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Design of the anti-tumor agents targeting the functional proteins involved in cancer cell growth

Research Project

Project/Area Number 15310154
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Living organism molecular science
Research InstitutionKansai University

Principal Investigator

UESATO Shinichi  Kansai University, Faculty of engineering, professor, 工学部, 教授 (50111969)

Co-Investigator(Kenkyū-buntansha) NAGAOKA Yasuo  Kansai University, Faculty of engineering, associate professor, 工学部, 助教授 (90243039)
Project Period (FY) 2003 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥12,400,000 (Direct Cost: ¥12,400,000)
Fiscal Year 2005: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2004: ¥4,300,000 (Direct Cost: ¥4,300,000)
Fiscal Year 2003: ¥7,300,000 (Direct Cost: ¥7,300,000)
Keywordshistone deacetylase / P388 / p21 / WAF1 / human normal fibroblast cell / Her2 / neu / SKBR3 / o-aminothiophenol / Herceptin / ヒト正常繊維芽細胞 / フッ素原子 / 血漿中安定性試験 / o-アミノチオフェノール誘導体 / Her2高発現型乳癌細胞 / ハーセプチン / ヒストン脱アセチル化酵素阻害剤 / P388担癌マウス実験 / HCT116 / SK-BR-3 / 細胞周期停止 / Her2高発現型乳がん細胞 / 緑茶カテキン / Her / HT-29 / SW620 / (-)-epigallocatechin gallate / (-)-epigallocatechin / 抗がん剤
Research Abstract

Design of new histone deacetylase (HDAC) inhibitors
We succeeded in the synthesis of 6-amino-2-naphthyl-containing HDAC inhibitor K-32 which exhibited a marked survival effect (%T/C, 185) in the P388 cell-inoculated mice experiment. It was found out that the inhibitory effect on cancer cell proliferation by K-32 involves p21/WAF1 induction and G2/M phase arrest. Among the 2-aminobenzyl-type HDAC inhibitors, K-198 possessing a 3,4-difluorobenzyl group was less toxic to the normal fibroblast cell than SAHA and MS-275 under clinical stages. Furthermore, K-197 comprising a 1,3-benzodioxol group showed more or less the same toxicity as did SAHA. These two compounds exhibited a high recovery in human plasma stability test. Further study on K-32, K-197 and K-198 is underway to investigate the therapeutic efficacy against human cancers.
Design of new low-molecular inhibitors bound to the Her2/neu protein
We demonstrated that green catechins : (-)-epigallocatechin and (-)-epigallocatechin gallate inhibited the cell growth of Her2/neu-overexpressing SKBR3. These catechins seem to suppress the cell growth through inhibition of Her2 dimerization and/or its phosphorylation. Additionally, we discovered the o-aminothiophenol derivative K-154 as an SKBR3 antiprolierative compound ; this compound might have displayed an efficacy through a S-S bond formation between the SH of K-154 and a cysteine of Her2 protein. Thus, K-154 can be a lead compound to seek a cancer therapeutic agent acting as substitute for Herceptin.

Report

(4 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • Research Products

    (34 results)

All 2006 2005 2004 2003 Other

All Journal Article (30 results) Patent(Industrial Property Rights) (1 results) Publications (3 results)

  • [Journal Article] Cytoprotective effect of novel histone deacetylase inhibitors against polyglutamine toxicity.2006

    • Author(s)
      Shingo Kariya, et al.
    • Journal Title

      Neuroscience Letters 392(3)

      Pages: 213-5

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Stereoselective conversion of anhydrovinblastine into vinblastine utilizing an anti-vinblastine monoclonal antibody as a chiral mould2006

    • Author(s)
      Tatsuya Shirahama, et al.
    • Journal Title

      Chem. Pharm. Bull. 54(5)(印刷中)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Synthesis and cancer antiproliferative activity of new histone deacehtylase inhibitors : hydrophilic hydroxamates and 2-aminobenzamide-contaning derivatives2006

    • Author(s)
      Yasuo Nagaoka, et al.
    • Journal Title

      Eur. J. Med. Chem. (印刷中)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Stereoselective conversion of anhydrovinblastine into vinblastine utilizing an anti-vinblastine monoclonal antibody as a chiral mould.2006

    • Author(s)
      Tatsuya Shirahama, et al.
    • Journal Title

      Chem.Pharm.Bull. 54(5)(in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Synthesis and cancer antiproliferative activity of new histone deacetylase inhibitors : hydrophilic hydroxamates and 2-aminobenzamide-containing derivatives.2006

