Basic research on personalized treatment of cancer by HDAC inhibitors

• Project/Area Number: 21590166
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Medical pharmacy
• Research Institution: Nagasaki University
• Principal Investigator: OZAKI Kei-ichi 長崎大学, 大学院・医歯薬学総合研究科, 准教授 (50252466)
• Research Collaborator: 坂元 利彰 , 大学院生 ; 藤尾 康祐 , 大学院生 ; 梶川 修平 , 大学院生
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2011: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2010: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2009: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: オーダーメード医療 / HDAC / 活性酸素 / ERK1/2 / アポトーシス / がん / HDAC阻害 / ERK / MEK阻害剤 / Bim / Thioredoxin / HDAC阻害剤 / ERK経路 / PI3キナーゼ / Rb / 活性酸素種 / ミトコンドリア

Research Abstract

Histone deacetylase(HDAC) inhibitors which are promising anti-tumor agents have high selectivity to the cancer cell in which the ERK-MAP kinase pathway is constitutively activated. The molecular mechanism which results in remarkable HDAC inhibitor sensitivity by blockade of this pathway with MEK inhibitors was clarified. Moreover, in vitro and the animal experiment with xenograft model proved that it is effective also in the cancers which are resistant to some molecular-targeted drugs such as tyrosine kinase inhibitors. It is expected that these results will be useful for the personalized treatment of cancer by HDAC inhibitors.

