Development of Selective Modulators for Autophagic Cell Death and Novel Chemotherapeutic Strategy for Leukemia

• Project/Area Number: 20200038
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research a proposed research project)
• Allocation Type: Single-year Grants
• Research Field: Drug development chemistry; Living organism molecular science
• Research Institution: Kumamoto University
• Principal Investigator: KUNIYASU Akihiko Kumamoto University, 大学院・生命科学研究部, 准教授 (90241348)
• Co-Investigator(Kenkyū-buntansha): HASHIMOTO Makoto 北海道大学, 大学院・農学研究院, 准教授 (90292094)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥33,540,000 (Direct Cost: ¥25,800,000、Indirect Cost: ¥7,740,000); Fiscal Year 2010: ¥11,050,000 (Direct Cost: ¥8,500,000、Indirect Cost: ¥2,550,000); Fiscal Year 2009: ¥10,920,000 (Direct Cost: ¥8,400,000、Indirect Cost: ¥2,520,000); Fiscal Year 2008: ¥11,570,000 (Direct Cost: ¥8,900,000、Indirect Cost: ¥2,670,000)
• Keywords: 医薬分子機能学 / 分子認識 / 生体機能利用 / 生体分子 / 薬学

Research Abstract

We developed a hybrid peptide, which induces leukemia cell death associated with autophagy. The mode of cell death induced with this peptide is different from previously recognized apoptosis. Further, the length of peptide sequence was shortened by analyzing active motif of the peptide. The hybrid peptide will be a useful tool for development of novel concept-based anti-leukemia agents.

