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Chemoprevention of hepatocellular carcinoma by dehydroepiandrosterone and its derivatives

Research Project

Project/Area Number 15390225
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Gastroenterology
Research InstitutionTokyo Medical University (2006)
University of Tsukuba (2003-2005)

Principal Investigator

MATSUZAKI Yasushi  Tokyo Medical University, Medicine, Professor, 医学部, 教授 (50209532)

Co-Investigator(Kenkyū-buntansha) SHODA Junichi  Tsukuba University, Medicine, Assistant Professor, 大学院・人間総合科学研究科, 講師 (90241827)
UCHIDA Kazuhiko  Tsukuba University, Medicine, Associate Professor, 大学院・人間総合科学研究科, 助教授 (90211078)
Project Period (FY) 2003 – 2006
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥9,800,000 (Direct Cost: ¥9,800,000)
Fiscal Year 2006: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2005: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2004: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2003: ¥6,700,000 (Direct Cost: ¥6,700,000)
KeywordsDehydroepiandrosterone / Cholesterol / Hepatocellular carcinoma / Oxysterols / Nuclear receptor / GC-MS / LC-MS / MS / Apoptosis / 肝細胞癌 / 胆汁酸 / ガスクロマトグラフィー / マススポクトロメトリー / ラット
Research Abstract

Dehydroepiandrosterone (DHEA) is the most abundant adrenal androgenic steroid in young adult humans. The physiological functions of DHEA in preventing human carcinogenesis are still controversial, but a lot of reports have shown that pharmacological doses of DHEA show chemopreventive and anti-proliferative effects on tumors in rodents. The present study was undertaken to obtain basic data and methods for the clinical use of DHEA in the future. The following results were obtained.
1.Sensitive and reliable method for the quantification of DHEA-related steroids by a stable isotope-dilution technique using high-resolution GC-MS was developed. The method made it possible to determine simultaneously DHEA and DHEA derivative levels in human serum. In addition, to evaluate the effects of DHEA on cholesterol metabolism, highly sensitive LC-MS/MS methods for the quantification of several key intermediates in the cholesterol and bile acid biosynthetic pathways were developed.
2.The effects of DHEA … More on the proliferation of hepatic cancer cell lines were studied. We demonstrated the following four mechanisms of the anti-proliferation by DHEA : 1) depletion of NADPH and ribose-5-phosphate due to the inhibition of glucose-6-phosphate dehydrogenase activity, 2) suppression of cholesterol biosynthetic pathway by inhibition of HMG-CoA reductase activity, 3) interference with a cell proliferation signaling pathway (MAPK cascade), and 4)induction of apoptosis through the inhibition of the PI3K/Akt signaling pathway.
3. Hypercholesterolemia is one of the important paraneoplastic syndromes in patients with hepatocellular carcinoma and DHEA inhibits the proliferation of hepatocellular carcinoma by inhibiting cholesterol biosynthetic pathway. Therefore, we investigated the molecular mechanisms of hypercholesterolemia associated with hepatoma by using a hepatoma-bearing rat model. As a result, hypercholesterolemia in the hepatoma-bearing rats was caused by the increased cholesterol efflux from tumors due to the activation of a nuclear receptor, LXRalpha. Over-expression of the sterol regulatory element-binding protein (SREBP) processing system contributes to the activation of LXRalpha by maintaining high tissue levels of oxysterols that are ligands for this nuclear receptor. Less

Report

(5 results)
  • 2006 Annual Research Report   Final Research Report Summary
  • 2005 Annual Research Report
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • Research Products

    (39 results)

All 2007 2006 2005 2004 Other

All Journal Article (29 results) Book (4 results) Publications (6 results)

  • [Journal Article] Highly sensitive quantification of 7alpha-hydroxy-4-cholesten-3-one in human serum by LC-ESI-MS/MS.2007

    • Author(s)
      Honda A et al.
    • Journal Title

      J. Lipid Res. 48

      Pages: 458-464

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Highly sensitive assay of HMG-CoA reductase activity by LC-ESI-MS/MS.2007

    • Author(s)
      Honda A et al.
    • Journal Title

      J. Lipid Res. 48(Epub ahead of print)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Highly sensitive quantification of 7alpha-hydroxy-4-cholesten-3-one in human serum by LC-ESI-MS/MS.2007

    • Author(s)
      Honda A et al.
    • Journal Title

      J.Lipid Res. 48

      Pages: 458-464

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Highly sensitive assay of HMG-CoA reductase activity by LC-ESI-MS/MS.2007

