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2011 Fiscal Year Annual Research Report

腹腔内転移のバイオイメージングと抑制物質の分子デザイン

Research Project

Project/Area Number 23310163
Research InstitutionKeio University

Principal Investigator

梅澤 一夫  慶應義塾大学, 理工学部, 教授 (70114402)

Co-Investigator(Kenkyū-buntansha) 清水 史郎  慶應義塾大学, 理工学部, 専任講師 (30312268)
尾崎 倫孝  北海道大学, 医学研究科, 特任教授 (80256510)
斉藤 毅  慶應義塾大学, 理工学部, 助教 (80609933)
Keywords転移 / 卵巣癌 / NF-κB / DHMEQ / DTCM-glutarimide / 探索プローブ / 標的タンパク質 / 光プローブ
Research Abstract

卵巣癌細胞の浸潤を抑える安全な医薬を発見した。ATP感受性K+チャネル(KATPチャネル)はあらゆる組織に発現し、インスリン分泌をはじめとする多くの生理機能に関与する。本研究で用いたKATPチャネルブロッカーglybenclamideは経口糖尿病治療薬として広く用いられている。この医薬がヒト卵巣明細胞腺癌ES-2細胞の遊走、浸潤を抑制することを見出した。KATPチャネルブロッカーが結合するSUR2Bをノックダウンすると、薬剤感受性の低下が見られたことから、KATPチャネルブロッカーがSUR2Bに結合し浸潤を抑制することが示された。プロテオーム解析結果からPDGF-AAに着目し、この因子が浸潤のmediatorで、glybenclamideはこの分泌を抑えていることがわかった。PDGF-Aをノックダウンすると浸潤能の低下が見られ、また、glybenclamideにより抑制された浸潤能がPDGF-AA刺激により回復した。以上の結果より、KATPチャネルブロッカーはPDGF-AAの分泌阻害を介して浸潤を抑制することが示され、KATPチャネルが卵巣癌転移抑制の新たな標的となり得ることが示された。
一方、浸潤抑制物質DTCM-Gが長時間作用させるとNF-κB阻害剤として働くことを見出した。すでにNF-κB阻害剤が卵巣癌抑制することを見出している。(ここまで梅澤、清水)
ビオチンを結合させ、DTCM-Gの標的分子探索プローブを合成した。(斉藤)
高転移能を有する胃癌細胞株にluciferaseを安定導入し、マウス腹腔内胃癌播種モデルを作成した。生体イメージング法により、DHMEQが有効に胃癌の播種・転移を抑制することを示した。また、分泌型ルシフェラーゼを恒常的に分泌する膵癌細胞株AsPC-1-Glucを樹立し、現在、同じプローブを卵巣癌細胞株ES-2細胞に発現させている。(尾崎)

Current Status of Research Progress
Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

新しい安全な卵巣癌腹腔内転移抑制剤の候補が糖尿病薬の中から見出された。さらにDTCM-Gの浸潤抑制機構が解明されたこと、およびビオチン付きプローブが合成されたこと。in vivoでは卵巣癌ではないが、胃癌で腹腔内転移のバイオイメージングができたこと、がプラス点。卵巣癌in vivoモデルがまだなのがマイナス点。

Strategy for Future Research Activity

天然から遊走・浸潤・転移抑制物質を探索してゆく。さらに、浸潤や転移に関与する新しいシグナルを転移関連タンパク質の翻訳語修飾に注目して、見出してゆく。このことは新しい腹腔内転移阻害物質の分子標的が得られるようになる意義がある。(梅澤、清水)DTCM-GがNF-κBを阻害し、細胞浸潤抑制を示すので、その標的を見出すさらに新しいプローブもデザイン・合成する。(斉藤)その一方で、まだできていない卵巣癌細胞へのluciferaseプローブ導入細胞を樹立して、バイオイメージングができるようにする。(尾崎)

  • Research Products

    (44 results)

All 2012 2011 Other

All Journal Article (29 results) (of which Peer Reviewed: 26 results) Presentation (14 results) Remarks (1 results)

  • [Journal Article] Antitumor effect of dehydroxymethylepoxyquinomicin (DHMEQ), a small molecule inhibitor of nuclear factor-κB, on glioblastoma2012

    • Author(s)
      T.Fukushima, K.Umezawa, et al
    • Journal Title

      Neuro-Oncology

      Volume: 14 Pages: 19-28

    • Peer Reviewed
  • [Journal Article] Determination of the absolute structure of (+)-akaterpin2012

    • Author(s)
      H.Hosoi, K.Umezawa, et al
    • Journal Title

      Chem.Pharm.Bull.

