緑茶カテキンＥＧＣＧをリード化合物とするがん幹細胞を殺傷する新規化合物の作製

• Project/Area Number: 14J30004
• Research Category: Grant-in-Aid for JSPS Fellows
• Allocation Type: Single-year Grants
• Section: 国内
• Research Field: Applied molecular and cellular biology
• Research Institution: Kyushu University
• Principal Investigator: 熊添 基文 九州大学, 農学研究院, 特別研究員(PD)
• Project Period (FY): 2014-04-25 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: がん / ケミカルバイオロジー / がん幹細胞 / ポリフェノール / EGCG / cGMP / 膵臓癌 / がん細胞 / 天然物

Outline of Annual Research Achievements

緑茶ポリフェノールであるEGCGのすい臓がん幹細胞性に対する影響をスフェロイドアッセイやコロニーアッセイ、及び動物実験に基づき評価を行い、高濃度のEGCGはがん幹細胞性を阻害することを見出した。さらに、その作用機構についてがん幹細胞の枢要とされるCD44の分解を誘導することを見出した。これまで、CD44を阻害する戦略としては発現レベルの阻害や、抗体による阻害がほとんどであり、CD44の分解を誘導する戦略は報告されていない。そこで予想される作用機構を活性化させるactivator を用いてマイクロアレイに基づく網羅的探索を行った結果、これまでがん抑制遺伝子と報告されていた分子、FOXO3ががん幹細胞性に重要であることを見出し、論文に掲載された(Kumazoe et al. Oncogene 2016)。また、EGCGの67LRアゴニストとしての作用を強化した誘導体を用いたところ、強力ながん幹細胞性阻害作用を見出し、論文に掲載された (Kumazoe et al. Scientific Reports 2017 in press)。

Research Progress Status

28年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

28年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] PDE3 inhibitor and EGCG combination treatment suppress cancer stem cell properties in pancreatic ductal adenocarcinoma (2017)
  • Author(s): Kumazoe, M. Takai, M. Hiroi, S. Takeuchi, C. Yamanouchi, M. Nojiri, T. Onda, H, Bae J, Huang, Y, Takamatsu, K. Yamashita, S. Yamada, S. Kangawa, S. Takahashi, T. Tanaka, H. and Tachibana, H.
  • Journal Title: Scientific Reports Volume: -
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] SphK1 inhibitor potentiates the anti-cancer effect of EGCG on leukaemia cells (2016)
  • Author(s): S. Tsukamoto, M. Kumazoe, Y. Huang, C. Lesnick, N.E. Kay, T.D. Shanafelt, H. Tachibana
  • Journal Title: British Journal of Haematology Volume: -
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] FOXO3 is essential for CD44 expression in pancreatic cancer cells (2016)
  • Author(s): M. Kumazoe, M. Takai, J. Bae, S. Hiroi, Y. Huang, K. Takamatsu, Y. Won, M. Yamashita, S. Hidaka, S. Yamashita, S. Yamada, M. Murata, S. Tsukamoto, H. Tachibana
  • Journal Title: Oncogene Volume: -
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] SphK1 inhibitor potentiates the anti-cancer effect of EGCG on leukaemia cells (2016)
  • Author(s): Tsukamoto M, Kumazoe M et al (equol contribution)
  • Journal Title: Br. J. Haematol.
  • Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Green tea polyphenol epigallocatechin-O-gallate induces cell death by acid sphingomyelinase activation in chronic myeloid leukemia cells. (2015)
  • Author(s): Huang Y., Kumazoe M. et. al.(equal contribution)
  • Journal Title: Oncology Reports Volume: 34 Issue: 3 Pages: 1162-1168
  • DOI: 10.3892/or.2015.4086
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Metabolic Profiling-based Data-mining for an Effective Chemical Combination to Induce Apoptosis of Cancer Cells. (2015)
  • Author(s): Kumazoe M, Fujimura Y, Hidaka S, Kim Y, Murayama K, Takai M, Huang Y, Yamashita S, Murata M, Miura D, Wariishi H, Maeda-Yamamoto M, Tachibana H.
  • Journal Title: Sci Rep. Volume: 31 Issue: 1 Pages: 9474-9474
  • DOI: 10.1038/srep09474
  • Peer Reviewed / Open Access
• [Journal Article] Metabolic Profiling-based Data-mining for an Effective Chemical Combination to Induce Apoptosis of Cancer Cells (2015)
  • Author(s): Kumazoe M, Fujimura Y, Hidaka S, Kim Y, Murayama K, Takai M, Huang Y, Yamashita S, Murata M, Miura D, Wariishi H, Maeda-Yamamoto M, Tachibana H.
  • Journal Title: Sci. Rep. Volume: 5
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Vardenafil, a clinically available phosphodiesterase inhibitor, potentiates the killing effect of EGCG on CLL cells. (2014)
  • Author(s): Kumazoe, M., Tsukamoto, S., Lesnick, C., Kay, N. E. Yamada, K., Shanafelt T. D. and Tachibana, H.
  • Journal Title: Br. J. Haematol. Volume: 168 Issue: 4 Pages: 610-613
  • DOI: 10.1111/bjh.13135
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Vardenafil, a clinically available phosphodiesterase inhibitor, potentiates the killing effect of EGCG on CLL cells (2014)
  • Author(s): Kumazoe M, Tsukamoto S, Lesnick C, Kay NE, Yamada K, Shanafelt TD, Tachibana H.
  • Journal Title: Br. J. Haematol. Volume: 168 Pages: 610-613
  • Peer Reviewed / Open Access
• [Presentation] 緑茶カテキン感知レセプターを介したがん細胞致死機構の解明 (2014)
  • Author(s): 熊添基文、山田耕路、立花宏文
  • Organizer: レドックス・ライフイノベーション第170委員会
  • Place of Presentation: 宮崎
  • Year and Date: 2014-08-22
  • Invited