PI3キナーゼを分子標的にした新たな治療戦略の開発

• Project/Area Number: 18015049
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Japanese Foundation For Cancer Research
• Principal Investigator: 矢守 隆夫 Japanese Foundation For Cancer Research, 癌化学療法センター・分子薬理部, 部長 (60200854)
• Co-Investigator(Kenkyū-buntansha): 旦 慎吾 癌化学療法センター, 分子薬理部, 研究員 (70332202)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥10,100,000 (Direct Cost: ¥10,100,000); Fiscal Year 2007: ¥5,100,000 (Direct Cost: ¥5,100,000); Fiscal Year 2006: ¥5,000,000 (Direct Cost: ¥5,000,000)
• Keywords: Cancer Cell Informatics / 分子標的予測 / がん / がん細胞パネル / PI3K / 薬剤感受性 / 抗がん剤探索 / データーベース / データベース

Research Abstract

1.ZSTK474の分子機序の解析およびその効果増強法の開発
ZSTK474は種々のがん細胞にG_0/G_lアレストを誘導したが、アポトーシスは起こさなかった。ZSTK474によるG_0/G_1アレストの分子機構を解析するために、平成18年度までにZSTK474曝露前後の遺伝子発現変動をGeneChipを用いて解析した。その結果、CDC25Aの発現抑制と、CDKN2Bの発現誘導を同定した。本年度は、これらの遺伝子について詳しい解析を進めた。ウェスタンブロットにより、ZSTK474暴露後3h以内にCDC25A蛋白質の発現が減少したこと、CDC25Aの減少に伴いその脱リン酸化基質であるCDK2蛋白質のリン酸化体が一過的に増加し、核内CDK2が減少したことを示した。また、CDKN2B遺伝子産物であるp15Ink4Bの発現が上昇し、リン酸化pRB蛋白質の減少が認められた。以上のことから、これらの遺伝子の発現変動が協調的に働いてG_0/G_1アレストを誘導しているものと示唆された。
2.PI3K触媒サブユニットサブタイプの機能解析と特異的阻害剤の探索
平成18年度までに確立したPI3K触媒サブユニットα・β・γ・δの各サブタイプの絶対定量法を利用して、39種類のヒト固形がん細胞株JFCR39での発現レベルを測定した。その結果、α・βは予想通りユビキタスに発現していた。一方、γ・δアイソフォームは造血系細胞で特異的に発現するとされているが、今回、これらが複数の固形がん細胞株で有意に発現していることが判明した。このことから、γ・δアイソフォームのがんへの関与が示唆された。

Research Products

• [Journal Article] Synthesis of hybrid acetogenins, alpha, beta-unsaturated-gamma-lactone-free nitrogen-containing heterocyclic analogues, and their cytotoxicity against human cancer cell lines. (2008)
  • Author(s): Kojima N, Fushimi T, Maezaki N, Tanaka T, Yamori T.
  • Journal Title: Bioorg Med Chem Lett. (in press)
  • Peer Reviewed
• [Journal Article] Synthesis and pharmacological evaluation of the novel pseudo-symmetric al tamoxifen derivatives as anti-tumor agents. (2008)
  • Author(s): Shiina I, Sano Y, Nakata K, Kiku chi T, Sasaki A, Ikekita M, Nagahara Y, Hasome Y, Yamori T, Yamazaki K.
  • Journal Title: Biochem Pharmacol 75(5) Pages: 1014-26
  • Peer Reviewed
• [Journal Article] Motif-programmed artificial protein induces apoptosis in several cancer cells by disrupting mitochondria. (2008)
  • Author(s): Saito H, Minamisawa T, Yamori T, Shiba K.
  • Journal Title: Cancer Sci. 99(2) Pages: 398-406
  • NAID: 10024002827
  • Peer Reviewed
• [Journal Article] Anticancer mechanisms of YC-1 in human lung cancer cell line, NCI-H226. (2008)
  • Author(s): Chen CJ, Hsu MH, Huang LJ, Yamori T, Chung JG, Lee FY, Teng CM, Kuo SC.
  • Journal Title: Biochem Pharmacol 75(2) Pages: 360-8
  • Peer Reviewed
• [Journal Article] Proteomics-based identification of biomarkers for predicting sensitivi ty to a PI3-kinase inhibitor in cancer. (2007)
  • Author(s): Akashi T, Nishimura Y, Wakatabe R, Shiwa M, Yamori T.