Research Products

• [Journal Article] Oxidized LDL and lysophosphatidylcholine stimulate plasminogen activator inhibitor-1 expression through reactive oxygen species generation and ERK1/2 activation in 3T3-L1 adipocytes (2011)
  • Author(s): Kuniyasu A., Tokunaga T., Yamamoto Y., Inoue S., Obama K., Kawahara K., Nakayama H.
  • Journal Title: Biochim.Biophys.Acta 1811 Pages: 153-162
  • Peer Reviewed
• [Journal Article] Targeting neuropilin-1 in human leukemia and lymphoma. (2011)
  • Author(s): Karjalainen K., Jaalouk D.E., Bueso- Ramos C.E., Zurita A.J., Kuniyasu A., Lichtiger B., O'Brien S., Kantarjian H.M., Cortes J.E., Koivunen E., Arap W., Pasqualini R.
  • Journal Title: Blood 117 Pages: 920-927
  • Peer Reviewed
• [Journal Article] Targeting neuropilin-1 in human leukemia and lymphoma. (2011)
  • Author(s): Karjalainen K., Jaalouk DE., Bueso-Ramos CE., Zurita AJ., Kuniyasu A., Lichtiger B., O'Brien S., Kantarjian HM., Cortes JE., Koivunen E., Arap W., Pasqualini R.
  • Journal Title: Blood Volume: 117 Pages: 920-927
  • Peer Reviewed
• [Journal Article] Oxidized LDL and lysophosphatidylcholine stimulate plasminogen activator inhibitor-1 expression through reactive oxygen species generation and ERK1/2 activation in 3T3-L1 adipocytes. (2011)
  • Author(s): Kuniyasu A., Tokunaga T., Yamamoto Y., Inoue S., Obama K., Kawahara K., Nakayama H.
  • Journal Title: Biochim.Biophys.Acta Volume: 1811 Pages: 153-162
  • Peer Reviewed
• [Journal Article] Interconversion between pure chemotactic ligands and chemoattractant/secretagogue ligands of neutrophil C5a receptor by a single amino acid substitution. (2010)
  • Author(s): Jia, N., Semba, U., Nishiura, H., Kuniyasu, A., Nsiama, T.K., Nishino, N., Yamamoto, T.
  • Journal Title: J.Leukoc.Biol. 87 Pages: 965-975
  • Peer Reviewed
• [Journal Article] Three-dimensional structure of α1-β complex in skeletal muscle dihydropyridine receptor by single particle electron microscopy (2010)
  • Author(s): Murata K., Nishimura S., Kuniyasu A., Nakayama H.
  • Journal Title: J.Electron Microsc. 59 Pages: 215-226
  • Peer Reviewed
• [Journal Article] Contribution of BCR-ABLindependent activation of ERK1/2 to acquired imatinib resistance in K562 chronic myeloid leukemia cells (2010)
  • Author(s): Nambu T., Araki N., Nakagawa A., Kuniyasu A., Kawaguchi T., Hamada A., Saito H.
  • Journal Title: Cancer Sci. 101 Pages: 137-142
  • NAID: 10027199844
  • Peer Reviewed
• [Journal Article] オートファジー誘導に基づく白血病治療薬の開発 (2010)
  • Author(s): 國安明彦
  • Journal Title: 薬事日報「研究戦略・YAKU 学-研究現場から臨床へ-」
• [Journal Article] Synthesis and properties of diazirinyl organoplatinum compounds for manipulations of photoaffinity labeled components (2010)
  • Author(s): Hashimoto M., Furukawa K., Tomohiro T., Hatanaka Y.
  • Journal Title: Chem.Pharm.Bull.(Tokyo) 58 Pages: 405-407
  • NAID: 130000255923
  • Peer Reviewed
• [Journal Article] Photoactive ligands probing the sweet taste receptor.Design and synthesis of highly potent diazirinyl D-phenylalanine derivatives (2010)
  • Author(s): Masuda K, Koizumi A, Misaka T, Hatanaka Y, Abe K, Tanaka T, Ishiguro M, Hashimoto M.
  • Journal Title: Bioorg.Med.Chem.Lett. 20 Pages: 1081-1083
  • Peer Reviewed
• [Journal Article] Interconversion between pure chemotactic ligands and chemoattractant/secretagogue ligands of neutrophil C5a receptor by a single amino acid substitution. (2010)
  • Author(s): Jia, N., Semba, U., Nishiura, H., Kuniyasu, A., Nsiama, T.K., Nishino, N., Yamamoto, T.
  • Journal Title: J.Leukoc.Biol. Volume: 87 Pages: 965-975
  • Peer Reviewed
• [Journal Article] Contribution of BCR-ABL-independent Activation of ERK1/2 to Acquired Imatinib Resistance in K562 Chronic Myeloid Leukemia Cells (2010)
  • Author(s): Nambu T, Araki N, Nakagawa A, Kuniyasu A, Kawaguchi T, Hamada A, Saito H
  • Journal Title: Cancer Sci. 101 Pages: 137-142
  • NAID: 10027199844
  • Peer Reviewed
• [Journal Article] Oral administration of synthetic retinoid Am80 (Tamibarotene) decreases brain β -amyloid Pharm. (2009)
  • Author(s): Kawahara K., Nishi K., Suenobu M., Ohtsuka H., Maeda A., Nagatomo K., Kuniyasu A., Staufenbiel M., Nakagomi M., Shudo K., Nakayama H.
  • Journal Title: Bull. 32 Pages: 1307-1309
  • Peer Reviewed
• [Journal Article] Marked induction of inducible nitric oxide synthase and tumor necrosis factor-α in rat CD40+ microglia by comparison to CD40 microglia (2009)
  • Author(s): Kawahara K., Yoshida A., Koga K., Yokoo S., Kuniyasu A., Gotoh, T., Sawada M., Nakayama H.
  • Journal Title: J.Neuroimmunol. 208 Pages: 70-79
  • Peer Reviewed
• [Journal Article] Linkage between phosphorylation of the origin recognition complex and its ATP-binding activity in Saccharomyces cerevisiae (2009)
  • Author(s): Makise M., Takehara M., Kuniyasu A., Matsui N., Nakayama H., Mizushima T.
  • Journal Title: J.Biol.Chem. 284 Pages: 3396-3407
  • Peer Reviewed