      Volume: 60 Pages: 137-143

    • Peer Reviewed
  • [Journal Article] Conophylline suppresses pancreatic stellate cells and improves islet fibrosis in Goto-Kakizaki rats2012

    • Author(s)
      R.Saito, K.Umezawa, et al
    • Journal Title

      Endocrinology

      Volume: 153 Pages: 621-630

    • Peer Reviewed
  • [Journal Article] Involvement of DNA binding domain in the cellular stability and importin affinity of NF-κB component RelB2012

    • Author(s)
      M.Takeiri, K.Umezawa, et al
    • Journal Title

      Org.Biomol.Chem.

      Volume: 10 Pages: 3053-3059

    • Peer Reviewed
  • [Journal Article] A novel NF-κB inhibitor, dehydroxymethylepoxyquinomicin, ameliorates inflammatory colonic injury in mice.2012

    • Author(s)
      T.Funakoshi, M.Ozaki, K.Umezawa, et al
    • Journal Title

      Journal of Crohn's and Colotis

      Volume: (in press)

    • Peer Reviewed
  • [Journal Article] Ligand-dependent EGFR activation induces the co-expression of IL-6 and PAI-1 via NFκB pathway on advanced-stage epithelial ovarian cancer2012

    • Author(s)
      C.Alberti, K.Umezawa, et al
    • Journal Title

      Oncogene

      Volume: (in press)

    • DOI

      10.1038/onc.2011.572

    • Peer Reviewed
  • [Journal Article] TGF-β-induced epithelial-mesenchymal transition of A549 lung adenocarcinoma cells is enhanced by proinflammatory cytokines derived from RAW 264.7 macrophage cells2012

    • Author(s)
      M.Kawata, K.Umezawa, et al
    • Journal Title

      J.Biochem.

      Volume: (in press)

    • Peer Reviewed
  • [Journal Article] The novel NF-kB inhibitor DHMEQ synergizes with Celecoxib to exert antitumor effects on human liver cancer cells by a ROS-dependent mechanism2012

    • Author(s)
      N.Lampiasi, K Umezawa, et al
    • Journal Title

      Cancer Lett.

      Volume: (in press)

    • Peer Reviewed
  • [Journal Article] Novel approaches to target cancer initiating cells-Eliminating the root of the cancer2012

    • Author(s)
      J.A.McCubrey, K.Umezawa, et al
    • Journal Title

      Advances in Enzyme Regulation

      Volume: (in press)

  • [Journal Article] Inhibition of nuclear factor-jB by dehydroxymethylepoxyquinomicin induces schedule-dependent chemosensitivity to anticancer drugs and enhances chemoinduced apoptosis in osteosarcoma cells2012

    • Author(s)
      A.M.Castro-Gamero, K.Umezawa, et al
    • Journal Title

      Anti-Cancer Drugs

      Volume: (in press)

    • Peer Reviewed
  • [Journal Article] The immunomodulatory effect of nuclear factor-κB inhibition by dehydroxymethylepoxyquinomicin in combination with donor-specific blood transfusion2012

    • Author(s)
      R.Goto, K.Umezawa, M.Ozaki, et al
    • Journal Title

      Transplantation

      Volume: (in press)

    • Peer Reviewed
  • [Journal Article] Structure-activity relationship Of 9-methylstreptimidone that induces selective apoptosis in adult T-cell leukemia cells2012

    • Author(s)
      M.Takeiri, S.Simizu, K.Umezawa, et al
    • Journal Title

      Oncology Res.

      Volume: (in press)

    • Peer Reviewed
  • [Journal Article] ErbB/NFkB signaling controls self-renewal of breast cancer stem cells2012

    • Author(s)
      K.Hinohara, K.Umezawa, et al
    • Journal Title

      Proc.Natl.Acad.Sci.USA

      Volume: (in press)

    • Peer Reviewed
  • [Journal Article] Suppression of inflammatory cytokine secretion by an NF-κB inhibitor in nasal polyps fibroblasts2012

    • Author(s)
      F.C.P.Valera, K.Umezawa, et al
    • Journal Title

      Cellular Physiology and Biochemistry

      Volume: (in press)

    • Peer Reviewed
  • [Journal Article] Involvement of NF-κB-mediated expression of galectin-3-binding protein in tumor necrosis factor-α-induced breast cancer cell adhesion2012

    • Author(s)
      N.Noma, S.Simizu, K.Umezawa, et al
    • Journal Title

      Oncology Reports

      Volume: (in press)

    • DOI

      10.3892/or.2012.1733

    • Peer Reviewed
  • [Journal Article] Placenta growth factor induces melanoma resistance to temozolomide through a mechanism that involves the activation of the transcription factor NF-κB2011

    • Author(s)
      L.Levati, K.Umezawa, et al
    • Journal Title

      International J.Oncol.