  • Journal Title: Biochemical and biophysical research communicatio ns 352(2) Pages: 514-21
  • Peer Reviewed
• [Journal Article] A novel method for analyzing phosphoproteins using SELDI-TOF MS in com bination with a series of recombinant proteins. (2007)
  • Author(s): Akashi T, Yamori T.
  • Journal Title: Proteomics 7(14) Pages: 2350-4
  • Peer Reviewed
• [Journal Article] Variation in cytostatic constituents of a sponge-derived Gymnascella dankaliensis by manipulating the carbon source. (2007)
  • Author(s): Amagata T, Tanaka M, Yamada T, Doi M, Minoura K, Ohishi H, Yamori T, Numata A.
  • Journal Title: Journal of natural products 70(11) Pages: 1731-40
  • Peer Reviewed
• [Journal Article] Enantioselective Total Synthesis of (+)-〇ttelione A, (-)-〇ttelione B, (+)-3-epi-Ottelione A and Preliminary Evaluation of Their Antitumor Activity. (2007)
  • Author(s): Araki H, Inoue M, Suzuki T, Yamori T, Kohno M, Watanabe K, Abe H, Katoh T.
  • Journal Title: Chemistry 13(35) Pages: 9866-81
  • Peer Reviewed
• [Journal Article] Synthesis and structure-activity relationships of taxuyunnanine C derivatives as multidrug resistance modulator in MDR cancer cells. (2007)
  • Author(s): Hasegawa T, Bai J, Dai J, Bai L, Sakai J, Nishizawa S, Bai Y, Kikuchi M, Abe M, Yamori T, Tomida A, Tsuruo T, Hirose K, Ando M.
  • Journal Title: Bioorganic & medicinal chemistry letters 17(13) Pages: 3722-8
  • Peer Reviewed
• [Journal Article] Application of in vivo ESR/spin-probe technique to monitor tumor in vivo in mouse footpad. (2007)
  • Author(s): Ichikawa K, Sakabe E, Kuninobu K, Yamori T, Tsuruo T, Yao T, Tsuneyoshi M, Utsumi H.
  • Journal Title: Antioxidants & redox signaling 9(10) Pages: 1699-707
  • Peer Reviewed
• [Journal Article] Comparative profiling of the gene expression for estrogen responsiveness in cultured human cell lines. (2007)
  • Author(s): Inoue A, Seino Y, Terasaka S, Hayashi S, Yamori T, Tanji M, Kiyama R.
  • Journal Title: Toxicol In Vitro 21(4) Pages: 741-52
  • Peer Reviewed
• [Journal Article] Development and characterization of a model of liver metastasis using human colon cancer HCT-116 cells. (2007)
  • Author(s): Ishizu K, Sunose N, Yamazaki K, Tsuruo T, Sadahiro S, Makuuchi H, Yamori T.
  • Journal Title: Biological & pharmaceutical bulletin 30(9) Pages: 1779-83
  • NAID: 110006380268
  • Peer Reviewed
• [Journal Article] Marine diterpenoids with a briarane skeleton from the Okinawan soft coral Pachyclavularia violacea. (2007)
  • Author(s): Ito H, Iwasaki J, Sato Y, Aoyagi M, Iguchi K, Yamori T.
  • Journal Title: Chemical & pharmaceutical bulletin 55(12) Pages: 1671-6
  • NAID: 110006532106
  • Peer Reviewed
• [Journal Article] ZSTK474 is an ATP-competitive inhibitor of class I phosphatidylinositol 3 kinase isoforms. (2007)
  • Author(s): Kong D, Yamori T.
  • Journal Title: Cancer science 98(10) Pages: 1638-42
  • NAID: 10019997789
  • Peer Reviewed
• [Journal Article] Sesquiterpenoids and flavonoids from the aerial parts of Tithonia diversifolia and their cytotoxic activity. (2007)
  • Author(s): Kuroda M, Yokosuka A, Kobayashi R, Jitsuno M, Kando H, Nosaka K, Ishii H, Yamori T, Mimaki Y.
  • Journal Title: Chemical & pharmaceutical bulletin 55(8) Pages: 1240-4
  • NAID: 110006366547
  • Peer Reviewed
• [Journal Article] Urukthapelstatin A, a novel cytotoxic substance from marine-derived Mechercharimyces asporophorigenens YM11-542. I. Fermentation, isolation and biological activities. (2007)
  • Author(s): Matsuo Y, Kanoh K, Yamori T, Kasai H, Katsuta A, Adachi K, Shin- Ya K. Shizuri Y.
