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Development of Novel Cell Regulation Technology targeting Nuclear Receptors

Research Project

Project/Area Number 18K06572
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 47010:Pharmaceutical chemistry and drug development sciences-related
Research InstitutionTokyo Medical and Dental University

Principal Investigator

Yuasa Mari  東京医科歯科大学, 生体材料工学研究所, 助教 (80506303)

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: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Keywords核内受容体 / レチノイド / エピジェネティクス / 創薬化学
Outline of Final Research Achievements

We investigated the effects of synthetic retinoid Am80 in combination with epigenetic inhibitors in various cancer cells. Histone deacetylation inhibitors belonging to Class IIb were effective in combination with Am80. This suggests that HSP90, one of the targets of HDAC6 in Class IIb showing affinity as a chaperone of RARα, is hyperacetylated and dissociates from RARα, thereby regulating nuclear translocation. Furthermore, we investigated whether the nuclear migration of RARα is commonly regulated in cell types other than solid tumors and in culture conditions such as aggregation and spheroid. We found that the combined effects of the two drugs and the regulation of RAR nuclear migration are more pronounced under some conditions than in normal two-dimensional culture.

Academic Significance and Societal Importance of the Research Achievements

核内受容体をターゲットとした創薬の成功例として、急性前骨髄急性白血病APLの治療薬Am80をはじめ、エストロゲンレセプター(ER)をターゲットとした乳がん治療薬タモキシフェン、ペルオキシソーム増殖因子活性化受容体γ(PPARγ)をターゲットとした2型糖尿病の治療薬ロシグリタゾンなどがある。しかしながら、疾患に関与する核内受容体の精緻な制御は未だ途上であり従来のアゴニスト・アンタゴニストによる制御に留まらない新しい概念が求められている。本研究成果は従来の核内受容体リガンドによる制御に留まらないユビキチン化などの分解制御や細胞内輸送の制御など、新しい核内受容体制御法の開発に貢献しうると考えられる。

Report

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

    (19 results)

All 2021 2020 2019 2018

All Journal Article (8 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 8 results,  Open Access: 8 results) Presentation (11 results) (of which Int'l Joint Research: 8 results)

  • [Journal Article] Activation of β2-adrenergic receptor signals suppresses mesenchymal phenotypes of oral squamous cell carcinoma cells.2021

    • Author(s)
      Sakakitani S, Podyma-Inoue KA, Takayama R, Takahashi K, Ishigami-Yuasa M, Kagechika H, Harada H, Watabe T.
    • Journal Title

      Cancer Sci

      Volume: 112 Issue: 1 Pages: 155-167

    • DOI

      10.1111/cas.14670

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Chemical Screening of Nuclear Receptor Modulators2020

    • Author(s)
      Ishigami-Yuasa Mari、Kagechika Hiroyuki
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 21 Issue: 15 Pages: 5512-5512

    • DOI

      10.3390/ijms21155512

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Development of Androgen-Antagonistic Coumarinamides with a Unique Aromatic Folded Pharmacophore2020

    • Author(s)
      Koga, H.; Negishi, M.; Kinoshita, M.; Fujii, S.; Mori, S.; Ishigami-Yuasa, M.; Kawachi, E.; Kagechika, H.; Tanatani, A.
    • Journal Title

      Int. J. Mol. Sci.

      Volume: 21 Issue: 15 Pages: 5584-5584

    • DOI

      10.3390/ijms21155584

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Class IIb HDAC Inhibition Enhances the Inhibitory Effect of Am80, a Synthetic Retinoid, in Prostate Cancer2019

    • Author(s)
      Ishigami-Yuasa Mari、Ekimoto Hisao、Kagechika Hiroyuki
    • Journal Title

      Biological and Pharmaceutical Bulletin

      Volume: 42 Issue: 3 Pages: 448-452

    • DOI

      10.1248/bpb.b18-00782

    • NAID

      130007606238

    • ISSN
      0918-6158, 1347-5215
    • Year and Date
      2019-03-01
    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Structure-activity relationship of novel (benzoylaminophenoxy)phenol derivatives as anti-prostate cancer agents2018

    • Author(s)
      Kazui Yuko、Fujii Shinya、Yamada Ayumi、Ishigami-Yuasa Mari、Kagechika Hiroyuki、Tanatani Aya
    • Journal Title

      Bioorganic & Medicinal Chemistry

      Volume: 26 Issue: 18 Pages: 5118-5127

    • DOI

      10.1016/j.bmc.2018.09.008

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Chemical compounds that suppress hypoxia-induced stress granule formation enhance cancer drug sensitivity of human cervical cancer HeLa cells2018

    • Author(s)
      Timalsina Shikshya、Arimoto-Matsuzaki Kyoko、Kitamura Masami、Xu Xiaoyin、Wenzhe Qiu、Ishigami-Yuasa Mari、Kagechika Hiroyuki、Hata Yutaka
    • Journal Title