      Volume: 38 Pages: 241-247

    • Peer Reviewed
  • [Journal Article] Inhibition of nuclear factor-kappaB suppresses peritoneal dissemination of gastric cancer by blocking cancer cell adhesion2011

    • Author(s)
      K.Mino, M.Ozaki, K.Umezawa, et al
    • Journal Title

      Cancer Science 102 : 1052-1058

      Volume: 102 Pages: 1052-1058

    • Peer Reviewed
  • [Journal Article] Apoptosis in mouse amniotic epithelium is induced by activated macrophages through the TNF receptor type 1/TNF pathway2011

    • Author(s)
      K.Kobayashi, K.Umezawa, et al
    • Journal Title

      Biology of Reproduction

      Volume: 84 Pages: 248-254

    • Peer Reviewed
  • [Journal Article] 新しいNF-κB阻害剤DHMEQの生物有機化学と抗炎症・抗がん剤への展望2011

    • Author(s)
      梅澤一夫、須貝威
    • Journal Title

      化学と生物

      Volume: 49 Pages: 406-414

  • [Journal Article] Chemoenzymatic synthesis of (2R,3R,4R)-dehydroxymethylepoxyquinomicin (DHMEQ), a new activator of antioxidant transcription factor Nrf22011

    • Author(s)
      Y.Niitsu, K.Umezawa, et al
    • Journal Title

      Org.Biomol.Chem.

      Volume: 9 Pages: 4635-4641

    • Peer Reviewed
  • [Journal Article] Possible role of peritoneal NF-κB in peripheral inflammation and cancer : Lessons from the inhibitor DHMEQ2011

    • Author(s)
      K.Umezawa
    • Journal Title

      Biomedicine & Pharmacotherapy

      Volume: 65 Pages: 252-259

    • Peer Reviewed
  • [Journal Article] Synthesis and determination of the relative structure of akaterpin, a potent inhibit or of PI-PLC2011

    • Author(s)
      H.Hosoi, K.Umezawa, et al
    • Journal Title

      Tetrahedron Letters

      Volume: 52 Pages: 4961-4964

    • Peer Reviewed
  • [Journal Article] Role of NF-κB/Snail/RKIP loop in the response of tumor cells to photodynamic therapy2011

    • Author(s)
      V.Rapozzi, K.Umezawa, et al
    • Journal Title

      Lasers in Surgery and Medicine 2011

      Volume: 43 Pages: 575-585

    • Peer Reviewed
  • [Journal Article] Coffee induces breast cancer resistance protein expression in Caco-2 cells2011

    • Author(s)
      M.Isshiki, K.Umezawa, et al
    • Journal Title

      Biol.Pharm.Bull.

      Volume: 34 Pages: 1624-1627

    • Peer Reviewed
  • [Journal Article] Design and synthesis of biotinylated DHMEQ for direct identification of its target NF-κB components., 20112011

    • Author(s)
      T.Saitoh, K.Umezawa, et al
    • Journal Title

      Bioorganic & Medicinal Chemistry Letters

      Volume: 21 Pages: 6293-6296

    • Peer Reviewed
  • [Journal Article] Molecular design, chemical synthesis, and biological evaluation of agents that selectively photo-degrade the transcription factor estrogen receptor-α2011

    • Author(s)
      K.Tsumura, K.Umezawa, et al
    • Journal Title

      Org.Biomol.Chem.

      Volume: 9 Pages: 6357-6366

    • Peer Reviewed
  • [Journal Article] Inhibition of macrophage activation and suppression of graft rejection by DTCM-glutarimide, a novel piperidine derived from the antibiotic 9-methylstreptimidone2011

    • Author(s)
      M.Takeiri, M.Ozaki, K.Umezawa, et al
    • Journal Title

      Inflammation Research

      Volume: 60 Pages: 879-888

    • Peer Reviewed
  • [Journal Article] Suppression of erosive arthritis by NF-κB Inhibitors2011

    • Author(s)
      T.Kubota, K.Umezawa
    • Journal Title

      Current Rheumatology Reviews

      Volume: 7 Pages: 275-281

  • [Journal Article] Synthesis and biological evaluation of molecular probes based on the 9-methylstr eptimidone derivative DTCM-glutarimide2011

    • Author(s)
      E.Ota, K.Umezawa, et al
    • Journal Title

      Bioorganic & Medicinal Chemistry Letters

      Volume: 22 Pages: 164-167

    • Peer Reviewed
  • [Presentation] NF-κB阻害剤の発見と臨床への橋渡し研究。文科省がん支援・化学療法基盤支援活動2012

    • Author(s)
      梅澤一夫
    • Organizer
      第2回シンポジウム「アカデミアからの抗がん剤創薬へ向けて」
    • Place of Presentation
      神奈川日吉(招待講演)
    • Year and Date
      2012-02-22
  • [Presentation] Screening and molecular design of signal transduction inhibitors active on inflammation and cancer2011

