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Oncogenic signaling and screening of anticancer leads

Research Project

Project/Area Number 17016085
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionIwate Medical University (2007, 2009)
Hirosaki Gakuin University (2008)
National Institute of Infectious Diseases (2005-2006)

Principal Investigator

UEHARA Yoshimasa  Iwate Medical University, 薬学部, 教授 (50160213)

Co-Investigator(Kenkyū-buntansha) 深澤 秀輔  国立感染症研究所, 生物活性物質部, 室長 (10218878)
Project Period (FY) 2005 – 2009
Project Status Completed (Fiscal Year 2009)
Budget Amount *help
¥49,600,000 (Direct Cost: ¥49,600,000)
Fiscal Year 2009: ¥9,400,000 (Direct Cost: ¥9,400,000)
Fiscal Year 2008: ¥9,400,000 (Direct Cost: ¥9,400,000)
Fiscal Year 2007: ¥10,400,000 (Direct Cost: ¥10,400,000)
Fiscal Year 2006: ¥10,400,000 (Direct Cost: ¥10,400,000)
Fiscal Year 2005: ¥10,000,000 (Direct Cost: ¥10,000,000)
Keywordsアポトーシス / anoikis / MEK阻害剤 / hypothemycin / BH3-only protein / Hsp90阻害剤 / anicequol / resorcylic acid lactones / 癌 / シグナル伝達 / 薬学 / チロシンキナーゼ / p38MAPK経路 / 足場非依存性増殖 / pDGF / MEK-ERK経路 / B-RAF / BimEL / K-ras / 25-hydroxycholesterol / tamoxifen / sesquiterpene / rapamycin / mTOR / geldanamycin
Research Abstract

We searched for compounds that induce apoptosis in cancer cells only when cells are nonanchored (anoikis sensitizer). We found that MEK-inhibitors such as hypothemycin induce anoikis sensitivity in human cancer cells that rely heavily on the MEK-ERK pathway, and elucidated the molecular mechanism. We also discovered anicequol, HSP90 inhibitors, and sesquiterpene lactones as inhibitors of oncogenic signaling, and analyzed their mechanisms of action.

Report

(6 results)
  • 2009 Annual Research Report   Final Research Report ( PDF )
  • 2008 Annual Research Report
  • 2007 Annual Research Report
  • 2006 Annual Research Report
  • 2005 Annual Research Report
  • Research Products

    (52 results)

All 2010 2009 2008 2007 2006 2005 2004

All Journal Article (30 results) (of which Peer Reviewed: 10 results) Presentation (16 results) Book (5 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] The resorcylic acid lactone hypothemycin selectively inhibits the mitogen-activated protein kinase kinase-extracellular signal-regulated kinase pathway in cells.2010

    • Author(s)
      Fukazawa H, Ikeda Y, Fukuyama M, Suzuki T, Hori H, Okuda T, Uehara Y
    • Journal Title

      Biol Pharm Bull. 33(2)

      Pages: 168-73

    • NAID

      130000156619

    • Related Report
      2009 Final Research Report
  • [Journal Article] The resorcylic acid lactone hypothemycin selectively inhibits the mitogen-activated protein kinase kinase-extracellular signal-regulated kinase pathway in cells2010

    • Author(s)
      Fukazawa H
    • Journal Title

      Biol Pharm Bull 33

      Pages: 168-173

    • NAID

      130000156619

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Alkyl isothiocyanates suppress epidermal growth factor receptor kinase activity but augment tyrosine kinase activity.2009

    • Author(s)
      Nomura T, UeharaY, et al. (6名中2番目)
    • Journal Title

      Cancer Epidemiology 33

      Pages: 288-292

    • Related Report
      2009 Final Research Report
  • [Journal Article] Bisebromoamide, a Potent Cytotoxic Peptide from the Marine Cyanobacterium Lyngbya sp.: Isolation, Stereostructure, and Biological Activity.2009

    • Author(s)
      Teruya T, Sasaki H, Fukazawa H, Suenaga K
    • Journal Title

      Org Lett 11

      Pages: 5062-5065

    • Related Report
      2009 Final Research Report
  • [Journal Article] Alkyl isothiocyanates suppress epidermal growth factor receptor kinase activity but augment tyrosine kinase activity2009

    • Author(s)
      Nomura T
    • Journal Title

      Cancer Epidemiology 33

      Pages: 288-292

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Design of antiangiogenic hypoxic cell radiosensitizers: 2- Nitroimidazoles containing a 2- aminomethylene-4-cyclopentene-1, 3- dione moiety.2008

    • Author(s)
      Uto Y, Uehara Y, et al. (15名中12番目)
    • Journal Title

      Bioorganic & Medicinal Chemistry 16

      Pages: 6042-6053

    • Related Report
      2009 Final Research Report
  • [Journal Article] Design of antiangiogenic hypoxic cell radiosensitizers : 2-Nitroimidazbles containing a 2-aminomethylene-4-cyclopentene-1,3-dione moiety.2008