    • Author(s)
      Honda A et al.
    • Journal Title

      J.Lipid Res. 48(Epub ahead of print)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Highly sensitive quantification of 7a-hydroxy-4-cholesten-3-one in human serum by LC-ESI-MS/MS2007

    • Author(s)
      Honda A et al.
    • Journal Title

      Journal of Lipid Research 48

      Pages: 458-464

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Highly sensitive assay of HMG-CoA reductase activity by LC-ESI-MS/MS2007

    • Author(s)
      Honda A et al.
    • Journal Title

      Journal of Lipid Research 48(Epub ahead of print)

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Dehydroepiandrosterone and its derivatives : potentially novel anti-proliferative and chemopreventive agents.2006

    • Author(s)
      Matsuzaki Y et al.
    • Journal Title

      Curr. Pharm. Des. 12

      Pages: 3411-3421

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Hypercholesterolemia in rats with hepatomas : increased oxysterols accelerate efflux but do not inhibit biosynthesis of cholesterol.2006

    • Author(s)
      Hirayama T et al.
    • Journal Title

      Hepatology 44

      Pages: 602-611

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Dehydroepiandrosterone and its derivatives : potentially novel anti-proliferative and chemopreventive agents.2006

    • Author(s)
      Matsuzaki Y et al.
    • Journal Title

      Curr.Pharm.Des. 12

      Pages: 3411-3421

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Dehydroepiandrosterone and its derivatives : potentially novel anti-proliferative and chemopreventive agents2006

    • Author(s)
      Matsuzaki Y et al.
    • Journal Title

      Current Pharmaceutical Design 12

      Pages: 3411-3421

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Hypercholesterolemia in rats with hepatomas : increased oxysterols accelerate efflux but do not inhibit bosynthesis of cholesterol2006

    • Author(s)
      Hirayama T et al.
    • Journal Title

      Hepatology 44

      Pages: 602-611

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Involvement of integrin-linked kinase in carbon tetrachloride-induced hepatic fibrosis in rats2006

    • Author(s)
      Zhang Y et al.
    • Journal Title

      Hepatology 44

      Pages: 612-622

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Apoptosis and inhibition of the phosphatidylinositol 3-kinase/Akt signaling pathway in the anti-proliferative actions of dehydroepiandrosterone.2005

    • Author(s)
      Jiang Y et al.
    • Journal Title

      J. Gastroenterol. 40

      Pages: 490-497

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Rapid inhibition of MAPK signaling and anti-proliferation effect via JAK/STAT signaling by interferon-alpha in hepatocellular carcinoma cell lines.2005

    • Author(s)
      Inamura K et al.
    • Journal Title

      Biochim. Biophys. Acta. 1745

      Pages: 401-410

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Apoptosis and inhibition of the phosphatidylinositol 3-kinase/Akt signaling pathway in the anti-proliferative actions of dehydroepiandrosterone.2005

    • Author(s)
      Jiang Y et al.
    • Journal Title

      J.Gastroenterol. 40

      Pages: 490-497

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Rapid inhibition of MAPK signaling and anti-proliferation effect via JAK/STAT signaling by interferon-alpha in hepatocellular carcinoma cell lines.2005

    • Author(s)
      Inamura K et al.
    • Journal Title

      Biochim.Biophys.Acta 1745

      Pages: 401-410

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Alcohol abuse and occult HBV-a risk factor for hepatocellular carcinoma2005

    • Author(s)
      Matsuzaki Y et al.
    • Journal Title

      Hepatol.Res. 32

      Pages: 67-70

    • NAID

      10016478272

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Disrupted coordinate regulation of farnesoid X receptor (FXR) target genes in a patient with cerebrotendinous xanthomatosis2005

    • Author(s)
      Honda A, Salen G, Matsuzaki Y et al.
    • Journal Title

      J.Lipid Res. 46

      Pages: 287-296

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Suppressive effect of ursodeoxycholic acid on type IIA phospholipase A2 expression in HepG2 cells2005

    • Author(s)
      Ikegami T, Matsuzaki Y, et al.
    • Journal Title

      Hepatology 41

      Pages: 896-905

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Apoptosis and inhibition of the phosphatidylinositol 3-kinase/Akt signaling pathway in the anti-proliferative actions of dehydroepiandrosterone2005

    • Author(s)
      Jiang Y et al.
    • Journal Title

      J.Gastroenterol. 40

      Pages: 490-497

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Rapid inhibition of MAPK signaling and anti-proliferation effect via JAK/STAT signaling by interferon-alpha in hepatocellular carcinoma cell lines2005

