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Search and function elucidation of highly active natural products targeting cancer microenvironmental signals

Research Project

Project/Area Number 17H03992
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Natural medicines
Research InstitutionChiba University

Principal Investigator

Ishibashi Masami  千葉大学, 大学院薬学研究院, 教授 (90212927)

Co-Investigator(Kenkyū-buntansha) 荒井 緑  千葉大学, 大学院薬学研究院, 准教授 (40373261)
原 康雅  千葉大学, 大学院薬学研究院, 助教 (10824625)
石川 直樹  千葉大学, 大学院薬学研究院, 助教 (20748826)
Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥18,200,000 (Direct Cost: ¥14,000,000、Indirect Cost: ¥4,200,000)
Fiscal Year 2019: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2018: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2017: ¥8,060,000 (Direct Cost: ¥6,200,000、Indirect Cost: ¥1,860,000)
Keywords生理活性 / シグナル伝達 / 生体分子 / 有機化学 / 薬学
Outline of Final Research Achievements

In this study, we examined screening programs using several kinds of luciferase cell-based assays mainly from natural products, with the aim of finding useful low-molecular compounds that act on cell signals that are enhanced in the cancer microenvironment. Screening studies were carried out targeting several intracellular signals involved in stem cell self-renewal and epigenetic gene transcription such as Wnt, Hedgehog, and Notch signals, cancer cell-selective apoptosis-inducing factors, and polycomb-constituting molecules. As a result, a number of useful bioactive natural products having Wnt signal inhibitory activity, TRAIL resistance overcoming activity, Bmi1 promoter inhibitory activity were isolated from our collection of plants and actinomycetes extracts, and their chemical structures were elucidated. We also investigated the mechanism of action of these active compounds through analyzing the effect on the expression of various proteins involved in cancer progression.

Academic Significance and Societal Importance of the Research Achievements

本研究で対象とする「がん微小環境」で亢進する細胞シグナルは,正常な幹細胞の自己複製,胚の発生,分化,成人組織再生などにおいて重要な役割を担っていることからきわめて注目度が高く,これまでにも世界的に熾烈な開発競争が繰り広げられてきている.しかしながら,まだ決して十分な状況ではなく,数多くの選択肢を用意することが強く求められている.本研究では「天然物」という独自の素材を用いて,これらのシグナルに作用する数種の低分子化合物が見出された.これらを有効に活用することにより,新しい切り口として創薬研究あるいは各種シグナルを介した生命システムの解明等,周辺分野の研究進展につながることが期待される.

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • Research Products

    (35 results)

All 2020 2019 2018 2017 2016 Other

All Int'l Joint Research (5 results) Journal Article (12 results) (of which Int'l Joint Research: 8 results,  Peer Reviewed: 12 results,  Open Access: 4 results,  Acknowledgement Compliant: 1 results) Presentation (16 results) (of which Int'l Joint Research: 3 results,  Invited: 9 results) Remarks (2 results)

  • [Int'l Joint Research] クルナ大学/ダッカ大学(バングラデシュ)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] シルパコン大学/コンケン大学(タイ)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] クルナ大学/ダッカ大学(バングラデシュ)

    • Related Report
      2017 Annual Research Report
  • [Int'l Joint Research] コンケン大学/マハサラカン大学(タイ)

    • Related Report
      2017 Annual Research Report
  • [Int'l Joint Research] ヘルワン大学(エジプト)

    • Related Report
      2017 Annual Research Report
  • [Journal Article] Cadinane sesquiterpenoids isolated from Santalum album using a screening program for Wnt signal inhibitory activity2020

    • Author(s)
      Tomoyuki Sato, Midori A. Arai, Yixizhuoma, Yasumasa Hara, Takashi Koyano, Thaworn Kowithayakorn, Masami Ishibashi
    • Journal Title

      Journal of Natural Medicines

      Volume: 74 Issue: 2 Pages: 476-481

    • DOI

      10.1007/s11418-019-01380-x

    • NAID

      40022183696

    • Related Report
      2019 Annual Research Report 2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Identification of BMI1 promoter inhibitors from Streptomyces sp. IFM-119582019

    • Author(s)
      Yusuke Yokoyama, Midori A. Arai, Yasumasa Hara, Masami Ishibashi
    • Journal Title

      Bioorganic and Medicinal Chemistry

      Volume: 27 Issue: 13 Pages: 2998-3003

    • DOI

      10.1016/j.bmc.2019.05.002

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Nonactic acid derivatives isolated from Streptomyces werraensis IFM12104 in a screening program for BMI1 promoter inhibitory activity2019

