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Development of a Potent Inhibitor of Metastasis Based on a Cyclic Lysophosphatidic Acid

Research Project

Project/Area Number 13557212
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field 医薬分子機能学
Research InstitutionTokyo University of Science

Principal Investigator

KOBAYASHI Susumu  Tokyo University of Science, Faculty of Pharmaceutical, Professor, 薬学部, 教授 (70101102)

Co-Investigator(Kenkyū-buntansha) UCHIRO Hiromi  Tokyo University of Science, Faculty of Pharmaceutical Sciences, Assistant Professor, 薬学部, 講師 (00307711)
MUROFUSHI Kimiko  Ochanomizu University, Faculty of Science, Professor, 理学部, 教授 (00103557)
Project Period (FY) 2001 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥13,400,000 (Direct Cost: ¥13,400,000)
Fiscal Year 2003: ¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 2002: ¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2001: ¥7,200,000 (Direct Cost: ¥7,200,000)
KeywordsMetastasis / Tumor cell invasion / phospholipid / Cyclic phosphatidic acid / Phosphatidic acid / Lysophosphatidic acid / 癌細胞の浸潤 / アポトーシス誘導作用
Research Abstract

Cyclic phosphatidic acid (1-acyl-sn-glycero-2,3-cyclic phosphate; cPA) is a naturally occurring analog of lysophosphatidic acid (LPA) with a variety of distinctly different biological activities from those of LPA. In sharp contrast to LPA, a potent inducer of tumor cell invasion, we previously discovered that palmitoyl-cPA inhibits FBS- and LPA-induced transcellular migration and metastasis. Cyclic phosphate is not a stable molecule. It might be hydrolyzed either by chemically or enzymatically. In this regard, we have observed that LPA and cPA are enzymatically produced from phosphatidyl choline by phospholipase D (PLD). It is quite important to design a novel molecule of cPA origin which resists to hydrolysis because resulting hydrolyzed product, LPA is known to induce metastasis. In order to prevent the conversion of cPL to LPA, we carried out a modification on cyclic phosphate moiety. One of the molecules which we designed is a carba analog. Carba derivatives, in which the phosphate oxygen was replaced with a methylene group either at the sn-2 or the sn-3 position, showed much more potent inhibitory effects on MM! tumor cell transcellular migration and the pulmonary metastasis of B16-F0 melanoma than the natural Pal-cPA. The antimetastatic effect of carba-cPA was accompanied by the inhibition of Pho activation and was not due to the inhibition or the activation of LPA receptors.

Report

(4 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • Research Products

    (19 results)

All 2007 2004 2003 2002 Other

All Journal Article (10 results) Publications (9 results)

  • [Journal Article] Inhibition of transcellular tumor cell migration and metastasis by novel carba-derivatives of cyclic phosphatidic acid2007

    • Author(s)
      内山綾子
    • Journal Title

      Biochimica et Biopysica Acta 1771

      Pages: 10-10

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Inhibition of transcellular tumor cell migration and metastasis by novel carba-derivatives of cyclic phosphatidic acid2007

    • Author(s)
      A.Uchiyama, M.Mukai, Y.Fujiwara, S.Kobayashi, N.Kawai, H.Murofushi, M.Inoue, S.Enoki, Y.Tanaka, T.Niki, T.Kobayashi, G.Tigyi, K.Murakami-Murofushi
    • Journal Title

      Biochimica et Biopysica Acta 1771

      Pages: 103-112

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Attenuation by Cyclic Phosphatidic Acid of Peritoncal Metastasis of Azoxymethanc-Induced Intestinal Cancers in Wister Rats2004

    • Author(s)
      石原 龍
    • Journal Title

      Int. J. Cancer 110・2

      Pages: 6-6

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Attenuation by Cyclic Phosphatidic Acid of Peritoneal Metastasis of Azoxymethane-Induced Intestinal Cancers in Wister Rats2004