    • Author(s)
      Yasuo Nagaoka, et al.
    • Journal Title

      Eur.J.Med.Chem. (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Cytoprotective effect of novel histone deacetylase inhibitors against polyglutamine toxicity.2006

    • Author(s)
      Shingo Kariya, et al.
    • Journal Title

      Neuroscience Letters,392(3),213-5 (2006), 392(3)

      Pages: 213-215

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Stereoselective conversion of anhydrovinblastine into vinblastine utilizing an anti-vinblastine monoclonal antibody as a chiral mould2006

    • Author(s)
      Tatsuya Shirahama, et al.
    • Journal Title

      Chem.Pharm.Bull. 54(in press)

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Synthesis and cancer antiproliferative activity of new histone deacetylase inhibitors : hydrophilic hydroxamates and 2-aminobenzamide-containing derivatives2006

    • Author(s)
      Y.Nagaoka, et al.
    • Journal Title

      Eur.J.Med.Chem. (in press)

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Tumor chemopreventive effect of orally administered (-)-epigallocatechinand its 3-O-acylated derivatives on the two stage mouse skin carcinogenesis induced by peroxynitrite and 12-O-tetradecanoylphorbol-13-acetate.2005

    • Author(s)
      Yasuo Nagaoka, et al.
    • Journal Title

      Natural Medicine 59(1)

      Pages: 49-51

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Inhibitory effect of cancer cell proliferation by novel histone deacetylase inhibitors involves p21/WAF1 induction and G2/M arrest.2005

    • Author(s)
      Taishi Maeda, et al.
    • Journal Title

      Biol. Pharm. Bull. 28(5)

      Pages: 849-853

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Effect of 3-O-Octanoly-(+)-catechin on the Responses of GABAA Receptors and Na+/Glucose Cotransporters Expressed in Xenopus Oocytes and on the Oocyte Membrane Potential.2005

    • Author(s)
      Hitoshi Aoshima, et al.
    • Journal Title

      J. Agric. Food Chem. 53

      Pages: 1955-1959

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Antioxidative activity of 3-O-octanoyl-(+)-catechin, a newly synthesized catechin, in vitro.2005

    • Author(s)
      Kazuo Nakagawa, et al.
    • Journal Title

      J. Health Science 51(4)

      Pages: 492-496

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] NGF-induced phosphatidylinositol 3-kinase signaling pathway prevents thapsigargin-triggered ER stress-mediated apoptosis in PC12 cells.2005

    • Author(s)
      Koji Shimoke, et al.
    • Journal Title

      Neuroscience Letters 389(3)

      Pages: 124-128

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Tumor chemopreventive effect of orally administered (-)-epigallocatechin and its 3-O-acylated derivatives on the two stage mouse skin carcinogenesis induced by peroxynitrite and 12-O-tetradecanoylphorbol-13-acetate.2005

    • Author(s)
      Yasuo Nagaoka, et al.
    • Journal Title

      Natural Medicine 59(1)

      Pages: 49-51

    • NAID

      110008732357

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Inhibitory effect of cancer cell proliferation by novel histone deacetylase inhibitors involves p21/WAF1 induction and G2/M arrest.2005

    • Author(s)
      Taishi Maeda, et al.
    • Journal Title

      Biol.Pharm.Bull. 28(5)

      Pages: 849-853

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Annual Research Report 2005 Final Research Report Summary
  • [Journal Article] Effect of 3-O-Octanoyl-(+)-catechin on the Responses of GABAA Receptors and Na+/Glucose Cotransporters Expressed in Xenopus Oocytes and on the Oocyte Membrane Potential.2005

    • Author(s)
      Hitoshi Aoshima, et al.
    • Journal Title

      J.Agric.Food Chem. 53

      Pages: 1955-1959

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Annual Research Report 2005 Final Research Report Summary
  • [Journal Article] Antioxidative activity of 3-O-octanoyl-(+)-catechin, a newly synthesized catechin, in vitro.2005

    • Author(s)
      Kazuo Nakagawa, et al.
    • Journal Title

      J.Health Science 51(4)

      Pages: 492-496

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Annual Research Report 2005 Final Research Report Summary
  • [Journal Article] Tumor chemopreventive effect of orally administered (-)-epigallocatechin and its 3-O-acylated derivatives on the two stage mouse skin carcinogenesis induced by peroxynitrite and 12-O-tetradecanoylphorbol- 13-acetate.2005

    • Author(s)
      Yasuo Nagaoka, et al.
    • Journal Title

      Natural Medicine 59(1)

