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2009 Fiscal Year Final Research Report

Targeting the ERK-MAP kinase pathway in cancer therapy

Research Project

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Project/Area Number 17016056
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionNagasaki University

Principal Investigator

KOHNO Michiaki  Nagasaki University, 大学院・医歯薬学総合研究科, 教授 (00027335)

Co-Investigator(Kenkyū-buntansha) OZAKI Kei-ichi  長崎大学, 大学院・医歯薬学研究科, 准教授 (50252466)
TANIMURA Susumu  長崎大学, 大学院・医歯薬学研究科, 助教 (90343342)
Project Period (FY) 2005 – 2009
Keywords細胞がん化 / がん化学療法 / ERK-MAPキナーゼ経路 / MEK阻害剤 / 微小管重合阻害剤 / HDAC 阻害剤 / 併用療法
Research Abstract

Specific blockade of the ERK pathway by MEK inhibitors alone induces mostly cytostatic rather than pro-apoptotic effects, resulting in a limited therapeutic efficacy of MEK inhibitors. However, MEK inhibitors specifically enhance the induction of apoptosis by microtubule-destabilizing agents and HDAC inhibitors in various tumor cells with aberrant activation of the ERK pathway. Our results clearly indicate that administration of both a MEK inhibitor and a microtubule-destabilizing agent/HDAC inhibitor represents a promising chemotherapeutic strategy with improved safety for cancer patients.

  • Research Products

    (21 results)

All 2010 2009 2008 2007 2006 2005

All Journal Article (15 results) Presentation (3 results) Book (3 results)

  • [Journal Article] Blockade of the extracellular signal-regulated kinase pathway enhances the therapeutic efficacy of microtubuledestabilizing agents in human tumor xenograft models.2010

    • Author(s)
      Watanabe, K., Tanimura, S., Uchiyama, A., Sakamoto, T., Kawabata, T., Ozaki, K., Kohno, M.
    • Journal Title

      Clin. Cancer Res. 16

      Pages: 1170-1178

  • [Journal Article] Blockade of the ERK or PI3K-Akt signaling pathway enhances the cytotoxicity of histone deacetylase inhibitors in tumor cells resistant to gefitinib or imatinib.2010

    • Author(s)
      Ozaki, K., Kosugi, M., Baba, N., Fujio, K., Sakamoto, T., Kimura, S., Tanimura, S., Kohno, M.
    • Journal Title

      Biochem. Biophys. Res. Commun. 391

      Pages: 1610-1615

  • [Journal Article] unprecedented NES non-antagonistic inhibitor for nuclear export of MEK.2010

    • Author(s)
      Tamura, S., Hattori, Y., Kaneko, M., Shimizu, N., Tanimura, S., Kohno, M., Murakami, N. Peumusolide A
    • Journal Title

      Tetrahedron Lett. 51

      Pages: 1678-1681

  • [Journal Article] GEF-H1 mediates tumor necrosis factor-α-induced Rho activation and myosin phosphorylation: Role in the regulation of tubular paracellular permeability.2009

    • Author(s)
      Kakiashvili, E., Speight, P., Waheed, F., Seth, R., Lodyga, M., Tanimura, S., Kohno, M., Rotstein, O.D., Kapus, A., Szaszi, K.
    • Journal Title

      J. Biol. Chem. 284

      Pages: 11454-11466

  • [Journal Article] Blockade of constitutively activated ERK signaling enhances cytotoxicity of microtubule-destabilizing agents in tumor cells.2009

    • Author(s)
      Tanimura, S., Uchiyama, A., Watanabe, K., Yasunaga, M., Inada, Y., Kawabata, T., Iwashita, K., Noda, S., Ozaki, K., Kohno, M.
    • Journal Title

      Biochem. Biophys. Res. Commun. 378

      Pages: 650-655

  • [Journal Article] ERK1/2 phosphorylate GEF-H1 to enhance its guanine nucleotide exchange activity toward RhoA.2008

    • Author(s)
      Fujishiro, S., Tanimura, S., Mure, S., Kashimoto, Y., Watanabe, K, Kohno, M.
    • Journal Title

      Biochem. Biophys. Res. Commun. 368

      Pages: 162-167

  • [Journal Article] Histone deacetylase inhibitors enhance the chemosensitivity of tumor cells with cross-resistance to a wide range of DNA-damaging drugs.2008

    • Author(s)
      Ozaki, K., Kishikawa, F., Tanaka, M., Sakamoto, T., Tanimura, S, Kohno, M.
    • Journal Title

      Cancer Sci. 99

      Pages: 376-384

  • [Journal Article] Anticancer drugs up-regulate HspBP1 and thereby antagonize the prosurvival function of Hsp70 in tumor cells.2007

