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Development of effective combinational chemopreventive therapies modulating IGF-1 receptor as a molecular target

Research Project

Project/Area Number 15590644
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Gastroenterology
Research InstitutionOsaka University

Principal Investigator

TSUJII Masahiko  Osaka University, Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (40303937)

Co-Investigator(Kenkyū-buntansha) KAWANO Sunao  Osaka University, Graduate School of Medicine, Professor, 医学系研究科, 教授 (60133138)
TSUJII Shingo  Osaka University, Graduate School of Medicine, Lecture, 医学系研究科, 講師 (40301262)
Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2004: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2003: ¥1,800,000 (Direct Cost: ¥1,800,000)
Keywordscyclooxygenase-2 / colon cancer / IGF-I receptor / angiotensin / ACE inhibitor / ARB / Akt / PI3K / celecoxib / cyclooxygenase-2 / アンギオテンシン / 化学予防 / IGF-I受容体 / PI3 / cyclooxygemuse / prostaglandinE_2 / NSAIDs / IGF / IGF受容体系
Research Abstract

An inducible isoform of cyclooxygenase (COX),COX-2, insulin-like growth factor (IGF) II, and IGF-I receptor (IGF-IR) are up-regulated in colon carcinoma and might have crucial roles in tumor growth and invasion. The aim of the present study was to investigate the effects of COX-2 inhibitor and drugs blocking the biological activities of angiotensin II [angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs)] on IGF-IR expression and tumor growth in vivo. In vivo, tumor growth and IGF-IR expression were investigated in Colon 26 cells inoculated into BALB/c mice. Celecoxib at the lowest effective dose for suppression of PG production (3 mg/kg) or an ACE inhibitor/ARB alone did not have a significant effect as compared with controls, although a high dose of celecoxib (>20 mg/kg) suppressed tumor growth. On the other hand, combination therapy with these two categories of drugs significantly reduced tumor growth in vivo. Treatment with both celecoxib and an ACE inhibitor/ARB decreased IGF-IR expression levels in inoculated tumor cells. In vitro, IGF-II-induced cell growth and invasion were analyzed in Colon 26. Celecoxib reduced IGF-IR expression and IGF-II-stimulated growth in a dose-dependent manner. PGE(2) or angiotensin II treatment reversed the celecoxib-induced down-regulation of IGF-IR expression, and growth. PGE(2) and angiotensin II-induced Akt phosphorylation, and LY294002 or wortmannin inhibited PGE(2)- or angiotensin II-induced IGF-IR expression, indicating that PGE(2) and angiotensin II both regulate IGF-IR expression by the same Akt/phosphatidylinositol-3 pathway. Thus, combination therapy with NSAIDs and ACE Inhibitors targeting IGF-IR might be a novel and potentially promising strategy for the chemoprevention of colon cancer.

Report

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

    (19 results)

All 2005 2004 2003 Other

All Journal Article (14 results) Publications (5 results)

  • [Journal Article] GARDと糖尿病2005

    • Author(s)
      西田 勉
    • Journal Title

      Progress in Medicine Vol.24

      Pages: 665-668

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Gastroesophageal reflux disease related to diabetes : Analysis of 241 Cases with type 2 diabetes melltus2004

    • Author(s)
      Nishida T
    • Journal Title

      Journal of Gastroenterology and Hepatology 19

      Pages: 258-165

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] 消化器機能的疾患の診断と治療 糖尿病におけるGARDの合併について2004

    • Author(s)
      西田 勉
    • Journal Title

      消化器医学 Vol.2

      Pages: 65-70

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] COX-2特異的阻害剤はNSAIDs潰瘍を予防できるか2004

    • Author(s)
      西田 勉
    • Journal Title

      日本臨床 62巻・3号

      Pages: 561-565

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Gastroesophageal reflux disease related to diabe Related to diabetes : Analysis of 241 Cases with type 2 diabetes melltus2004

    • Author(s)
      Nishida T
    • Journal Title

      Journal of Gastroenterology and Hepatology 19

      Pages: 258-265

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Castroesophageal reflux disease related to diabetes : anslysis of 241 cases with type 2 diabetes mellitus2004

    • Author(s)
      Nishida T, Tsujii M, et al.
    • Journal Title

      J Gastroenterol Hepatol. 19

      Pages: 258-265

    • Related Report
      2004 Annual Research Report
  • [Journal Article] COX-2 and advanced digestive cancer phenotypes.2004

    • Author(s)
      Tsuji S, Tsujii M.
    • Journal Title

      J Gastroenterol. 39

      Pages: 1224-1225

    • NAID

      10014091943

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Helicobacter bilis infection in biliary tract cancer.2004

    • Author(s)
      Murata H, Tsuji S, Tsujii M, et al.
    • Journal Title

      Aliment Pharmacol Ther. 20

      Pages: 90-94

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Promoter hypermethylation silences cyclooxygenase-2(Cox-2)and regulates growth of humanhepatocellular carcinoma cells.2004

    • Author(s)
      Murata H, Tsuji S, Tsujii M, et al.
    • Journal Title

      Lab Invest. 84

      Pages: 1050-1059

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Inhibition of Angiotensin II Actvity Enhanced the Antitumor Effect of Cyclooxygenase-2 Inhibitors via Insulin-Like Growth Factor I2003

    • Author(s)
      Yasumaru M
    • Journal Title

      CANCER RESEARCH 63

      Pages: 6726-6734

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] 大腸癌の診断と治療 最新の研究動向 COX-2阻害剤、ACE阻害剤併用療法2003

    • Author(s)
      安丸 正一
    • Journal Title

      日本臨床 61巻

      Pages: 510-513

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Inhibition of Angiotensin II Activity Enhanced Effect of cyclooxygenase-2 Inhibitors via Insulin-Like Growth Factor I2003

    • Author(s)
      Yasumaru M
    • Journal Title

      CANCER RESEARCH 63

      Pages: 6726-6734

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Review article : inflammation-related promotion of gastrointestinal carcinogenesis a perigenetic pathway2003

    • Author(s)
      Tsuji S, Tsujii M, et al.
    • Journal Title

      Aliment Pharmacol Ther 18

      Pages: 82-89

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Inhibition of angiotensin II activity enhanced the antitumar effect of cyclooxygenase-2 inhibitors via insulin-like growth factor I receptorpathway2003

    • Author(s)
      Yasumaru M, Tsujii M, et al.
    • Journal Title

      Cancer Res. 15

      Pages: 6726-6734

    • Related Report
      2004 Annual Research Report
  • [Publications] Tsuji S, Tsujii M, et al.: "Review article : inflammation-related promotion of gastrointestinal carcinogenesis--a perigenetic pathway"Aliment Pharmacol Ther.. 18. 82-89 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yasumaru M, Tsujii M, et al.: "Combination therapies using cyclooxygenase-2 inhibitors and angiotensin-converting enzyme inhibitors incolon carcinogenesis"Nippon Rinsho. 61. 510-514 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yasumaru M, Tsujii M, et al.: "Inhibition of angiotensin II activity enhanced the antitumor effect of cyclooxygenase-2 inhibitors via insulin-like growth factor I receptor pathway"Cancer Res.. 15. 6726-6734 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Nishida T, Tsujii M, et al.: "Gastroesophageal reflux disease related to diabetes : Analysis of 241 cases with type 2 diabetes mellitus"J Gastroenterol Hepatol.. 19. 258-265 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Nishida T, Tsujii M, et al.: "Are COX-2 inhibitors truly able to prevent NSAIDs-associated ulcer?"Nippon Rinsho. 62. 561-565 (2004)

    • Related Report
      2003 Annual Research Report

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

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