      Pages: 49-51

    • NAID

      110008732357

    • Related Report
      2005 Annual Research Report
  • [Journal Article] NGF-induced phosphatidylinositol 3-kinase signaling pathway prevents thapsigargin-triggered ER stress-mediated apoptosis in PC12 cells.2005

    • Author(s)
      Koji Shimoke, et al.
    • Journal Title

      Neuroscience Letters,389(3),124-128 (2005). 389(3)

      Pages: 124-128

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Anti-Staphylococcus aureus activity and oxacillin resistance modulating capacity of 3-O-acyl-catechins.2004

    • Author(s)
      Stapleton PD, et al.
    • Journal Title

      Int. J. Antimicrob. Agents 22

      Pages: 1709-1716

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Potent histone deacetylase inhibitors : N-hydroxybenzamides with antitumor activities.2004

    • Author(s)
      Maeda, T. et al.
    • Journal Title

      Bioorg. & Med. Chem. 12

      Pages: 4351-4360

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Anti-Staphylococcus aureus activity and oxacillin resistance modulating capacity of 3-O-acyl-catechins.2004

    • Author(s)
      Stapleton PD, et al.
    • Journal Title

      Int.J.Antimicrob.Agents. 22

      Pages: 1709-1716

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Potent histone deacetylase inhibitors : N-hydroxybenzamides with antitumor activities.2004

    • Author(s)
      Maeda, T., et al.
    • Journal Title

      Bioorg.& Med.Chem. 12

      Pages: 4351-4360

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Potent histone deacetylase inhibitors : N-hydroxybenzamides with antitumor activities.2004

    • Author(s)
      S.Uesato, et al.
    • Journal Title

      Bioorg.& Med.Chem. 12

      Pages: 4351-4360

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Antiproliferative Activity of Some Catechins against Her2/neu-Overexpressing Human Breast Carcinoma SKBR32003

    • Author(s)
      Taishi Maeda, et al.
    • Journal Title

      Natural Medicines 57(1)

      Pages: 31-33

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Tumor Chemopreventive Activity of 3-O-Acylated (-)-Epigallocatechins2003

    • Author(s)
      Ayako Kumagai, et al.
    • Journal Title

      Bioorg. & Med. Chem. 11(23)

      Pages: 5143-5148

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Inhibitory Effects of 3-O-Acyl-(+)-catechins on Epstein-Barr Virus Activation2003

    • Author(s)
      Shinichi Uesato, et al.
    • Journal Title

      Chem. Pham. Bull. 51(12)

      Pages: 1448-1450

    • NAID

      110003615244

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Tumor Chemopreventive Activity of 3-O-Acylated (-)-Epigallocatechins2003

    • Author(s)
      Ayako Kumagai, et al.
    • Journal Title

      Bioorg.& Med.Chem. 11(23)

      Pages: 5143-5148

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Inhibitory Effects of 3-O-Acyl-(+)-catechins on Epstein-Barr Virus Activation2003

    • Author(s)
      Shinichi Uesato, et al.
    • Journal Title

      Chem.Pharm.Bull. 51(12)

      Pages: 1448-1450

    • NAID

      110003615244

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Inhibitory effect of cancer cell proliferation by novel histone deacetylase inhibitors involves p21/WAF1 induction and G2/M arrest.

    • Author(s)
      S.Uesato, et al.
    • Journal Title

      Biol.Pharm.Bull. (Accepted on Feb.2005)(in press)

    • Related Report
      2004 Annual Research Report
  • [Patent(Industrial Property Rights)] カルボキサミド誘導体2005

    • Inventor(s)
      上里新一, 長岡康夫, 前田泰司
    • Industrial Property Rights Holder
      学校法人関西大学
    • Industrial Property Number
      2005-181043
    • Filing Date
      2005-06-21
    • Related Report
      2005 Annual Research Report
  • [Publications] Shinichi Uesato, et al.: "Antiproliferative Activity of Some Catechins against Her2/neu-Overexpressing Human Breast Carcinoma SKBR3"Natural Medicines. 57・1. 31-33 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Shinichi Uesato, et al.: "Tumor Chemopreventive Activity of 3-O-Acylated (-)-Epigallocatechins"Bioorg.& Med.Chem.. 11・23. 5143-5148 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Shinichi Uesato, et al.: "Inhibitory Effects of 3-O-Acyl-(+)-catechins on Epstein-Barr Virus Activation"Chem.Pharm.Bull.. 51・12. 1448-1450 (2003)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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