    • Author(s)
      Tanimura, S., Hirano, A., Hashizume, J., Yasunaga, M., Kawabata, T., Ozaki, K, Kohno, M.
    • Journal Title

      J. Biol. Chem. 282

      Pages: 35430-35439

  • [Journal Article] Blockade of the phosphatidylinositol 3-kinase-Akt signaling pathway enhances induction of apoptosis by microtubuledestabilizing agents in tumor cells in which the pathway is constitutively activated.2007

    • Author(s)
      Fujiwara, Y., Hosokawa, Y., Watanabe, K., Tanimura, S., Ozaki, K, Kohno, M.
    • Journal Title

      Mol. Cancer Ther. 6

      Pages: 1133-1142

  • [Journal Article] Enantioselective total synthesis of (+)- Ottelione A, (-)-Ottelione B, (+)-3-epi- Otterlione A and preliminary evaluation of antitumor activity.2007

    • Author(s)
      Araki, H., Inoue, M., Suzuki, T., Yamori, T., Kohno, M., Watanabe, K., Abe, H., Katoh, T.
    • Journal Title

      Chem. Eur. J. 13

      Pages: 9866-9881

  • [Journal Article] Requirement of ERK MAP kinase in mouse preimplantation development.2007

    • Author(s)
      Maekawa, M., Yamamoto, T., Kohno, M., Takeichi, M., Nishida, E.
    • Journal Title

      Development 134

      Pages: 2751-2759

  • [Journal Article] Targeting the ERK signaling pathway in Cancer Therapy. Ann.2006

    • Author(s)
      Kohno, M., Pouyssegur, J.
    • Journal Title

      Medicine 38

      Pages: 200-211

  • [Journal Article] Blockade of the ERK pathway markedly sensitizes tumor cells to HDAC inhibitor-induced cell death.2006

    • Author(s)
      Ozaki, K., Minoda, A., Kishikawa, F, Kohno, M.
    • Journal Title

      Biochem. Biophys. Res. Commun. 339

      Pages: 1171-1177

  • [Journal Article] Suppression of tumor cell invasiveness by hydrolysable tannins (plant polyphenols) via the inhibition of matrix metalloproteinase-2/ -9 activity.2005

    • Author(s)
      Tanimura, S., Kadomoto, R., Tanaka, T., Zhang, Y., Kouno, I, Kohno, M.
    • Journal Title

      Biochem. Biophys. Res. Commun. 330

      Pages: 1306-1313

  • [Journal Article] Efficient Suppression of Fibroblast Growth Factor-2-induced ERK Activation by the Cooperative Interaction among Mammalian Sprouty Isoforms.2005

    • Author(s)
      Ozaki, K., Miyazaki, S., Tanimura, S, Kohno, M.
    • Journal Title

      J. Cell Sci. 118

      Pages: 5861-5871

  • [Presentation] Blockade of the ERK pathway enhances the antitumor activity of microtubule-destabilizing agents in vitro and in vivo.2008

    • Author(s)
      Watanabe, K., Tanimura, S., Yasunaga, M. Uchiyama, A, Kohno, M.
    • Organizer
      AACR Annual Meeting 2008
    • Place of Presentation
      San Diego
    • Year and Date
      20080000
  • [Presentation] Blockade of the PI3-kinase-Akt signaling pathway enhances induction of apoptosis by microtubule- destabilizing agents in tumor cells in which the pathway is constitutively activated.2007

    • Author(s)
      Watanabe, K., Fujiwara, Y., Tanimura, S., Ozaki, K, Kohno, M.
    • Organizer
      AACR Annual Meeting 2007
    • Place of Presentation
      Los Angeles
    • Year and Date
      20070000
  • [Presentation] Targeting the ERK signaling pathway in cancer therapy2007

    • Author(s)
      河野通明、谷村進、尾崎惠一、渡邊一石
    • Organizer
      第65回日本癌学会総会
    • Place of Presentation
      横浜
    • Year and Date
      20070000
  • [Book] 細胞内シグナル伝達経路の選択的遮断を基盤としたがん治療戦略2008

    • Author(s)
      尾崎恵一、谷村進、河野通明
    • Total Pages
      219-224
    • Publisher
      ファルマシア
  • [Book] シグナル伝達- 1. MAPキナーゼ経路, がんの分子標的治療(鶴雄隆編)2008

    • Author(s)
      河野通明
    • Total Pages
      107-112
    • Publisher
      南山堂
  • [Book] シグナル伝達系, 新臨床腫瘍学(日本臨床腫瘍学会編)2006

    • Author(s)
      河野通明
    • Total Pages
      13-18
    • Publisher
      南江堂

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Published: 2011-06-18   Modified: 2016-04-21  

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