Studies on cytostatic antitumor mechanism by a new PI3K inhibitor ZSTK474

• Project/Area Number: 20790087
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Biological pharmacy
• Research Institution: Japanese Foundation For Cancer Research
• Principal Investigator: DAN Shingo Japanese Foundation For Cancer Research, 分子薬理部, 研究員 (70332202)
• Project Period (FY): 2008 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2009: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2008: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: PI3K / DNAチップ / 細胞周期 / アポトーシス / 抗がん剤

Research Abstract

We demonstrated that PI3K inhibitors including ZSTK474 did not induce apoptosis but G_0/G_1 arrest of cell cycle in cancer cell lines with PIK3CA/PTEN aberrations in vitro. In parallel, PI3K inhibitors exhibited their antitumor effect without inducing apoptosis in vivo. We examined gene expression changes after treatment of cancer cells with ZSTK474 by using GeneChip, and found induction of CDK inhibitor p15 and repression of CDC25A after ZSTK474 treatment. These changes would be involved in G_0/G_1 arrest of cell cycle.

Research Products

• [Journal Article] Correlating PI3K inhibitor efficacy with signaling pathway status: in silico and biological evaluations (2010)
  • Author(s): Dan S, Okamura M, Seki M, Yamazaki K, Sugita H, Okui M, Mukai Y, Nishimura H, Asaka R, Nomura K, Ishikawa Y, Yamori T.
  • Journal Title: Cancer Res. 70(12) Pages: 4982-94
• [Journal Article] Inhibition profiles of phosphatidyl inositol 3-kinase inhibitors against PI3K superfamily and human cancer cell line panel JFCR39 (2010)
  • Author(s): Kong D, Dan S, Yamazaki K, Yamori T.
  • Journal Title: Eur. J. Cancer 46(6) Pages: 1111-21
• [Journal Article] Correlating PI3K inhibitor efficacy with signaling pathway status : in silico and biological evaluations (2010)
  • Author(s): Dan S, Okamura M, Seki M, Yamazaki K, Sugita H, Okui M, Mukai Y, Nishimura H, Asaka R, Nomura K, Ishikawa Y, Yamori T.
  • Journal Title: Cancer Res (in press)
  • Peer Reviewed
• [Journal Article] Inhibition profiles of phosphatidylinositol 3-kinase inhibitors against PI3K superfamily and human cancer cell line panel JFCR39 (2010)
  • Author(s): Kong D, Dan S, Yamazaki K, Yamori T.
  • Journal Title: Eur J Cancer 46(6) Pages: 1111-21
  • Peer Reviewed
• [Journal Article] Inhibition of PI3K by ZSTK474 suppressed tumor growth not via apoptosis but G0/G1 arrest (2009)
  • Author(s): Dan S, Yoshimi H, Okamura M, Mukai Y, Yamori T.
  • Journal Title: Biochem. Biophys. Res. Commun 379(1) Pages: 104-9
• [Journal Article] Identification of Candidate Genes Determining Chemosensitivity to Anti-cancer Drugs of Gastric Cancer Cell Lines (2009)
  • Author(s): Nakamura T, Nakatsu N, Yoshida Y, Yamazaki K, Dan S, Sadahiro S, Makuuchi H, Yamori T.
  • Journal Title: Biol. Pharm. Bull. 32(11) Pages: 1936-9
  • NAID: 130000116973
• [Journal Article] Inhibition of PI3K by ZSTK474 suppressed tumor growth not via apoptosis but G0/G1 arrest (2009)
  • Author(s): Dan S, Yoshimi H, Okamura M, Mukai Y, Yamori T.
  • Journal Title: Biochem Biophys Res Commun 379(1) Pages: 104-9