    • Author(s)
      Inamura K, Matsuzaki Y, et al.
    • Journal Title

      Biochim Biophys Acta 1745(3)

      Pages: 401-410

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Proton beam therapy for hepatocellular carcinoma : a retrospective review of 162 patients.2005

    • Author(s)
      Chiba T, tokuuye K, Matsuzaki Y, et al.
    • Journal Title

      Clin Cancer Res 15;11(10):

      Pages: 799-805

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Simultaneous determination of dehydroepiandrosterone and its 7-oxygenated metabolites in human serum by high-resolution gas chromatography-mass spectrometry.2004

    • Author(s)
      Matsuzaki Y et al.
    • Journal Title

      Steroids 69

      Pages: 817-824

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Simultaneous determination of dehydroepiandrosterone and its 7-oxygenated metabolites in human serum by high-resolution gas chromatography-mass spectrometry2004

    • Author(s)
      Matsuzaki Y et al.
    • Journal Title

      Steroids 69

      Pages: 817-824

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Dehydroepiandrosterone and its derivatives : potentially novel antiproliferative and chemopreventive agents

    • Author(s)
      Matsuzaki Y et al.
    • Journal Title

      Curr.Pharm.Des. in press

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Apoptosis and inhibition of the phosphatidylinositol 3-kinase/Akt signaling pathway in the anti-proliferative actions of dehydroepiandrosterone

    • Author(s)
      Jiang Y et al.
    • Journal Title

      J.Gastroenterol. in press

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Effect of Ursodeoxycholic Acid on Pro-Inflammatory Cytokine-Induced Type IIA Phospholipase A a ^*1 Expression in HepG2 cells.

    • Author(s)
      Ikegami T et al.
    • Journal Title

      Hepatology in press

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Taurin inhibits oxidative damage and prevents fibrosis in carbon tetrachroride-induced hepatic fibrosis

    • Author(s)
      Miyazaki T, st al.
    • Journal Title

      J Hepatology in press

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Alcohol abuse and Occult HBV -a risk factor for hepatocellular carcinoma (Editorial).

    • Author(s)
      Matsuzaki Y et al.
    • Journal Title

      Hepatol.Res in press

    • Related Report
      2004 Annual Research Report
  • [Book] 今日の治療指針 2005:黄疸、胆汁うっ滞2005

    • Author(s)
      松崎靖司
    • Total Pages
      1676
    • Publisher
      医学書院
    • Related Report
      2005 Annual Research Report
  • [Book] 消化器疾患診療実践ガイド 肝内胆汁うっ滞2005

    • Author(s)
      本多彰, 松崎靖司
    • Total Pages
      1076
    • Publisher
      文光堂
    • Related Report
      2005 Annual Research Report
  • [Book] 内科疾患診療マニュアル 原発性胆汁性肝硬変2005

    • Author(s)
      伊藤進一, 松崎靖司
    • Total Pages
      973
    • Publisher
      中外医学社
    • Related Report
      2005 Annual Research Report
  • [Book] 科学大辞典(第2版)編集委員, 医学/バイテク部門委員2005

    • Author(s)
      松崎靖司
    • Total Pages
      1831
    • Publisher
      丸善株式会社
    • Related Report
      2005 Annual Research Report
  • [Publications] Honda, A.et al.: "Significance of plasma 7α-hydroxy-4-cholesten-3-one and 27-hydroxycholesterol concentrations as markers for hepatic bile acid synthesis in cholesterol-fed rabbits"Metabolism. 53・1. 42-48 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Shoda, J.et al.: "Novel mutations identified in the human multidrug resistance-associated protein 2 (MRP2/ABCC2)gene in a Japanese patient with Dubin-Johnson syndrome"Hepatology Research. 27・4. 323-326 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Miyazaki, T.et al.: "Amimo acid ratios in plasma and tissues in a rat model of liver cirrhosis before and after exercise"Hepatology Research. 27・3. 230-237 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yoshida, T.et al.: "Origin of oxysterols in hepatic bile of patients with biliary infection"American Journal of Gastroenterology. 98・10. 2275-2280 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Unno, R.et al.: "Progression of autoimmune-mediated hepatic lesions in a murine graft-versus-host reaction by neutralizing IL-10"Hepatology Research. 26・4. 354-361 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yoshida, S.et al.: "Anti-proliferative action of endogenous dehydroepiandrosterone metabolites on human cancer cell lines"Steroids. 68・1. 73-83 (2003)

    • Related Report
      2003 Annual Research Report

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

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