    • Author(s)
      Uto, Y.
    • Journal Title

      Bioorganic & Medicinal Chemistry 16

      Pages: 6042-6053

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Identification of the putative protein phosphatase gene PTC1 as a virulence-related gene using a silkworm model of Candida albicans infection.2008

    • Author(s)
      Hanaoka, N.
    • Journal Title

      Eukaryotic Cell 7

      Pages: 1640-1648

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] In Identification of the P-TEFb complex-interacting domain of Brd4 as an inhibitor of HIV-1 replication by functional cDNA library screening in. MT-4 cellshibition of fungal ABC transporters by unnarmicin A and unnarmicin C, novel cyclic peptides from marine bacterium2008

    • Author(s)
      Urano, E.
    • Journal Title

      FEBS Letters 582

      Pages: 4053-4058

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Cyclin K/CPR4 inhibits primate lentiviral replication by inactivating Tat/P-TEITh-dependent LTR transcription2008

    • Author(s)
      Urano, E.
    • Journal Title

      AIDS 22

      Pages: 1081-1083

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Gamma-herpesviruses and cellular signaling in AIDS-associated malignancies.2007

    • Author(s)
      Noguchi K, Fukazawa H, Murakami Y, Takahashi N, Yamagoe S, Uehara Y
    • Journal Title

      Cancer Sci 98

      Pages: 1288-1296

    • Related Report
      2009 Final Research Report
  • [Journal Article] Highly effective recombinant format of a humanized IgG-like bispecific antibody for cancer immunotherapy with retargeting of lymphocytes to tumor cells.2007

    • Author(s)
      Asano R
    • Journal Title

      J Biol Chem 282

      Pages: 27659-27665

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Gamma-herpesviruses and cellular signaling in AIDS-associated malignancies2007

    • Author(s)
      Noguchi K
    • Journal Title

      Cancer Sci 98

      Pages: 1288-1296

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Inhibition of fungal ABC transporters by unnarmicin A and unnarmicin C, novel cyclic peptides from marine bacterium2007

    • Author(s)
      Tanabe K
    • Journal Title

      Biochem. Biophys. Res. Commun 364

      Pages: 990-995

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Characterization of three classes of membrane proteins involved in fungal azole resistance by functional hyper-expression in Saccharomyces cerevisiae.2007

    • Author(s)
      Lamping E.
    • Journal Title

      Eukaryotic Cell 6

      Pages: 1150-1165

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Synthesis and biological evaluation of benzamides and benzamidines as selective inhibitors of VEGFR tyrosine kinases.2006

    • Author(s)
      Nakamura H, Sasaki Y, Uno M, Yoshikawa T, Asano T, Ban HS, Fukazawa H, Shibuya M, Uehara Y
    • Journal Title

      Bioorg Med Chem Lett 16

      Pages: 5127-5131

    • Related Report
      2009 Final Research Report
  • [Journal Article] Ets-1 dependent expression of vascular endothelial growth factor receptors is activated by latency-associated nuclear antigen of Kaposi's sarcoma herpesvirus through interaction with Daxx.2006

    • Author(s)
      Murakami Y, Yamagoe S, Noguchi K, Takebe Y, Takahashi N, Uehara Y, Fukazawa H
    • Journal Title

      J Biol Chem 281

      Pages: 28113-28121

    • Related Report
      2009 Final Research Report
  • [Journal Article] Modification of pyrimidine derivatives from antiviral agents to antitumor agents.2006

    • Author(s)
      Kimura H
    • Journal Title

      Anticancer Res. 26

      Pages: 91-97

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Synthesis and biological evaluation of benzamides and benzamidines as selective inhibitors of VEGFR tyrosine kinases.2006

    • Author(s)
      Nakamura H
    • Journal Title

      Bioorg. Med. Chem. Lett. 16

      Pages: 5127-5131

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Ets-1 dependent expression of vascular endothelial growthfactor receptors is activated by latency-associated nuclear antigen of Kaposi's sarcoma herpesvirus through interaction with Daxx.2006

    • Author(s)
      Murakami Y
    • Journal Title

      J. Biol. Chem. 281

      Pages: 28113-28121

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Repression of CDC28 reduces the expression of the morphology-related transcription factors, Efglp, Nrglp, Rbflp, Rim101p, Fkh2p, and Teclp, and induces cell elongation in Candida albicans.2006

    • Author(s)
      Umeyama, T
    • Journal Title

      Yeast 23

      Pages: 537-552

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Regulation of SV40 large T-antigen stability by reversible acetylation.2006

