Molecular targeted cancer therapy with HDAC inhibitors

• Project/Area Number: 19590148
• 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 Keiichi Nagasaki University, 大学院・医歯薬学総合研究科, 准教授 (50252466)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2008: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2007: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: オーダーメード医療 / ヒストン脱アセチル化酵素阻害剤 / がん分子標的療法 / ERK / 活性酸素 / ERK-MAPキナーゼ / PI3キナーゼ / シグナル遮断剤 / vヒストン脱アセチル化酵素 / MEK阻害剤

Research Abstract

ERK-MAPキナーゼ経路という細胞増殖に必須な経路の異常かつ恒常的活性化のみられるがん細胞では、その経路遮断薬であるMEK阻害剤と新しい抗がん剤であるヒストン脱アセチル化酵素(HDAC)阻害剤との併用によって、相乗的な抗がん作用が発現する。その細胞死増強効果は、ミトコンドリア傷害と抗酸化酵素の発現抑制が連動し、致死的な活性酸素の蓄積に至ることで発現した。さらに、ヌードマウスに移植したヒト癌細胞に対しても、併用による相乗効果が劇的に認められ、これらは今後のHDAC阻害剤を用いた癌治療において重要な知見となる。

Research Products

• [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, Y. Inada, T. Kawabata, K. Iwashita, K. Ozaki and M. Kohno
  • Journal Title: Biochem. Biophys. Res. Commun 378 Pages: 650-655
  • Peer Reviewed
• [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
• [Journal Article] 細胞内シグナル伝達経路の選択的遮断を基盤としたがん治療戦略 (2008)
  • Author(s): 尾崎恵一, 谷村進, 河野通明
  • Journal Title: ファルマシア 44巻 Pages: 219-224
• [Journal Article] Histone deacetylase inhibitors enhance the chemosensitivity of tumor cells with cross-resistance to a wide range of DNA-damaging agents (2008)
  • Author(s): K. Ozaki, F. Futaba, M. Tanaka, T. Sakamoto, S. Tanimura and M. Kohno
  • Journal Title: Cancer Sci. 99 Pages: 376-384
  • Peer Reviewed
• [Journal Article] Histone deacetylase inhibitors enhance the chemosensitivity of tumor cells with cross-resistance to a wide range of DNA-damaging agents. (2008)
  • Author(s): Ozaki, K., et al.
  • Journal Title: Cancer Sci. 99 Pages: 376-384
  • Peer Reviewed
• [Journal Article] 細胞内シグナル伝達経路の選択的遮断を基盤としたがん治療戦略 (2008)
  • Author(s): 尾崎恵一, 他
  • Journal Title: ファルマシア 44 Pages: 219-224
• [Journal Article] Histone deacetylase inhibitors enhance the chemosensitivity of tumor cells with cross-resistance to a wide range of DNA-damaging agents (2008)
  • Author(s): Ozaki, K.
  • Journal Title: Cancer Sci. 99 Pages: 376-384
  • Peer Reviewed
• [Journal Article] Anticancerdrugs upregulate HspBP1 and therby antagonize the prosurvival function of Hsp70 in tumor cells (2007)
  • Author(s): S. Tanimura, A. Hirano, J. Hashizume, M. Yasunaga, T. Kawabata, K. Ozaki and M. Kohno
  • Journal Title: J. Biol. Chem 282 Pages: 35430-35439
  • Peer Reviewed
• [Journal Article] Blockade of the phosphatidylinositol-3-kinase Akt signaling pathway enhances induction of apoptosis by microtubule-destabilizing agents in tumor cells in which the pathway is constitutively activated (2007)
  • Author(s): Y. Fujiwara, Y. Hosokawa, K. Watanabe, S. Tanimura, K. Ozaki and M. Kohno
  • Journal Title: Mol. Cancer Ther 6 Pages: 1133-1142
  • Peer Reviewed
• [Journal Article] Targeted molecular strategies for cancer therapy based on the blockade of oncogenic pathways in human tumor cells (2007)
  • Author(s): K. Ozaki
  • Journal Title: J. Pharm. Soc.Japan 127 Pages: 983-991
  • Peer Reviewed
• [Journal Article] Targeted molecular strategies for cancer therapy based on the blockade of oncogenic pathways in human tumor cells (2007)