Research Products

• [Journal Article] Targeting the extracellular signal-regulated kinase pathway in cancer therapy (2011)
  • Author(s): M. Kohno, S. Tanimura, and K. Ozaki
  • Journal Title: Biol. Pharm. Bull Volume: 34 Pages: 1781-1784
• [Journal Article] Targeting the Extracellular Signal-Regulated Kinase Pathway in Cancer Therapy (2011)
  • Author(s): Kohno M., Tanimura S., Ozaki K.
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 34 Issue: 12 Pages: 1781-1784
  • DOI: 10.1248/bpb.34.1781
  • NAID: 130001872595
  • ISSN: 0918-6158, 1347-5215
  • Peer Reviewed
• [Journal Article] Blockade of the extracellular signal-regulated kinase pathway enhances the therapeutic efficacy of microtubule-destabilizing agents in human tumor xenograft models (2010)
  • Author(s): K. Watanabe, S. Tanimura, A. Uchiyama, T. Sakamoto, T. Kawabata, K. Ozaki, and M. Kohno
  • Journal Title: Clin. Cancer Res Volume: 16 Pages: 1170-1178
• [Journal Article] Blockade of the ERK or PI3K-Akt pathway enhances the cytotoxicity of histone deacetylase inhibitors in tumor cells resistant to gefitinib or imatinib (2010)
  • Author(s): K. Ozaki, M. Kosugi, N. Baba, T. Sakamoto, K. Fujio, S. Kimura and M. Kohno
  • Journal Title: Biochem. Biophys. Res. Commun Volume: 391 Pages: 1610-1615
• [Journal Article] Blockade of the ERK or PI3K-Akt signaling pathway enhances the cytotoxicity of histone deacetylase inhibitors in tumor cells resistant to gefitinib or imatinib. (2010)
  • Author(s): Ozaki, K., et al.
  • Journal Title: Biochem. Biophys. Res.Commun. 391 Pages: 1610-1615
  • Peer Reviewed
• [Journal Article] Blockade of the extracellular signal-regulated kinase pathway enhances the therapeutic efficacy of microtubule-destabilizing agents in human tumor xenograft models. (2010)
  • Author(s): Watanabe, K., et al.
  • Journal Title: Clin.Cancer Res. 16 Pages: 1170-1178
  • Peer Reviewed
• [Journal Article] Blockade of constitutively activated ERK signaling enhances cytotoxicity of microtubule-destabilizing agents in tumor cells (2009)
  • Author(s): S. Tanimura, A. Uchiyama, K. Watanabe, M. Yasunaga, T. Kawabata, K. Ozaki and M. Kohno
  • Journal Title: Biochem. Biophys. Res. Commun Volume: 378 Pages: 650-655
• [Journal Article] Blockade of constitutively activated ERK signaling enhances cytotoxicity of microtubule-destabilizing agents in tumor cells. (2009)
  • Author(s): Tanimura, S., et al.
  • Journal Title: Biochem. Biophys. Res.Commun. 378 Pages: 650-655
  • Peer Reviewed
• [Presentation] ERK経路の活性化及びp53遺伝子型とHDAC阻害剤感受性の相関 (2011)
  • Author(s): 梶川修平、坂元利彰、尾崎惠一
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜(横浜)
  • Year and Date: 2011-12-14
• [Presentation] HC-toxin and PD184352 synergistically up-regulate Bim and TBP-2 to induce the enhanced ROS accumulation and cell death (2011)
  • Author(s): 尾崎惠一、藤尾康祐、河野通明
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場(名古屋)
  • Year and Date: 2011-10-03
• [Presentation] HC-toxin and PD184352 synergistically up-regulate Bim and TBP-2 to induce the enhanced ROS accumulation and cell death (2011)
  • Author(s): K, Ozaki, K, Fujio, T, Sakamoto, S, Kajikawa, and M, Kohno
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
• [Presentation] ERK経路の活性化及びp53遺伝子型とHDAC阻害剤感受性の相関 (2011)
  • Author(s): 梶川修平, 坂元利彰, 尾崎惠一, 河野通明
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 横浜
• [Presentation] HDAC阻害剤とMEK阻害剤の併用による細胞死誘導増強-FOXO転写因子ファミリーの役割- (2010)
  • Author(s): 藤尾康祐, 梶川修平, 坂元利彰, 尾崎恵一, 河野通明
  • Organizer: 第27回日本薬学会九州支部大会
  • Place of Presentation: 長崎
  • Year and Date: 2010-12-11
• [Presentation] Blockade of the ERK pathway enhances the therapeutic efficacy of HDAC inhibitors in human tumor xenograft models. (2010)
  • Author(s): 坂元利彰, 藤尾康祐, 梶川修平, 上里新一, 尾崎恵一, 河野通明
  • Organizer: 第68回日本癌学会総会
  • Place of Presentation: 大阪
  • Year and Date: 2010-09-22
• [Presentation] がん細胞におけるERK経路活性化とHDAC阻害剤感受性の相関 (2010)
  • Author(s): 梶川修平, 坂元利彰, 藤尾康祐, 尾崎惠一, 河野通明
  • Organizer: 第9回次世代を担う若手ファーマ・バイオフォーラム2010
  • Place of Presentation: 京都
• [Presentation] Blockade of the ERK pathway enhances the therapeutic efficacy of HDAC inhibitors in human tumor xenograft models (2010)
  • Author(s): T. Sakamoto, K. Fujio, S. Kajikawa, S. Uesato, K. Watanabe, S. Tanimura, K. Ozaki, M. Kohno
  • Organizer: 第69回日本癌学会学術総会
  • Place of Presentation: 大阪
• [Presentation] HDAC阻害剤とMEK阻害剤の併用による細胞死誘導増強-FOXO転写因子ファミリーの役割 (2010)
  • Author(s): 藤尾康祐, 梶川修平, 坂元利彰, 尾崎惠一, 河野通明
  • Organizer: 第27回日本薬学会九州支部大会
  • Place of Presentation: 長崎
• [Presentation] HDAC阻害剤とMEK阻害剤の併用による細胞死増強の分子機構 (2009)
  • Author(s): 坂元利彰、尾崎恵一, 他
  • Organizer: 日本アポトーシス研究会
  • Place of Presentation: 長崎
  • Year and Date: 2009-08-02
• [Presentation] HDAC阻害剤とMEK阻害剤の併用による細胞死増強の分子機構 (2009)
  • Author(s): 坂元利彰, 尾崎惠一, 馬場伸幸, 藤尾康祐, 梶川修平, 河野通明
  • Organizer: 第18回日本アポトーシス研究会学術集会
  • Place of Presentation: 長崎
• [Presentation] MEK阻害剤とHDAC阻害剤の併用による抗腫瘍効果増強-xenograftでの検討 (2009)
  • Author(s): 坂元利彰, 藤尾康祐, 梶川修平, 尾崎惠一, 河野通明
  • Organizer: 第26回日本薬学会九州支部大会
  • Place of Presentation: 福岡
• [Presentation] イマチニブ抵抗性Bcr-Abl変異(T315I)白血病細胞に対する効果的治療法の開発 (2009)
  • Author(s): 馬場伸幸, 尾崎惠一, 河野通明
  • Organizer: 第26回日本薬学会九州支部大会
  • Place of Presentation: 福岡