autophagy; however, activated autophagy was inhibited midway, and autophagic flux was not completed. This study revealed that the site of inhibition of autophagy by doxorubicin is the fusion inhibition of autophagosomes and lysosomes. In addition, mitochondrial function was impaired. Therefore, autophagy, which removes dysfunctional mitochondria, is inhibited by doxorubicin, which induces myocardial cell death due to the increased oxidative stress caused by the intracellular accumulation of dysfunctional mitochondria.

Academic Significance and Societal Importance of the Research Achievements

抗ガン剤であるドキソルビシンの副作用である心筋障害にオートファジー障害がある。しかしながらその分子機構の詳細は、これまで不明であった。本研究においてドキソルビシンはオートファジーを活性化するが、その途中過程を阻害するために、オートファジーが完結せず、オートファジー不全を起こすことを見出した。
今後、この問題に着目して、ドキソルビシンのオートファジー不全を改善する方法を見出すことにより、ドキソルビシン誘発心筋障害を軽減することができると期待される。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (27 results)

All 2021 2020 2019 2018 Other

All Journal Article (4 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 4 results,  Open Access: 4 results) Presentation (22 results) (of which Int'l Joint Research: 4 results,  Invited: 1 results) Remarks (1 results)

  • [Journal Article] Tctex-1 augments G protein-coupled receptor-mediated G<sub>s</sub> signaling by activating adenylyl cyclase2021

    • Author(s)
      Saito Masaki、Chiba Ayano、Sato Takeya、Moriya Takahiro、Sukegawa Jun、Nakahata Norimichi
    • Journal Title

      Journal of Pharmacological Sciences

      Volume: 145 Issue: 1 Pages: 150

    • DOI

      10.1016/j.jphs.2020.11.011

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Activity of adenylyl cyclase type 6 is suppressed by direct binding of the cytoskeletal protein 4.1G2019

    • Author(s)
      Saito Masaki、Cui Linran、Hirano Marina、Li Guanjie、Yanagisawa Teruyuki、Sato Takeya、Sukegawa Jun
    • Journal Title

      Molecular Pharmacology

      Volume: 96 Issue: 4 Pages: 441

    • DOI

      10.1124/mol.119.116426

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Current situation of researches on a sensor organelle, primary cilium, to understand the pathogenesis of ciliopathy2019

    • Author(s)
      斎藤 将樹、佐藤 岳哉
    • Journal Title

      Folia Pharmacologica Japonica

      Volume: 153 Issue: 3 Pages: 117-123

    • DOI

      10.1254/fpj.153.117

    • NAID

      130007610670

    • ISSN
      0015-5691, 1347-8397
    • Related Report
      2019 Research-status Report 2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Ciliary assembly/disassembly assay in non-transformed cell lines2018

    • Author(s)
      Masaki Saito#,*、Kensuke Sakaji#、Wataru Otsu、Ching-Hwa Sung (#; equally contributed, *; corresponding author)
    • Journal Title

      Bio-protocol

      Volume: 8 Issue: 6

    • DOI

      10.21769/bioprotoc.2773

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Molecular mechanisms of Doxorubicin-induced cardiomyopathy, involvement in the impairment of mitophagy2021

    • Author(s)
      Takeya Sato, Mikio Muraoka, Noriko Toda, Guanjie Li, Masanori Yamauchi, Masaki Saito, Teruyuki Yanagisawa
    • Organizer
      第94回日本薬理学会年会
    • Related Report
      2020 Annual Research Report
  • [Presentation] EGFP-tagged Syntaxin 17 (STX17) localized on autophagosome is increased by Doxorubicin2021

    • Author(s)
      Guanjie Li, Delan Lin, Noriko Toda, Masaki Saito, Masanori Yamauchi, Kazuhiko Yanai, Takeya Sato
    • Organizer
      第94回日本薬理学会年会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Tctex-1 augments parathyroid hormone receptor-mediated Gs signaling by activating adenylyl cyclase2021

    • Author(s)
      Masaki Saito, Ayano Chiba, Takeya Sato, Jun Sukegawa
    • Organizer
      第94回日本薬理学会年会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Mechanism of primary ciliary resorption by phosphorylated Tctex-12020

    • Author(s)
      M. Saito, K. Sakaji, S. Ebrahimi Azar, T. Sato, C. Sung
    • Organizer
      American Society of Cell Biology 2020
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] ドキソルビシンの心筋障害の分子機構 ミトコンドリア選択的オートファジー、 ミトファジー障害による2020

    • Author(s)
      佐藤岳哉、村岡幹夫、戸田法子、山内正憲、斎藤将樹、柳澤輝行
    • Organizer
      第71回日本薬理学会北部会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 完成オートファゴソーム定量系の構築2020

    • Author(s)
      李 冠傑、林 德嵐、戸田 法子、斎藤 将樹、  山内 正憲、谷内 一彦、佐藤 岳哉
    • Organizer
      第71回日本薬理学会北部会
    • Related Report
      2020 Annual Research Report
  • [Presentation] MASR4 accelerates primary culiary resorption and cell cycle re-rntry through activation of Cdc422020

    • Author(s)
      Sara Ebrahimi Azar、阪路 健祐、佐藤 岳哉、斎藤 将樹
    • Organizer
      第71回日本薬理学会北部会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Tctex-1を介した一次繊毛の短縮・消失におけるCdc42の活性化機構2020