    • Author(s)
      Yusuke Yokoyama, Midori A. Arai, Yasumasa Hara, Masami Ishibashi
    • Journal Title

      Natural Products Communications

      Volume: 14 Issue: 7 Pages: 1-5

    • DOI

      10.1177/1934578x19866583

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Sucupiranins M-Q, five new furanocassane-type diterpenoids from the seeds of Bowdichia virgilioides2019

    • Author(s)
      Endo Yuta, Kasahara Taku, Asakura Kenta, Mori Ayana, Funasaki Mariko, Akisue Gokithi, Etoh Tadahiro, Harada Kenichi, Fukuyama Yoshiyasu, Matsuzaki Keiichi, Ishibashi Masami, Ohsaki Ayumi
    • Journal Title

      Tetrahedron

      Volume: 75 Issue: 37 Pages: 130511-130511

    • DOI

      10.1016/j.tet.2019.130511

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Two new alkaloids from Crinum asiaticum var. japonicum2019

    • Author(s)
      Endo, Y., Sugiura, Y., Funasaki, M., Kagechika, H., Ishibashi, M., Ohsaki, A.
    • Journal Title

      J. Nat. Med.

      Volume: 73 Issue: 3 Pages: 648-652

    • DOI

      10.1007/s11418-019-01304-9

    • NAID

      40021912759

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Isolation of Nabscessin C from <i>Nocardia abscessus</i> IFM 10029<sup>T</sup> and a Study on Biosynthetic Pathway for Nabscessins2018

    • Author(s)
      Shoko Hara, Yasumasa Hara, Midori A. Arai, Yoko Kusuya, Hiroki Takahashi, Takashi Yaguchi, Masami Ishibashi
    • Journal Title

      Chemical and Pharmaceutical Bulletin

      Volume: 66 Issue: 10 Pages: 976-982

    • DOI

      10.1248/cpb.c18-00430

    • NAID

      130007492854

    • ISSN
      0009-2363, 1347-5223
    • Year and Date
      2018-10-01
    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Coculture of a pathogenic actinomycete and animal cells to produce nocarjamide, a cyclic nonapeptide with Wnt signal-activating effect2018

    • Author(s)
      Yasumasa Hara, Midori A. Arai, Kazufumi Toume, Hyuma Masu, Tomoyuki Sato, Katsuko Komatsu, Takashi Yaguchi, Masami Ishibashi
    • Journal Title

      Organic Letters

      Volume: 20 Pages: 5831-5834

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Identification of BMI1 Promoter Inhibitors from Beaumontia murtonii and Eugenia operculata2017

    • Author(s)
      Kaneta Yui、Arai Midori A.、Ishikawa Naoki、Toume Kazufumi、Koyano Takashi、Kowithayakorn Thaworn、Chiba Tetsuhiro、Iwama Atsushi、Ishibashi Masami
    • Journal Title

      Journal of Natural Products

      Volume: 80 Issue: 6 Pages: 1853-1859

    • DOI

      10.1021/acs.jnatprod.7b00138

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Elmenols C-H, new angucycline derivatives isolated from a culture of Streptomyces sp. IFM 114902017

    • Author(s)
      Yixizhuoma、Ishikawa Naoki、Abdelfattah Mohamed S、Ishibashi Masami
    • Journal Title

      Journal of Antibiotics

      Volume: 70 Issue: 5 Pages: 601-606

    • DOI

      10.1038/ja.2016.158

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Hes1 binding compounds isolated by Target Protein Oriented Natural Products Isolation (TPO-NAPI)2017

    • Author(s)
      Arai, M. A.*; Tanaka, M.; Tanouchi, K.; Ishikawa, N.; Ahmed, F.; Sadhu, S. K.; Ishibashi, M.*
    • Journal Title

      J. Nat. Prod.

      Volume: 80 Issue: 2 Pages: 538-543

    • DOI

      10.1021/acs.jnatprod.6b01072

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Notch Inhibitors from Calotropis gigantea That Induce Neuronal Differentiation of Neural Stem Cells2017

    • Author(s)
      Yoneyama Tatsuro、Arai Midori A.、Akamine Ryuta、Koryudzu Kazune、Tsuchiya Anna、Sadhu Samir K.、Ahmed Firoj、Itoh Motoyuki、Okamoto Ryuichi、Ishibashi Masami
    • Journal Title

      Journal of Natural Products

      Volume: 80 Issue: 9 Pages: 2453-2461

    • DOI

      10.1021/acs.jnatprod.7b00282

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Nabscessins A and B, new aminocyclitol derivatives from Nocardia abscessus IFM 10029T2016