      The Journal of Biochemistry

      Volume: 164 Issue: 5 Pages: 381-391

    • DOI

      10.1093/jb/mvy062

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Efficient high-throughput screening by ER Ca2+measurement to identify inhibitors of ryanodine receptor Ca2+-release channels2018

    • Author(s)
      Murayama Takashi、Kurebayashi Nagomi、Ikegami-Yuasa Mari、Mori Shuichi、Suzuki Yukina、Akima Ryunosuke、Ogawa Haruo、Suzuki Junji、Kanemaru Kazunori、Oyamada Hideto、Kiuchi Yuji、Iino Masamitsu、Kagechika Hiroyuki、Sakurai Takashi
    • Journal Title

      Molecular Pharmacology

      Volume: - Issue: 1 Pages: 722-730

    • DOI

      10.1124/mol.117.111468

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Identification of selective inhibitors for diffuse-type gastric cancer cells by screening of annotated compounds in preclinical models.2018

    • Author(s)
      Shimada S, Akiyama Y, Mogushi K, Ishigami-Yuasa M, Kagechika H, Nagasaki H, Fukamachi H, Yuasa Y, Tanaka S.
    • Journal Title

      British Journal of Cancer

      Volume: - Issue: 7 Pages: 972-984

    • DOI

      10.1038/s41416-018-0008-y

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] ヒト前立腺がん細胞におけるタミバロテンとヒストン脱アセチル化 酵素阻害薬の併用効果の検討および作用機序の解明2020

    • Author(s)
      湯浅 磨里、影近 弘之
    • Organizer
      第79回日本癌学会学術集会
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] nhibitory effect of a synthetic retinoid, tamibarotene in combination with epigenetic drugs on human cancer cell growth.2019

    • Author(s)
      Mari Ishigami-Yuasa, Hiroyuki Kagechika
    • Organizer
      第78回日本癌学会学術総会
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] 前立腺がんLNCapにおける合成レチノイドAm80とクラス選択的ヒストン脱アセチル化酵素阻害剤の併用効果.2019

    • Author(s)
      湯浅 磨里, 影近 弘之
    • Organizer
      第23回日本がん分子標的治療学会学術集会
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] エピジェネティック阻害薬との併用効果2019

    • Author(s)
      湯浅 磨里, 影近 弘之.
    • Organizer
      第361回脂溶性ビタミン総合研究委員会
    • Related Report
      2019 Research-status Report
  • [Presentation] Discovery of novel RyR2 inhibitors as candidates for anti-arrhythmic drugs.2018

    • Author(s)
      Tamura M, Kurebayashi N, Murayama T, Mori S, Ishigami-Yuasa M, Kagechika H, Suzuki J, Kanemaru K, Iino M, Sakurai T.
    • Organizer
      WCP 2018 KYOTO 18 th WORLD CONGRESS OF BASIC AND CLINICAL PHARMACOLOGY
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Growth inhibition of AML cell lines by a synthetic retinoid in combination with the epigenetic modulators, and protein level of RARα.2018

    • Author(s)
      Ishigami-Yuasa M, Kagechika H.
    • Organizer
      FASEB The 4th International Conference on Retinoids
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Search for type 2 ryanodine receptor inhibitor by monitoring endoplasmic reticulum Ca2+.2018

    • Author(s)
      Tamura M, Kurebayashi N, Murayama T, Mori S, Ishigami-Yuasa M, Kagechika H, Suzuki J, Kanemaru K, Iino M, Sakurai T.
    • Organizer
      BSP18 62ND Annual Meeting Biophysical Society
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Growth inhibition of several human cancer cell lines by a synthetic retinoid in combination with the epigenetic modulators.2018

    • Author(s)
      Ishigami-Yuasa M
    • Organizer
      JSPS Core-to-core Program Symposium Frontier of Genomic Medicine “Retinoid (Am80, Tamibarotene) as therapeutics for intractable diseases”
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Development of WNK Signaling Inhibitors as a New Class of Antihypertensive Drugs.2018

    • Author(s)
      Ishigami-Yuasa M, Watanabe Y, Suzuyama H, Masuno H, Fujii S, Mori T, Kikuchi E, Uchida S, Kagechika H.
    • Organizer
      SPS Core-to-core Program Symposium Frontier of Genomic Medicine “Retinoid (Am80, Tamibarotene) as therapeutics for intractable diseases”
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] 急性骨髄性白血病細胞株Kasumi-1における Am80(タミバロテン)とヒストン脱アセチル化酵素阻害薬との併用効果.2018

    • Author(s)
      湯浅 磨里, 影近 弘之
    • Organizer
      第22回日本がん分子標的治療学会学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] 変異1型リアノジン受容体のCa2+遊離を抑制する新規化合物の創製.2018

    • Author(s)
      森 修一、飯沼 大翔、間中 紀暁、湯浅 磨里、村山 尚、呉林 なごみ、影近 弘之.
    • Organizer
      日本薬学会 第138年会
    • Related Report
      2018 Research-status Report

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Published: 2018-04-23   Modified: 2022-01-27  

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