    • Author(s)
      斎藤 将樹, 阪路 健祐, Sara EbrahimiAzar, 佐藤 岳哉
    • Organizer
      第93回日本生化学会大会
    • Related Report
      2020 Annual Research Report
  • [Presentation] ドキソルビシン誘発心筋症の分子機構 オートファジー融合過程の阻害2020

    • Author(s)
      李冠傑、戸田法子、斎藤将樹、山内正憲、谷内一彦、佐藤岳哉
    • Organizer
      第13回リトリート大学院生研究発表会
    • Related Report
      2019 Research-status Report
  • [Presentation] 医学部学生に対してイオントラップの概念を理解するためのアスピリンを用いた薬物動態学実習2020

    • Author(s)
      佐藤岳哉、斎藤将樹、吉川雄朗、長沼史登、中村正帆、岡村信行、柳澤輝行、谷内一彦
    • Organizer
      第93回日本薬理学会年会
    • Related Report
      2019 Research-status Report
  • [Presentation] 膜裏打ちタンパク質4.1Gはアデニル酸シクラーゼ6に直接結合しPTH受容体のGsシグナルを抑制する2020

    • Author(s)
      斎藤将樹、崔林然、平野鞠菜、李冠傑、柳澤輝行、佐藤岳哉、助川淳
    • Organizer
      第93回日本薬理学会年会
    • Related Report
      2019 Research-status Report
  • [Presentation] ドキソルビシン誘発心筋症の原因は、オートファジーの融合過程の阻害のためである2020

    • Author(s)
      李冠傑、斎藤将樹、戸田法子、山内正憲、谷内一彦、佐藤岳哉
    • Organizer
      第93回日本薬理学会年会
    • Related Report
      2019 Research-status Report
  • [Presentation] MAST4, a function-unknown protein, promotes cell cycle progression through accelerating primary cilliary resorption2020

    • Author(s)
      Sara Ebrahimi Azar, Kenji Sakaji, Takeya Sato, Masaki Saito
    • Organizer
      Tohoku Forum for Creativity
    • Related Report
      2019 Research-status Report
  • [Presentation] Regulatory Mechanisms of Primary Ciliary Resorption and Cell Cycle Progression by a Dynein Light Chain, Tctex-12020

    • Author(s)
      Sara Ebrahimi Azar, Kensuke Sakaji, Takeya Sato, Masaki Saito
    • Organizer
      第93回日本薬理学会年会
    • Related Report
      2019 Research-status Report
  • [Presentation] 致死性心筋症を誘発する薬物性オートファジー障害の分子機構2019

    • Author(s)
      李冠傑、戸田法子、山内正憲、斎藤将樹、佐藤岳哉
    • Organizer
      日本生化学会東北支部第85回例会・シンポジウム
    • Related Report
      2019 Research-status Report
  • [Presentation] "Regulatory mechanisms of cell cycle progression through primary ciliary resorption."2019

    • Author(s)
      Masaki Saito, Sara Ebrahimi Azar, Kenji Sakaji, Takeya Sato
    • Organizer
      Tohoku Forum for Creativity Thematic Program 2019
    • Related Report
      2019 Research-status Report
  • [Presentation] Mitochondrial nonspecific channel is crucial for the manintenance of theur function.2019

    • Author(s)
      佐藤岳哉、野村亮介、斎藤将樹、助川淳、久志本茂樹、柳澤輝行
    • Organizer
      第92回日本薬理学会年会
    • Related Report
      2018 Research-status Report
  • [Presentation] Mitochondrial quality control system and autophagy2018

    • Author(s)
      佐藤岳哉
    • Organizer
      43th SNUH R&D SEMINAR
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] 融合タンパク質プローブを用いるAutophagic flux定量方法確立2018

    • Author(s)
      佐藤 岳哉、李 冠傑、斎藤 将樹、助川 淳、柳澤輝行
    • Organizer
      第69回日本薬理学会北部会
    • Related Report
      2018 Research-status Report
  • [Presentation] Disruption of mitochondrial dynamics by azidothymidine-triphosphate causes lethal cardiomyopathy2018

    • Author(s)
      Takeya Sato, Ryosuke Nomura, Shigeki Kushimoto, Teruyuki Yanagisawa
    • Organizer
      第91回日本薬理学会年会 第18回 国際薬理学・臨床薬理学会議
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] 戸田法子1、村Autophagic fluxの阻害によるドキソルビシン誘発性心筋障害の分子機構2018

    • Author(s)
      戸田法子、村岡幹夫、荒木峻、山内正憲、柳澤輝行、佐藤岳哉
    • Organizer
      第69回日本薬理学会北部会
    • Related Report
      2018 Research-status Report
  • [Presentation] Anthracycline antibiotics, doxorubicin impacts on the fusion of autophagosome with lysosome on the autophagy flux2018

    • Author(s)
      Noriko Toda, Guanjie Li, Masanori Yamauchi, Teruyuki Yanagisawa
    • Organizer
      第91回日本薬理学会年会 第18回 国際薬理学・臨床薬理学会議
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Remarks] 東北大学医学部分子薬理学分野

    • URL

      http://www.molpharm.med.tohoku.ac.jp/fen_zi_yao_lihomupeji/HOME.html

    • Related Report
      2019 Research-status Report

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Published: 2018-04-23   Modified: 2024-01-30  

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