    • Author(s)
      Kazuo Umezawa
    • Organizer
      BIT's 9^<th> Annual Congress of International Drug Discovery Science and Technology (IDDST)-2011
    • Place of Presentation
      Shenzhen, China(invited speaker)
    • Year and Date
      2011-11-03
  • [Presentation] Amelioration of atopic dermatitis model in mice by NF-κB inhibitor DHMEQ and its mechanism of action2011

    • Author(s)
      K.Horie, K.Umezawa, et al
    • Organizer
      BIT's 9^<th> Annual Congress of International Drug Discovery Science and Technology (IDDST)-2011
    • Place of Presentation
      Shenzhen, China
    • Year and Date
      2011-11-03
  • [Presentation] Induction of apoptosis in adult T-cell leukemia cells by a novel PDK-1 inhibitor DTCM-glutarimide2011

    • Author(s)
      Ayumi Ito, Kazuo Umezawa, et al
    • Organizer
      The 16^<th> World Congress on Advances in Oncology, and 14^<th> International Symposium on Molecular Medicine
    • Place of Presentation
      Rhodes, Greece
    • Year and Date
      2011-10-06
  • [Presentation] Role of peritoneal NF-κB on inflammation and cancer progression ; Lessons from the inhibitor DHMEQ2011

    • Author(s)
      Kazuo Umezawa
    • Organizer
      The 16^<th> World Congress on Advances in Oncology, and 14^<th> International Symposium on Molecular Medicine
    • Place of Presentation
      Rhodes, Greece
    • Year and Date
      2011-10-06
  • [Presentation] 新規PDK1阻害剤DTCM-glutarimideによるマウスメラノーマ細胞のアノイキス誘導および浸潤抑制2011

    • Author(s)
      竹入雅敏、梅澤一夫, ほか
    • Organizer
      日本癌学会
    • Place of Presentation
      大阪
    • Year and Date
      2011-10-03
  • [Presentation] (-)-DHMEQによるNF-kappa BのDNA結合および核局在の抑制2011

    • Author(s)
      堀江佳奈、梅澤一夫, ほか
    • Organizer
      日本癌学会
    • Place of Presentation
      大阪
    • Year and Date
      2011-10-03
  • [Presentation] 9-methylstreptimidone由来新規PDK-1阻害物質DTCM-glutarimideによるin vivo炎症反応の抑制2011

    • Author(s)
      伊藤あゆみ、梅澤一夫, ほか
    • Organizer
      天然有機化合物討論会
    • Place of Presentation
      大阪
    • Year and Date
      2011-09-27
  • [Presentation] Screening from nature and molecular design of signal transduction inhibitors active on inflammation and cancer2011

    • Author(s)
      Kazuo Umezawa
    • Organizer
      14^<th> Asian Chemical Congress
    • Place of Presentation
      Bangkok, Thailand(invited speaker)
    • Year and Date
      2011-09-05
  • [Presentation] Screening of NO production inhibitors in macrophages from microorganisms2011

    • Author(s)
      Chino Matsui, Kazuo Umezawa, et al
    • Organizer
      14^<th> Asian Chemical Congress
    • Place of Presentation
      Bangkok, Thailand
    • Year and Date
      2011-09-05
  • [Presentation] Galectin-3 binding proteinの作用と発現におけるNF-κBの関与。Regulation of Galectin-3 binding protein expression by NF-kappa B2011

    • Author(s)
      野間成人、清水史郎、梅澤一夫
    • Organizer
      日本分子標的がん治療学会
    • Place of Presentation
      東京
    • Year and Date
      2011-06-22
  • [Presentation] 新規PDK1阻害剤DTCM-glutarimideによるマウス悪性黒色腫細胞の浸潤抑制およびアノイキス誘導。Inhibition of cellular invasion and induction of anoikis by a novel PDK1 inhibitor, DTCM-glutarimide, in mouse melanoma cells2011

    • Author(s)
      兼田亜弓、梅澤一夫, ほか
    • Organizer
      日本分子標的がん治療学会
    • Place of Presentation
      東京
    • Year and Date
      2011-06-22
  • [Presentation] (-)-DHMEQによるnoncanonical NF-kappa Bの新規阻害機構2011

    • Author(s)
      竹入雅敏、清水史郎、梅澤一夫, ほか
    • Organizer
      日本ケミカルバイオロジー学会
    • Place of Presentation
      神奈川
    • Year and Date
      2011-05-23
  • [Presentation] カビ由来pyranopaxillineおよび類縁体によるマクロファージ活性の抑制2011

    • Author(s)
      松井知野、梅澤一夫, ほか
    • Organizer
      日本ケミカルバイオロジー学会
    • Place of Presentation
      神奈川
    • Year and Date
      2011-05-23
  • [Remarks]

    • URL

      http://www.umelab.net

URL: 

Published: 2013-06-26  

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