  • Journal Title: The Journal of antibiotics 60(4) Pages: 251-5
  • Peer Reviewed
• [Journal Article] A novel candidate compound with urethane structure for anticancer drug development. (2007)
  • Author(s): Matsuoka A, Isama K, Tanimura S, Kohno M, Yamori T.
  • Journal Title: Current drug discovery technologies 4(2) Pages: 69-76
  • Peer Reviewed
• [Journal Article] Absolute quantification of four isoforms of the class I phosphoinositide-3-kinase catalytic subunit by real-time RT-PCR. (2007)
  • Author(s): Nakamura H, Dan S, Akashi T, Unno M, Yamori T.
  • Journal Title: Biological & pharmaceutical bulletin 30(6) Pages: 1181-4
  • NAID: 110006278417
  • Peer Reviewed
• [Journal Article] Evaluation of Action Mechanisms of Toxic Chemicals Using JFCR39, a Panel of Human Cancer Cell Lines. (2007)
  • Author(s): Nakatsu N, Nakamura T, Yamazaki K, Sadahiro S, Makuuchi H, Kanno J, Yamori T.
  • Journal Title: Mol Pharmacol 72(5) Pages: 1171-80
  • Peer Reviewed
• [Journal Article] Identification of JTP-70902, a p15(INK4b)-inductive compound, as a novel MEKI/2 inhibitor. (2007)
  • Author(s): Yamaguchi T, Yoshida T, Kurachi R, Kakegawa J, Hori Y, Nanayama T, Hayakawa K, Abe H, Takagi K, Matsuzaki Y, Koyama M, Yogosawa S, Sowa Y, Yamori T, Tajima N, Sakai T.
  • Journal Title: Cancer science 98(11) Pages: 1809-16
  • Peer Reviewed
• [Journal Article] laziovianin A, a new isoflavone, from the leaves of Ateleia glaziovian a and its cytotoxic activity against human cancer cells. (2007)
  • Author(s): Yokosuka A, Haraguchi M, Usui T, Kazami S, Osada H, Yamori T, Mimaki Y.
  • Journal Title: Bioorganic & medicinal chemistry letters 17(11) Pages: 3091-4
  • Peer Reviewed
• [Journal Article] Glaziovianin A, a new isoflavone, from the leaves of Ateleia glazioviana and its cytotoxic activity against human cancer cells. (2007)
  • Author(s): Yokosuka, A., Haraguchi, M., Usui, T., Kazami, S., Osada, H., Yamori, T., Mimaki, Y.
  • Journal Title: Bioorg. Med. Chem. Lett. (in press)
• [Journal Article] Absolute quantification of four isoforms of the class I phosphoinositide-3-kinase catalytic subunit by real-time RT-PCR. (2007)
  • Author(s): Nakamura, H., Dan, S., Akashi, T., Unno, M., Yamori, T.
  • Journal Title: Biol. Pharm. Bull. (in press)
  • NAID: 110006278417
• [Journal Article] Comparative profiling of the gene expression for estrogen responsiveness in cultured human cell lines. (2007)
  • Author(s): Inoue, A., Seino, Y., Terasaka, S., Hayashi, SI., Yamori, T., Tanji, M., Kiyama, R.
  • Journal Title: Toxicol. In Vitro. 21・4 Pages: 741-752
• [Journal Article] Proteomics-based identification of biomarkers for predicting sensitivity to a PI3-kinase inhibitor in cancer. (2007)
  • Author(s): Akashi, T., Nishimura, Y., Wakatabe, R., Shiwa, M., Yamori, T.
  • Journal Title: Biochem. Biophys. Res. Commun. 352・2 Pages: 514-521
• [Journal Article] Modification of pyrimidine derivatives from antiviral agents to antitumor agents. (2006)
  • Author(s): Kimura, H., Katoh, T., Kajimoto, T., Node, M., Hisaki, M., Sugimoto, Y., Majima, T., Uehara, Y., Yamori, T.
  • Journal Title: Anticancer Res. 26 Pages: 91-97
• [Journal Article] Antitumor Activity of ZSTK474, a Novel Phosphatidylinositol 3-Kinase Inhibitor. (2006)
  • Author(s): Yaguchi, S., Fukui, Y., Koshimizu, I., Yoshimi, H., Matsuno, T., Gouda, H., Hirono, S., Yamazaki, K., Yamori, T.
  • Journal Title: J. Natl. Cancer Inst. 98・8 Pages: 545-556
  • NAID: 40015603056
• [Journal Article] Autotaxin is overexpressed in glioblastoma multiforme and contributes to cell motility of glioblastoma by converting lysophosphatidylcholine to lysophosphatidic acid. (2006)
  • Author(s): Kishi, Y., Okudaira, S., Tanaka, M., Hama, K., Shida, D., Kitayama, J., Yamori, T., Aoki, J., Fujimaki, T., Arai, H.
