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Development of anti-tumor therapy by novel compounds targeting pyruvate dehydrogenase kinase

Research Project

Project/Area Number 16K08711
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Experimental pathology
Research InstitutionShiga University of Medical Science

Principal Investigator

Inoue Hirokazu  滋賀医科大学, 医学部, 准教授 (30176440)

Research Collaborator Kim Chul Jang  
Mukaisho Ken-ichi  
Tambe Yukihiro  
Ushio Akiyo  
Nakano Hirofumi  
Omura Satoshi  
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
KeywordsKRAS / ピルビン酸代謝 / 膵臓癌 / PDK4 / cryptotanshinone / Cryptotanshinone / PDK4 / エネルギー代謝 / PDK4阻害剤 / ワールブルグ効果 / K-Ras / mTOR / 癌幹細胞 / 新規抗癌剤
Outline of Final Research Achievements

Most proliferating tumor cells preferentially metabolize glucose via glycolysis even under aerobic conditions. This metabolic shift, the Warburg effect, is a hallmark of malignant cancer cells. We found that the novel specific inhibitors of PDK4 (KIS) significantly suppressed the malignant phenotypes of human colon and pancreatic cancer cells in vitro. A novel PDK4 inhibitor, KIS37 (cryptotanshinone), reduced the phosphorylation of pyruvate dehydrogenase and the expression of mutant K-Ras protein in human pancreatic and colon cancer cell lines. KIS37 also suppressed the phosphorylation of PI3K-Akt-mTOR pathway and expression of cyclin D1 protein. Furthermore, KIS37 suppressed pancreatic tumor formation in orthotopic model of nude mouse without detectable adverse effects. These results indicate that this novel PDK4 inhibitor can be a potential therapeutic drug for mutant KRAS-containing intractable pancreatic and colorectal cancers.

Academic Significance and Societal Importance of the Research Achievements

K-ras遺伝子変異が90%を占める膵臓癌は癌の中でも最も10年生存率が低い難治性癌であり、有効で副作用の少ない新規分子標的治療薬の開発は大きな課題である。また、大腸癌は最も罹患率が高い癌で、特にK-ras遺伝子変異は44%を占めこれらは予後が悪く難治性が高い。米国でも癌治療の最重要課題として”The RAS project”を立ち上げているが、これまでのRas阻害剤では未だ有効な臨床的成果を上げていない。これらの難治癌に対する新しい作用機作の抗癌剤の開発は重要であり、我々が見出したピルビン酸代謝を標的としたKIS化合物の抗腫瘍活性を示した今回の成果は臨床での治験にも直接つながると考えられる。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (12 results)

All 2019 2018 2017 2016 2015

All Journal Article (6 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 6 results,  Open Access: 5 results,  Acknowledgement Compliant: 2 results) Presentation (6 results)

  • [Journal Article] Antitumor activity of potent pyruvate dehydrogenase kinase 4 inhibitors from plants in pancreatic cancer.2019

    • Author(s)
      Tambe, Y., Terado, T., Kim, C. J., Mukaisho, K., Yoshida, S., Sugihara, H., Tanaka, H., Chida, J., Kido, H., Yamaji, K., Yamamoto, T., Nakano, H., Omura, S. and Inoue, H
    • Journal Title

      Mol. Carcinog.

      Volume: 印刷中

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Anti-oncogenic activities of cyclin D1b siRNA on human bladder cancer cells via induction of apoptosis and suppression of cancer cell stemness and invasiveness.2018

    • Author(s)
      Kim CJ, Terado T, Tambe Y, Mukaisho KI, Sugihara H, Kawauchi A, Inoue H.
    • Journal Title

      Int J Oncol.

      Volume: 52 Pages: 231-240

    • DOI

      10.3892/ijo.2017.4194

    • Related Report
      2018 Annual Research Report 2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Transplantation of iPS-derived tumor cells with a homozygous MHC haplotype induces GRP94 antibody production in MHC-matched macaques.2018

    • Author(s)
      Ishigaki, H., Maeda, T., Inoue, H., Akagi, T., Sasamura, T., Ishida, H., Inubushi, T., Okahara, J., Shiina, T., Nakamura, M., Otoh, Y., Ogasawara, K.
    • Journal Title

      Cancer Res.