    • Author(s)
      Shimazu T
    • Journal Title

      Oncogene. 25

      Pages: 7391-7400

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Nucleolin is involved in interferon regulatory factor-2-dependenttranscriptional activation.2006

    • Author(s)
      Masumi A
    • Journal Title

      Oncogene. 24

      Pages: 5113-5124

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Modification of pyrimidine derivatives from antiviral agents to antitumor agents.2006

    • Author(s)
      Kimura, H.
    • Journal Title

      Anticancer Res. 26

      Pages: 91-97

    • Related Report
      2005 Annual Research Report
  • [Journal Article] New cytotoxic bisindole alkaloids with protein tyrosine kinase inhibitory activity from a myxomycete Lycogala epidendrum.2005

    • Author(s)
      Hosoya T, Uehara Y, et al. (6名中3番目)
    • Journal Title

      Bioorg Med Chem Lett 15

      Pages: 2776-2780

    • Related Report
      2009 Final Research Report
  • [Journal Article] Anicemycin, a novel antitumor substance from Streptomyces thermoviolaceus TP-A0648.2005

    • Author(s)
      Igarashi Y, Uehara Y, et al. (6名中5番目)
    • Journal Title

      J Antibiotics 58

      Pages: 322-326

    • Related Report
      2009 Final Research Report
  • [Journal Article] Anicemysin, a novel antitumor substance from Streptomyces thermoviolaceus TP-A0648.2005

    • Author(s)
      Igarashi, Y.
    • Journal Title

      J.Antibitics 58

      Pages: 322-326

    • Related Report
      2005 Annual Research Report
  • [Journal Article] New cytotoxic bisidole alkaloids with protein tyrosine kinase inhibitory activity from a myxomycete Lycogala epidendrum.Bioorg.2005

    • Author(s)
      Hosoya, T.
    • Journal Title

      Med.Chem.Lett. 15

      Pages: 2776-2780

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Phosphorylation of Candida glabrata ATP-binding cassette transporter Cdrlp regulates drug efflux activity and ATPase stability.2005

    • Author(s)
      Wada, S.
    • Journal Title

      J.Biol.Chem. 280

      Pages: 94-103

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Candid albicans protein kinase CaHs11p regulates cell elongation and virulence.2005

    • Author(s)
      Umeyama, T.
    • Journal Title

      Mol.Microbiol. 55

      Pages: 381-395

    • Related Report
      2005 Annual Research Report
  • [Presentation] ゼブラフィッシュ胚を用いたがん分子標的薬探索系の開発2009

    • Author(s)
      西谷直之、津田香代子、上原至雅
    • Organizer
      第13回日本がん分子標的治療学会学術集会
    • Place of Presentation
      徳島
    • Year and Date
      2009-06-26
    • Related Report
      2009 Final Research Report
  • [Presentation] cis-enone resorcylic acid lactonesによるチロシンキナーゼ阻害2009

    • Author(s)
      深澤秀輔
    • Organizer
      第13回日本がん分子標的治療学会学術集会
    • Place of Presentation
      徳島
    • Related Report
      2009 Final Research Report
  • [Presentation] Hypothemycinは細胞内で選択的にMEK-ERK経路を阻害する2009

    • Author(s)
      池田好美、鈴木岳之、深澤秀輔
    • Organizer
      日本薬学会第129年会
    • Place of Presentation
      京都
    • Related Report
      2009 Final Research Report
  • [Presentation] Resorcyclic acid lactoneは細胞内で選択的にMEK-ERK経路を阻害する2009

    • Author(s)
      池田好美
    • Organizer
      日本薬学会第129年会
    • Place of Presentation
      京都
    • Related Report
      2008 Annual Research Report
  • [Presentation] がん分子標的治療薬の開発現況と将来動向2008

    • Author(s)
      上原至雅
    • Organizer
      第67回日本癌学会学術総会レクチャーシンポジウム:がん分子標的治療におけるがん専門薬剤師の役割
    • Place of Presentation
      名古屋
    • Year and Date
      2008-10-30
    • Related Report
      2009 Final Research Report
  • [Presentation] レクチャーシンポジウム : がん分子標的治療におけるがん専門薬剤師の役割「がん分子標的治療薬の開発現況と将来動向」2008

    • Author(s)
      上原至雅
    • Organizer
      菊67回日本癌学会学術総会
    • Place of Presentation
      名古屋
    • Year and Date
      2008-10-30
    • Related Report
      2008 Annual Research Report
  • [Presentation] 課題と展望-日本発の創薬をめざして2008

    • Author(s)
      上原至雅
    • Organizer
      第67回日本癌学会学術総会シンポジウム1:アカデミアから創薬パイプライン創設へ向けての新しい流れ
    • Place of Presentation
      名古屋
    • Year and Date
      2008-10-28
    • Related Report
      2009 Final Research Report
  • [Presentation] シンポジウム1 : アカデミアから創薬パイプライン創設へ向けての新しい流れ「課題と展望 : 日本発の創薬をめざして」2008