  • Journal Title: J. Biol. Chem. 281・25 Pages: 17492-17500
• [Journal Article] Synthesis and biological evaluation of boronic acid containing cis-stilbenes as apoptotic tubulin polymerization inhibitors. (2006)
  • Author(s): Nakamura, H., Kuroda, H., Saito, H., Suzuki, R., Yamori, T., Maruyama, K., Haga, T.
  • Journal Title: Chem. Med. Chem. 1・7 Pages: 729-740
• [Journal Article] Potent antitumor activity of 3,4-seco-8betaH-Ferna-4(23),9(11)-dien-3-oic acid (EC-2) and 3,4-seco-Oleana-4(23),18-dien-3-oic acid (EC-4), evaluated by an in vitro human cancer cell line panel. (2006)
  • Author(s): Tanaka, R., Wada, S., Yamada, T., Yamori, T.
  • Journal Title: Planta Med. 72・14 Pages: 1347-1349
• [Presentation] Cancer Cell Informaticsとは〜その分子標的治療薬の創薬への応用〜 (2008)
  • Author(s): 矢守隆夫.
  • Organizer: 北里大学薬学部公開シンポジウム
  • Place of Presentation: 北里大学
  • Year and Date: 2008-02-22
• [Presentation] Identification of candidates for new drug, target and biomarker by mining data sets from a panel of human cancer cell lines: JFCR39. (2007)
  • Author(s): Yamori T.
  • Organizer: MBI Chemogenomics Workshop.
  • Place of Presentation: Ohio, USA
• [Presentation] Epigenetic silencing of the RecQ helicase genes in Japanese lung cancer. (2007)
  • Author(s): Okui M, Ishikawa Y, Yamori T, Nakagawa K.
  • Organizer: The 98-th Am Assoc Cancer Res (AACR) Annual Meeting.
  • Place of Presentation: Los Angeles, CA, U.S.A.
• [Presentation] Proteomic screening for biomarkers for predicting sensitivity to anticancer drugs by using SELDI-TOF MS. (2007)
  • Author(s): Akashi T, Nishimura Y, Shiwa M, Yamori T.
  • Organizer: The 98-th Am Assoc Cancer Res (AACR) Annual Meeting.
  • Place of Presentation: Los Angeles, CA, U.S.A.
• [Presentation] EGFR signal pathways selectively activated in lung adenocarcinoma. (2007)
  • Author(s): Hiramatsu M, Ninomiya H, Inamura K, Okui M, Satoh Y, Fujiiwara M, Yamori T, Kitagawama. T, Ishikawa Y.
  • Organizer: The 98-th Am Assoc Cancer Res (AACR) Annual Meeting.
  • Place of Presentation: Los Angeles, CA, U.S.A.
• [Presentation] Informatics-guided identification of candidates for new drug, target and biomarker based on JFCR39. (2007)
  • Author(s): Yamori T.
  • Organizer: 66-th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Yokohama
• [Presentation] Proteomic screening for signaling proteins involved in PI3-kina se pathways by using SELDI-TOF MS. (2007)
  • Author(s): Akashi T, Yaguchi S, Yamori T.
  • Organizer: 66-th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Yokohama
• [Presentation] Promoter methylation of WRN gene in cancer. (2007)
  • Author(s): Okui M, Yamori T, Nakagawa K, Ishikawa Y.
  • Organizer: 66-th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Yokohama
• [Presentation] ZSTK474 inhibits class I PI3 kinase isoforms competitively with ATP. (2007)
  • Author(s): Kong D, Yaguchi S, Yamori T.
  • Organizer: 66-th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Yokohama
• [Presentation] MEL1 cooperates with c-ski to repress TGF-beta signaling in gastric cancer cells. (2007)
  • Author(s): Takahata M, Koinuma D, inazawa J, Yamori T, Miyazawa K, Miyazono K, Imamura T.
  • Organizer: 66-th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Yokohama
• [Presentation] PI3K inhibitor, down-regulates CDC25A and induces G_1, phase cell cycle arrest in human cancer cells. (2007)
  • Author(s): Dan S, Mukai Y, Yaguchi S, Yamori T.
  • Organizer: 66-th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Yokohama
• [Presentation] PIK3CA mutations in JFCR-39 human cancer cell lines. (2007)
  • Author(s): Sugita H, Dan S, Nakamura H, Yamori T.