  • Peer Reviewed
• [Journal Article] Identification of Candidate Genes Determining Chemosensitivity to Anticancer Drugs of Gastric Cancer Cell Lines (2009)
  • Author(s): Nakamura T, Nakatsu N, Yoshida Y, Yamazaki K, Dan S, Sadahiro S, Makuuchi H, Yamori T.
  • Journal Title: Biol Pharm Bull 32(11) Pages: 1936-9
  • Peer Reviewed
• [Journal Article] Inhibition of PI3K by ZSTK474 suppressed tumor growth not via apoptosis but GO/G1 arrest. (2009)
  • Author(s): Dan S, Yoshimi H, Okamura M, Mukai Y, Yamori T.
  • Journal Title: Biochemical and biophysical research communications 379(1) Pages: 104-9
  • Peer Reviewed
• [Journal Article] A new evaluation method for quantifying PI3K activity by HTRF assay (2008)
  • Author(s): Sugita H, Dan S, Kong D, Tomida A, Yamori T.
  • Journal Title: Biochem. Biophys. Res. Commun 377(3) Pages: 941-5
• [Journal Article] Anew evaluation method for quantifying PI3K activity by HTRF assay. (2008)
  • Author(s): Sugita H, Dan S, Kong D, Tomida A, Yamori T.
  • Journal Title: Biochemical and biophysical research communications 377(3) Pages: 941-5
  • Peer Reviewed
• [Presentation] Correlation between efficacy of PI3K inhibitors and aberration of PI3K3CA/PTEN in a panel of 39 human cancer cell lines (JFCR39) (2010)
  • Author(s): Dan S, Sugita H, Seki M, Mukai Y, Yamazaki K, Ishikawa Y, Yamori T.
  • Organizer: The 8th AACR/JCA joint conference
  • Place of Presentation: Hawaii, USA
• [Presentation] Correlation between efficacy of PI3K inhibitors and aberration of PI3K3CA/PTEN in a panel of 39 human cancer cell lines(JFCR39) (2010)
  • Author(s): Dan S, Sugita H, Seki M, Mukai Y, Yamazaki K, Ishikawa Y, Yamori T.
  • Organizer: The 8^<th> AACR/JCA Joint Conference
  • Place of Presentation: Hawaii, USA
• [Presentation] PI3K阻害剤の変異型PI3Kへの効果 (2009)
  • Author(s): 旦慎吾、山崎佳波、矢守隆夫
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2009-10-01
• [Presentation] PI3キナーゼ阻害剤の変異型PI3キナーゼへの効果 (2009)
  • Author(s): 旦慎吾、山崎佳波、矢守隆夫
  • Organizer: 第13回日本がん分子標的治療学会学術集会
  • Place of Presentation: 徳島
  • Year and Date: 2009-06-26
• [Presentation] Efficary of PI3K inhibitors to PI3K mutants in enzyme and cell levels (2009)
  • Author(s): 旦慎吾、杉田裕宣、山崎佳波、矢守隆夫
  • Organizer: AACR Annual Meeting
  • Place of Presentation: Denver, USA
  • Year and Date: 2009-04-21
• [Presentation] Efficacy of PI3K inhibitors to PI3K mutants in enzyme and cell levels (2009)
  • Author(s): Dan S, Sugita H, Yamazaki K, Yamori T.
  • Organizer: AACR Annual Meeting
  • Place of Presentation: Denver, USA
• [Presentation] Efficacy of PI3K inhibitors to cancer cells with PIK3CA mutation or loss of PTEN expression (2009)
  • Author(s): Dan S, Sugita H, Seki M, Mukai Y, Yamazaki K, Ishikawa Y, Yamori T.
  • Organizer: The 21th AACR-NCI- EORTC symposium
  • Place of Presentation: Boston, USA
• [Presentation] JFCR39 COMPARE system can predict molecular targets of phophatidylinositol 3-kinase inhibitors with high resolution (2009)
  • Author(s): Kong D, Dan S, Yamazaki K, Yamori T.
  • Organizer: The 21th AACR-NCI-EORTC symposium
  • Place of Presentation: Boston, USA