      Volume: 印刷中 Issue: 21 Pages: 6001-6010

    • DOI

      10.1158/0008-5472.can-17-0775

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Periostin suppresses in vitro invasiveness via PDK1/Akt/mTOR signaling pathway in a orthotopic model of bladder cancer.2017

    • Author(s)
      Kim, C. J., Tambe, Y., Mukaisho, K., Sugihara, H., Kageyama, S., Kawauchi, A., Inoue, H.
    • Journal Title

      Oncology Letters

      Volume: 13 Issue: 6 Pages: 4276-4284

    • DOI

      10.3892/ol.2017.6004

    • Related Report
      2017 Research-status Report 2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Akt-dependent activation of Erk by cyclin D1b contributes to cell invasiveness and tumorigenicity.2016

    • Author(s)
      Kim CJ, Tambe Y, Mukaisho KI, Sugihara H, Kawauchi A, Inoue H.
    • Journal Title

      Oncology Letters

      Volume: 12 Issue: 6 Pages: 4850-4856

    • DOI

      10.3892/ol.2016.5286

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The drs tumor suppressor regulates glucose metabolism via lactate dehydrogenase-B.2015

    • Author(s)
      Tambe, Y., Hasebe, M., Kim, C. J., Yamamoto, A., Inoue, H.
    • Journal Title

      Molecular Carcinogenesis

      Volume: in press Issue: 1 Pages: 52-63

    • DOI

      10.1002/mc.22258

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Presentation] 新規PDK4阻害剤によるH-Rasと癌細胞性の抑制を介した膀胱癌に対する抗腫瘍活性2018

    • Author(s)
      金哲将、寺戸勅男、旦部幸博、中野洋文、河内明宏、井上寛一
    • Organizer
      第77回日本癌学会学術総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 膵臓癌におけるKRAS発現抑制を介した新規PDK4阻害剤Cryptotanshinoneの抗腫瘍活性2018

    • Author(s)
      旦部幸博、寺戸勅男、金哲将、中野洋文、向所賢一、杉原洋行、井上寛一
    • Organizer
      第77回日本癌学会学術総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] ヒト膵臓癌細胞株のin vivo造腫瘍能と癌幹細胞性に対するPDK4阻害剤の作用2017

    • Author(s)
      旦部幸博、寺戸勅雄、金哲将、中野洋文、向所賢一、杉原洋行、井上寛一
    • Organizer
      日本癌学会学術総会
    • Related Report
      2017 Research-status Report
  • [Presentation] Cyclin D1bによるアポトーシス誘導と癌幹細胞特性の抑制を介したヒト膀胱癌細胞に対する抗腫瘍活性の検討2017

    • Author(s)
      金哲将、寺戸勅雄、旦部幸博、向所賢一、杉原洋行、河内明宏、井上寛一
    • Organizer
      日本癌学会学術総会
    • Related Report
      2017 Research-status Report
  • [Presentation] ヒト膵臓癌細胞株に対するPDK4阻害剤の作用2016

    • Author(s)
      旦部幸博、金哲将、中野洋文、井上寛一
    • Organizer
      日本癌学会学術総会
    • Place of Presentation
      横浜
    • Year and Date
      2016-10-06
    • Related Report
      2016 Research-status Report
  • [Presentation] ヒト膀胱癌細胞株に対するCyclin D1b siRNAの抗腫瘍作用の検討2016

    • Author(s)
      金哲将、旦部幸博、河内明宏、井上寛一
    • Organizer
      日本癌学会学術総会
    • Place of Presentation
      横浜
    • Year and Date
      2016-10-06
    • Related Report
      2016 Research-status Report

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Published: 2016-04-21   Modified: 2020-03-30  

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