  • Organizer: 66-th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Yokohama
• [Presentation] 新規PI3キナーゼ阻害剤ZSTK474による抗腫瘍効果の分子機構の解析. (2007)
  • Author(s): 旦慎吾, 向井由美子, 矢口信一, 矢守隆夫.
  • Organizer: 第11回がん分子標的治療研究会総会
  • Place of Presentation: 大阪
• [Presentation] 新規PI3K阻害剤ZSTK474の分子薬理機序の解析. (2007)
  • Author(s): 孔徳新.矢守隆夫.
  • Organizer: 第11回がん分子標的治療研究会総会
  • Place of Presentation: 大阪
• [Presentation] 山菜のシゲト(モミジガサ)から単離されたビサボラン型セスキテルペンエンドパーオキサイドの抗癌活性. (2007)
  • Author(s): 西川耕司, 山田京平, 土屋英子, 矢守隆夫, 木村賢一.
  • Organizer: 第11回がん分子標的治療研究会総会
  • Place of Presentation: 大阪
• [Presentation] PI3キナーゼを標的とする新規分子標的薬候補ZSTK474. (2007)
  • Author(s): 矢守隆夫.
  • Organizer: 第16回日本がん転移学会総会
  • Place of Presentation: 富山
• [Book] 新規PI3キナーゼ阻害剤ZSTK474の抗がん活性. (2007)
  • Author(s): 矢口信一, 矢守隆夫.
  • Publisher: 細胞 The CELL
• [Book] 分子標的治療薬の開発と発展. (2007)
  • Author(s): 矢守隆夫.
  • Publisher: 日本病院薬剤師会雑誌
• [Book] クリニカル プラクティス (2007)
  • Author(s): 矢守隆夫.
  • Publisher: 分子標的治療薬.
• [Book] Cancer Cell Informaticsとケミカルバイオロジー. (2007)
  • Author(s): 矢守隆夫.
  • Publisher: 蛋白質 核酸 酵素
• [Book] 分子標的治療薬とは. (2007)
  • Author(s): 矢守隆夫.
  • Publisher: 月刊薬事
• [Book] 特集・制がん剤の分子標的スクリーニング成績 「化学療法基盤情報支援班」報告-制がん候補物質のスクリーニング成績・第12報-. (2007)
  • Author(s): 矢守隆夫, 上原至雅, 吉田稔, 井上正哉, 清宮啓之, 水上民夫, 川田学, 長田裕之, 松浦正明.
  • Publisher: 癌と化学療法
• [Book] 特集・制がん剤の分子標的スクリーニング成績 「新しい戦略による抗がん剤のスクリーニングのための委員会」報告-制がん候補物質のスクリーニング成績・第11報-. (2007)
  • Author(s): 矢守隆夫, 安藤俊夫, 上原至雅, 小野眞弓, 河野通明, 済木育夫, 内藤幹彦, 早川洋一, 鶴尾隆, 吉田稔, 杉本芳一, 馬島哲夫.
  • Publisher: 癌と化学療法
• [Book] 分子標的治療薬 (2007)
  • Author(s): 矢守隆夫
  • Publisher: クリニカルプラクティス
• [Book] 分子標的治療薬の開発と発展 (2007)
  • Author(s): 矢守隆夫
  • Publisher: 日本病院薬剤師会雑誌
• [Book] 分子標的治療法の開発と発展 (2006)
  • Author(s): 矢守隆夫
  • Publisher: 血液フロンティア
• [Book] 分子標的治療薬のオーバービュー (2006)
  • Author(s): 矢守隆夫
  • Publisher: Drug Delivery System
• [Patent(Industrial Property Rights)] PI3キナーゼ阻害剤の効果判定方法 (2007)
  • Inventor(s): 明石哲行、矢守隆夫、岡村睦美
  • Industrial Property Rights Holder: 財団法人癌研究会
  • Industrial Property Number: 2007-218234
  • Filing Date: 2007-08-24
• [Patent(Industrial Property Rights)] PI3キナーゼ阻害剤に対する感受性予測方法 (2006)
  • Inventor(s): 明石哲行, 西村由美子, 矢守隆夫
  • Industrial Property Rights Holder: 財団法人癌研究会
  • Industrial Property Number: 2006-221146
  • Filing Date: 2006-08-14
• [Patent(Industrial Property Rights)] PI3キナーゼ阻害剤の効果判定法 (2006)
  • Inventor(s): 旦慎吾, 矢守隆夫
  • Industrial Property Rights Holder: 財団法人癌研究会
  • Industrial Property Number: 2006-229568
  • Filing Date: 2006-08-25