    • Author(s)
      R.Ishihara, M.Tatsuta, H.Iishi, M.Baba, N.Ucdo, K.Higashino, M.Mukai, S.Ishiguro, S.Kobayashi, K.Murakami-Murofushi
    • Journal Title

      Int. J. Cancer 110 (2)

      Pages: 188-193

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Cyclic phosphatidic acid inhibits RhoA-mediated autophosphorylation of FAK at Tyr-397 and subsequent tumor-cell invasion2003

    • Author(s)
      向井睦子
    • Journal Title

      Int. J. Oncology 22

      Pages: 10-10

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Cyclic phosphatidic acid inhibits RhoA-mediated autophosphorylation of FAK at Tyr-397 and subsequent tumor-cell invasion2003

    • Author(s)
      M.Mukai, T.Iwasaki, M.Tatsuta, A.Togawa, H.Nakamura, K.Murakami-Murofushi, S.Kobayashi, F.Imamura, M.Inoue
    • Journal Title

      Int. J. Oncology 22

      Pages: 1247-1256

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Biological functions of a novel lipid mediator, cyclic phosphatidic acid2002

    • Author(s)
      室伏きみ子
    • Journal Title

      Biochem. Biophys, Acta 1582

      Pages: 7-7

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Steryl Glucoside is a Lipid Mediator in Stress-responsive Signal Transduction2002

    • Author(s)
      国本正子
    • Journal Title

      Cell Struct. Funct 27

      Pages: 6-6

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Biological functions of a novel lipid mediator, cyclic phosphatidic acid2002

    • Author(s)
      K.Murakami-Murofushi, A.Uchiyama, Y.Fujiwara, T Kobayashi, S.Kobayashi, M.Mukai, H.Murofushi, G.Tigyi
    • Journal Title

      Biochim. Biophys. Acta 1582

      Pages: 1-7

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Steryl Glucoside is a Lipid Mediator in Stress-responsive Signal Transduction2002

    • Author(s)
      S.Kunimoto, W.Murofushi, H.Kai, Y.Ishida, A.Uchiyama, T.Kobayashi, S.Kobayashi, H.Murofushi, K.Murakami-Murofushi
    • Journal Title

      Cell Struct. Funct. 27

      Pages: 157-162

    • NAID

      50000617080

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 向井 睦子: "Cyclic phosphatidic acid inhibits RhoA-mediated autophosphorylation of FAK at Tyr-397 and subsequent tumor-cell invasion"Int.J.Oncology. 22巻. 1247-1256 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] S.Richter: "Clerocidin alkylates DNA through its epoxide function : evidence for a fine tuned mechanism of action"Nucleic Acids Research. 31巻・17号. 5146-5156 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 松田 大介: "New Beauveriolides Produced by Amino Acid-supplemented Fermentation of Beauveria sp. FO-6979"J.Antibiot. 57巻・1号. 1-9 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] 室伏きみ子: "Biological functions of a novel lipid mediator, cyclic phosphatidic acid"Biochem. Biophys, Acta. 1582. 1-7 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 國本正子: "Steryl Glucoside is a Lipid Mediator in Stress-responsive Signal Transduction"Cell Struct. Funct.. 27巻. 157-162 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 沼尾長徳: "Novel Biological Activity of the Region (106-126) on Human Prion Sequence"Biol. Pharm. Bull.. 26巻2号. 229-232 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] 小林 哲幸: "Bioactions and Synthesis of a Novel Lipid Mediator,Cyclic Phosphatidic Acid(cPA)"World Rev.Nutr.Diet. 88巻. 228-232 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 内呂 拓実: "Asymmetric Total Synthesis of 9-Methoxystrobilurin K"Tetrahedron Letters. 42巻27号. 4531-4534 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 内呂 拓実: "Total Synthesis and Antifungal Activity of 9-Methoxystrobirulin L as the Originally Proposed 1,4-Benzodioxan Structure"Bioorg.Med.Chem.Lett.. 11巻. 2783-2786 (2001)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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