  • Author(s): Ozaki, K.
  • Journal Title: Yakugaku Zasshi 127 Pages: 983-991
  • Peer Reviewed
• [Journal Article] Blockade of the phosphatidylinositol-3-kinase-Akt signaling pathway enhances induction of apoptosis by microtubule-destabilizing agents in tumor cells in which the pathway is constitutively activated (2007)
  • Author(s): Fujiwara, Y.
  • Journal Title: Mol.Cancer Ther. 6 Pages: 1133-1142
  • Peer Reviewed
• [Presentation] Blockade of constitutively activated ERK signaling enhances cytotoxicity of HDAC inhibitors in tumor cells (2009)
  • Author(s): T. Sakamoto, K. Ozaki, N. Baba, K. Fujio, S. Tanimura, M. Kohno
  • Organizer: The Second Asian Symposium on Pharmaceutical Sciences in Nagasaki
  • Place of Presentation: 長崎
• [Presentation] PI3キナーゼ/Akt経路遮断剤とドキソルビシの併用による細胞死誘導増強 : セラミドの関与 (2008)
  • Author(s): 積佳江, 尾崎惠一, 坂野 喜子, 河野通明
  • Organizer: Biochemistry and Molecular Biology 2008
  • Place of Presentation: 神戸
• [Presentation] Molecular mechanisim via which solid tumors become chemoresistant under hypoxic conditions (2008)
  • Author(s): 尾崎恵一, 田中将人, 河野通明
  • Organizer: 第67回日本癌学会総会
  • Place of Presentation: 名古屋
• [Presentation] Molecular mechanism for the enhanced cell death induced by the combination of HDAC inhibitors and MEK inhibitors (2008)
  • Author(s): 坂元利彰, 尾崎恵一, 河野通明
  • Organizer: 第67回日本癌学会総会
  • Place of Presentation: 名古屋
• [Presentation] Molecular mechanism for the enhanced cell death induced by the combination of HDAC inhibitors and MEK inhibitors (2008)
  • Author(s): 坂元利彰, 他
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
• [Presentation] HDAC阻害剤とMEK阻害剤の併用による細胞死誘導の分子機構 (2007)
  • Author(s): 尾崎 恵一
  • Organizer: 第24回 日本薬学会九州支部大会
  • Place of Presentation: 福岡
  • Year and Date: 2007-12-08
• [Presentation] Effective chemotherapeutic strategies for the treatment of lung adenocarcinoma cells harboring EGFR mutation (2007)
  • Author(s): 尾崎 恵一
  • Organizer: 第65回 日本癌学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-05
• [Presentation] PI3キナーゼ/Akt経路遮断剤とドキソルビシの併用による細胞死誘導増強-セラミドの関与 (2007)
  • Author(s): 積佳江, 尾崎惠一, 河野通明
  • Organizer: 第24回日本薬学会九州支部大会
  • Place of Presentation: 福岡
• [Presentation] 低酸素環境下における癌細胞の抗癌剤耐性獲の分子機構 (2007)
  • Author(s): 田中将人, 尾崎惠一, 河野通明
  • Organizer: 第24回日本薬学会九州支部大会
  • Place of Presentation: 福岡
• [Presentation] HDAC阻害剤とMEK阻害剤の併用による細胞死誘導の分子機構 (2007)
  • Author(s): 坂元利彰, 馬場伸幸, 尾崎惠一, 河野通明
  • Organizer: 第24回日本薬学会九州支部大会
  • Place of Presentation: 福岡
• [Presentation] Effective chemotherapeutic strategies for the treatment of lung adenocarcinoma cells harboring EGFR mutation (2007)
  • Author(s): 尾崎惠一, 小杉正生, 坂元利彰, 河野通明
  • Organizer: 第66回日本癌学会総会
  • Place of Presentation: 横浜
• [Presentation] Targeting the ERK signaling pathway in cancer therapy (2007)
  • Author(s): 河野通明, 谷村進, 尾崎惠一
  • Organizer: 第66回日本癌学会総会
  • Place of Presentation: 横浜
• [Presentation] Blockade of the PI3K-Akt pathway selectively enhances induction of apoptosis by microtubule-destabilizing agents (2007)
  • Author(s): 藤原雄介, 渡邊一石, 谷村進, 尾崎惠一, 河野通明
  • Organizer: 第66回日本癌学会総会
  • Place of Presentation: 横浜