    • Author(s)
      Shoko Hara, Naoki Ishikawa, Yasumasa Hara, Tatsuo Nehira, Kanae Sakai, Tohru Gonoi, Masami Ishibashi
    • Journal Title

      Journal of Natural Products

      Volume: 80 Issue: 2 Pages: 565-568

    • DOI

      10.1021/acs.jnatprod.6b00935

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] Screening studies for bioactive natural products on disease and development pathways2019

    • Author(s)
      Masami Ishibashi
    • Organizer
      The 50th Annual Meeting and Conference of the Korean Society of Pharmacognosy
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 植物からの創薬分子のスクリーニング2019

    • Author(s)
      石橋正己
    • Organizer
      千葉大学植物分子科学研究センター開所記念シンポジウム
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 生物活性天然物化学:細胞シグナルに作用する天然物のスクリーニング2019

    • Author(s)
      石橋正己
    • Organizer
      日本薬学会北海道支部セミナー
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Natural products screening study on disease and development signals2019

    • Author(s)
      Masami Ishibashi
    • Organizer
      The 1st Pharmaceutical Sciences Asia Conference 2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 放線菌からのBMI1 プロモーター阻害作用をもつ天然物の探索2019

    • Author(s)
      横山夕将, 荒井緑, 原康雅, 石橋正己
    • Organizer
      第8回食品薬学シンポジウム
    • Related Report
      2019 Annual Research Report
  • [Presentation] Santalum album からのWnt シグナル阻害作用をもつ天然物の探索2019

    • Author(s)
      佐藤知幸,荒井緑,原康雅,益西卓瑪,小谷野喬,Thaworn Kowithayakorn,石橋正己
    • Organizer
      日本生薬学会第66回年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 生物活性天然機能性有機分子の探索2018

    • Author(s)
      石橋正己
    • Organizer
      第28回万有福岡シンポジウム
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 生物活性スクリーニングを基盤とする包括的天然物化学2018

    • Author(s)
      石橋正己
    • Organizer
      日本生薬学会第65年会日本生薬学会賞受賞講演
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 放線菌二次代謝産物からのBMI1プロモーター阻害剤の探索2018

    • Author(s)
      横山夕将,荒井緑,石橋正己
    • Organizer
      日本生薬学会第65年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] センダン科植物によるrocaglamide関連天然物の探索2018

    • Author(s)
      野﨑はるか,荒井緑,Samir K. Sadhu,Firoj Ahmed,小谷野喬,Thaworn Kowithayakorn,石橋正己
    • Organizer
      日本生薬学会第65年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 植物成分からのWnt経路に影響を与える化合物の探索2018

    • Author(s)
      佐藤知幸,荒井緑,小谷野喬,Thaworn Kowithayakorn,石橋正己
    • Organizer
      第22回天然薬物の開発と応用シンポジウム
    • Related Report
      2018 Annual Research Report
  • [Presentation] Search for bioactive constituents having effects on disease and development Pathways2017

    • Author(s)
      Masami Ishibashi
    • Organizer
      The 2nd international conference on herbal and traditional medicine (HTM2017)
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] ものとりのサイエンス:シグナル伝達分子を標的とした天然物の探索2017

    • Author(s)
      石橋正己
    • Organizer
      第11回日本ポリフェノール学会年次大会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] ものとりのサイエンス:天然物探索を基盤とする生薬学研究2017

    • Author(s)
      石橋正己
    • Organizer
      日本生薬学会第64年会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] 標的タンパク質指向型天然物単離による生物活性天然物の探索2017

    • Author(s)
      荒井緑,越智富美江,林奈留美,橋本真波,田中光葉,田内加奈,石川直樹,F. Ahmed,S. K. Sadhu,石橋正己
    • Organizer
      第59回天然有機化合物討論会
    • Related Report
      2017 Annual Research Report
  • [Presentation] GLI1ビーズを用いたヘッジホッグシグナル阻害剤の探索2017

    • Author(s)
      越智富美江,荒井緑,S. K. Sadhu,F. Ahmed,石橋正己
    • Organizer
      第7回食品薬学シンポジウム
    • Related Report
      2017 Annual Research Report
  • [Remarks] 千葉大学大学院薬学研究院活性構造化学研究室

    • URL

      http://www.p.chiba-u.jp/lab/kassei/

    • Related Report
      2019 Annual Research Report
  • [Remarks] 千葉大学大学院薬学研究院活性構造化学研究室

    • URL

      http://www.p.chiba-u.jp/lab/kassei/index.html

    • Related Report
      2017 Annual Research Report

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Published: 2017-04-28   Modified: 2021-02-19  

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