• [Presentation] PI3キナーゼ阻害剤の変異型PI3キナーゼへの効果 (2009)
  • Author(s): 旦慎吾、山崎佳波、矢守隆夫
  • Organizer: 第13回日本がん分子標的治療学会
  • Place of Presentation: 徳島
• [Presentation] PI3キナーゼ阻害剤ZSTK474の変異型PI3キナーゼへの効果 (2009)
  • Author(s): 旦慎吾、杉田裕宣、山崎佳波、矢守隆夫
  • Organizer: 第25回日本DDS学会
  • Place of Presentation: 東京
• [Presentation] PI3K阻害剤の変異型PI3Kへの効果 (2009)
  • Author(s): 旦慎吾、山崎佳波、矢守隆夫
  • Organizer: 第68回日本癌学会
  • Place of Presentation: 横浜
• [Presentation] JFCR39 COMPARE system can predict molecular targets of phophatidyl inositol 3-kinase inhibitors with high resolution (2009)
  • Author(s): Kong D, Dan S, Yamazaki K, Yamori T.
  • Organizer: The 21th EORTC-NCI-AACR Symposium
  • Place of Presentation: Boston, USA
• [Presentation] Efficacy of PI3K inhibitors to cancer cells with PIK3CA mutation or loss of PTEN expression (2009)
  • Author(s): Dan S, Sugita H, Seki M, Mukai Y, Yamazaki K, Ishikawa Y, Yamori T.
  • Organizer: The 21th EORTC-NCI-AACR Symposium
  • Place of Presentation: Boston, USA
• [Presentation] PI3キナーゼ阻害剤ZSTK474の変異型PI3キナーゼへの効果 (2009)
  • Author(s): 旦慎吾、杉田裕宣、山崎佳波、矢守隆夫
  • Organizer: 第25回日本DDS学会学術集会
  • Place of Presentation: 東京
• [Presentation] ZSTK474, a novel PI3K inhibitor, down-regulates CDC25A and induces G1 phase cell cycle arrest in human cancer cells (2008)
  • Author(s): Dan S, Mukai Y, Yaguchi S, Yamori T.
  • Organizer: The 100-th Am Assoc Cancer Res (AACR) Annual Meeting
  • Place of Presentation: San Diego, CA, USA
• [Presentation] 新規PI3キナーゼ阻害剤ZSTK474によるG1アレスト誘導 (2008)
  • Author(s): 旦慎吾, 向井由美子, 矢口信一, 矢守隆夫
  • Organizer: 第12回がん分子標的治療研究会
  • Place of Presentation: 東京
• [Presentation] HTRFアッセイを用いた定量的なPI3キナーゼ活性測定法の構築 (2008)
  • Author(s): 杉田裕宣, 旦慎吾, 孔徳新, 矢守隆夫
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
• [Presentation] 新規PI3K阻害剤ZSTK474による抗腫瘍メカニズムの解析 (2008)
  • Author(s): 旦慎吾, 向井由美子, 岡村睦美, 吉見直, 矢口信一, 矢守隆夫
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
• [Presentation] インピーダンスによるリアルタイム細胞増殖測定法の開発 (2008)
  • Author(s): 小林雅明, 旦慎吾, 大橋愛美, 矢守隆夫
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
• [Presentation] ZSTK47, a novel PI3K infibitor, down-regulates CDC25A and induces G1 phase cell cycle arrest in fuman cancer cells. (2008)
  • Author(s): Dan S, Mukai Y, YaguchiS, Yamori T.
  • Organizer: The100-th Am Assoc Cancer Res (AACR) Annual Meeting.
  • Place of Presentation: San Diego, CA, USA
• [Presentation] 新規PI3キナーゼ阻害剤ZSTK474によるG1アレスト誘導. (2008)
  • Author(s): 旦慎吾,向井由美子,矢口信一,矢守隆夫
  • Organizer: 第12回がん分子標的治療研究会
  • Place of Presentation: 東京
• [Presentation] HTRFアッセイを用いた定量的なPI3キナーゼ活性測定法の構築. (2008)
  • Author(s): 杉田裕宣,旦慎吾,孔徳新,矢守隆夫.
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
• [Presentation] 新規PI3キナーゼ阻害剤ZSTK474による抗腫瘍メカニズムの解析. (2008)
  • Author(s): 旦慎吾,向井由美子,岡村睦美,吉見直,矢口信一,矢守隆夫.
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
• [Presentation] インピーダンスによるリアルタイム細胞増殖測定法の開発. (2008)
  • Author(s): 小林雅明,旦慎吾,大橋愛美,矢守隆夫.
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
• [Book] Cancer Cell Informaticsと分子標的薬剤 (2008)
  • Author(s): 旦慎吾, 矢守隆夫
  • Publisher: 南山堂
• [Book] がんの分子標的治療 Cancer Cell Informaticsと分子標的薬剤. (2008)
  • Author(s): 旦慎吾,矢守隆夫.
  • Total Pages: 441
  • Publisher: 南山堂