    • Author(s)
      上原至雅
    • Organizer
      第67回日本癌学会学術総会
    • Place of Presentation
      名古屋
    • Year and Date
      2008-10-23
    • Related Report
      2008 Annual Research Report
  • [Presentation] HypothemycinによるMEK-ERK経路の選択的阻害。2008

    • Author(s)
      池田好美、鈴木岳之、上原至雅、深澤秀輔
    • Organizer
      日本薬学会第128年会
    • Place of Presentation
      横浜
    • Related Report
      2009 Final Research Report
  • [Presentation] 感染細胞系を用いたスクリーニングにより見い出された新規標的を持つ抗HCV物質の作用機構解析2008

    • Author(s)
      村上裕子
    • Organizer
      第56回日本ウイルス学会学術集会
    • Place of Presentation
      岡山
    • Related Report
      2008 Annual Research Report
  • [Presentation] HypothemycinによるMEK-ERK経路の選択的阻害2008

    • Author(s)
      池田好美
    • Organizer
      日本薬学会第128年会
    • Place of Presentation
      横浜市
    • Related Report
      2007 Annual Research Report
  • [Presentation] がん関連ウイルスEBVやKSHVの持続感染維持機構を標的とした分子標的薬開発のための研究2007

    • Author(s)
      野口耕司、深澤秀輔、上原至雅
    • Organizer
      第11回がん分子標的治療研究会総会
    • Place of Presentation
      大阪
    • Year and Date
      2007-07-06
    • Related Report
      2009 Final Research Report
  • [Presentation] がん関連ウイルスEBVやKSHVの持続感染維持機構を標的とした分子標的薬開発のための研究2007

    • Author(s)
      野口耕司
    • Organizer
      第11回がん分子標的治療研究会総会
    • Place of Presentation
      大阪市
    • Year and Date
      2007-07-06
    • Related Report
      2007 Annual Research Report
  • [Presentation] Cell-based screening approaches for identification of signal transduction inhibitors.2007

    • Author(s)
      深澤秀輔、上原至雅
    • Organizer
      第66回日本癌学会学術総会シンポジウム分子標的としてのシグナル伝達
    • Place of Presentation
      横浜
    • Related Report
      2009 Final Research Report
  • [Presentation] Cell-based screening approaches for identification of signal transduction inhibitors2007

    • Author(s)
      深澤秀輔
    • Organizer
      第66回日本癌学会学術総会シンポジウムSignal transduction as a molecular target
    • Place of Presentation
      横浜市
    • Related Report
      2007 Annual Research Report
  • [Presentation] プロテインキナーゼ阻害物質の探索。2005

    • Author(s)
      深澤秀輔、上原至雅
    • Organizer
      文部科学省がん特定領域研究・化学療法基盤情報支援班共催シンポジウム「ケミカルゲノミクスから抗癌剤創薬への展開」
    • Place of Presentation
      長浜
    • Year and Date
      2005-11-04
    • Related Report
      2009 Final Research Report
  • [Book] 足場非依存性細胞増殖測定法および併用効果評価法。「がん分子標的治療研究実践マニュアル」(日本がん分子標的治療学会編集、曽根三郎/鶴尾隆 編集代表)2009

    • Author(s)
      西谷直之、上原至雅
    • Publisher
      金芳堂
    • Related Report
      2009 Final Research Report
  • [Book] がん分子標的治療研究実践マニュアル2009

    • Author(s)
      西谷直之
    • Publisher
      金芳堂
    • Related Report
      2009 Annual Research Report
  • [Book] 化学療法学病原微生物・がんと戦う2009

    • Author(s)
      西谷直之
    • Publisher
      南江堂
    • Related Report
      2009 Annual Research Report
  • [Book] 細胞がん化のシグナル伝達と新規リード探索。シリーズ「がん研究のいま」3. がんの診断と治療(中村祐輔/稲澤譲治編)2006

    • Author(s)
      上原至雅、深澤秀輔
    • Publisher
      東京大学出版会
    • Related Report
      2009 Final Research Report
  • [Book] がんの診断と治療2006

    • Author(s)
      中村 祐輔
    • Total Pages
      236
    • Publisher
      東京大学出版会
    • Related Report
      2005 Annual Research Report
  • [Patent(Industrial Property Rights)] 抗ガン作用を有する化合物、その製造方法及び抗ガン剤2004

    • Inventor(s)
      上原至雅、深澤秀輔, ほか2名
    • Industrial Property Rights Holder
      倉田毅:国立感染症研究所所長
    • Industrial Property Number
      2004-186572
    • Filing Date
      2004-06-24
    • Related Report
      2009 Final Research Report

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Published: 2005-04-01   Modified: 2018-03-28  

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