• [Journal Article] A synthetic approach to develop peptide inhibitors selective for brain-type sodium channels on the basis of pompilidotoxin structure (2009)
  • Author(s): Yokote S., Setoguchi R., Shimizu E., Mishima N., Kawahara K., Kuniyasu A., Shirasaki S., Takahama K., Konno K., Kawai N., Yamaoka K., Kinoshita E., Nakayama H.
  • Journal Title: Heterocycles 79 Pages: 925-933
  • NAID: 120005255069
  • Peer Reviewed
• [Journal Article] オートファジーを誘導するペプチド (2009)
  • Author(s): 國安明彦
  • Journal Title: ケミカルエンジニヤリング 54 Pages: 819-824
• [Journal Article] Effective synthesis of optically active trifluoromethyldiazirinyl homophenylalanine and aroylalanine derivatives with the Friedel-Crafts reaction in triflic acid (2009)
  • Author(s): Murashige R., Murai Y., Hatanaka Y., Hashimoto M.
  • Journal Title: Biosci.Biotechnol.Biochem. 73 Pages: 1377-1380
  • NAID: 10027542555
  • Peer Reviewed
• [Journal Article] Three-dimensional structure of alpha 1-beta complex in skeletal muscle dihydropyridine receptor by single particle electron microscopy (2009)
  • Author(s): Murata K, Nishimura S,. Kuniyasu, A, Nakayama H
  • Journal Title: J.Electron Microsc. Pages: 1-12
  • Peer Reviewed
• [Journal Article] Oral administration of syntetic retinoid Am80 (Tamibarotene) decreases brainbeta-amyloid peptides in APP23 mice. (2009)
  • Author(s): Kawahara K, Nishi K, Suenobu M, Ohtsuka H, Maeda A, Nagatomo K, Kuniyasu A, Staufenbiel M, Nakagomi M, Shudo K, Nakayama H
  • Journal Title: Biol.Pharm.Bull. 32 Pages: 1307-1309
  • Peer Reviewed
• [Journal Article] Marked induction of inducible nitric oxide synthase and tumor necrosis factor-a in rat CD40+ microglia by comparison to CD40 microglia (2009)
  • Author(s): Kawahara K., et.al.
  • Journal Title: J. Neuroimmunol 208 Pages: 70-79
  • Peer Reviewed
• [Journal Article] A synthetic approach to develop peptide inhibitors selective for brain-type sodium channels on the basis of pompilidotoxin, structure (2009)
  • Author(s): Yokote S., et.al.
  • Journal Title: Heterocycles 79 Pages: 925-933
  • Peer Reviewed
• [Journal Article] Linkage between phosphorylation of the origin recognition complex and its ATP-binding activity in Saccharomyces cerevisiae (2009)
  • Author(s): Makise M., et.al.
  • Journal Title: J. Biol. Chem 284 Pages: 3396-3407
  • Peer Reviewed
• [Journal Article] Constitutive overexpression of P-glycoprotein, rather than breast cancer resistance protein or organic cation transporter 1, contributes to acquisition of imatinib-resistance in K562 cells (2008)
  • Author(s): Hirayama C., Watanabe H., Nakashima R., Nanbu T., Hamada A., Kuniyasu A., Nakayama H., Kawaguchi T., Saito H.
  • Journal Title: Pharm.Res. 25 Pages: 827-835
  • Peer Reviewed
• [Journal Article] Combinatorial targeting of the macropinocytotic pathway in leukemia and lymphoma cells (2008)
  • Author(s): Nishimura S., Takahashi S., Kamikatahira H., Kuroki Y., Jaalouk DE., O'Brien S., Koivunen E., Arap W., Pasqualini R., Nakayama H., Kuniyasu A.
  • Journal Title: J.Biol.Chem. 283 Pages: 11752-11762
  • Peer Reviewed
• [Journal Article] Combinatorial targeting of the macropinocytotic pathway in leukemia and lymphoma cells (2008)
  • Author(s): Nishimura S., et.al.
  • Journal Title: J. Biol. Chem 283 Pages: 11752-11762
  • Peer Reviewed
• [Presentation] Cell-selective cell penetrating peptide as an intelligent molecular carrier (2010)
  • Author(s): Akihiko Kuniyasu
  • Organizer: BIT 1st Annual World Congress of NanoMedicine-2010
  • Place of Presentation: 北京国際会議場(北京市, 中国)
  • Year and Date: 2010-10-26
• [Presentation] Cell-selective cell penetrating peptide as an intelligent molecular carrier (2010)
  • Author(s): 國安明彦
  • Organizer: BIT 1st Annual World Congress of NanoMedicine-2011
  • Place of Presentation: 北京国際会議場(中華人民共和国北京市)
  • Year and Date: 2010-10-26
• [Presentation] 両親媒性ペプチドによる白血病細胞株に対する非カスパーゼ依存性細胞死誘導 (2010)
  • Author(s): 國安明彦
  • Organizer: 第69回日本癌学会学術総会
  • Place of Presentation: リーガロイヤルホテル(大阪府大阪市)
  • Year and Date: 2010-09-23
• [Presentation] 両親媒性ペプチドによる白血病細胞株に対する非カスパーゼ依存性細胞死誘導 (2010)
  • Author(s): 國安明彦
  • Organizer: 第69回日本癌学会総会
  • Place of Presentation: リーガロイヤルホテル(大阪府)
  • Year and Date: 2010-09-23
• [Presentation] オートファジー性細胞死を誘導するペプチドミメティックの開発と応用 (2010)
  • Author(s): 國安明彦
  • Organizer: JSTイノベーションプラザ福岡研究成果発表会
  • Place of Presentation: アクロス福岡(福岡県福岡市)
  • Year and Date: 2010-09-03
• [Presentation] オートファジー性細胞死を誘導するペプチドミメティックの開発と応用 (2010)
  • Author(s): 國安明彦
  • Organizer: JSTイノベーションプラザ福岡研究成果発表会
  • Place of Presentation: アクロス福岡(福岡県)
  • Year and Date: 2010-09-03
• [Presentation] 腫瘍選択的オートファジー誘導に基づく白血病治療薬の開発 (2010)
  • Author(s): 國安明彦,西村真平,中山仁
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: 岡山桃太郎アリーナ(岡山県岡山市)
  • Year and Date: 2010-03-29
• [Presentation] 腹瘍選択的オートファジー誘導に基づく白血病治療薬の開発 (2010)
  • Author(s): 國安明彦, 西村真平, 中仙仁
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: 桃太郎フリーナ(岡山県)
  • Year and Date: 2010-03-29
• [Presentation] 細胞選択的物質導入に向けたキャリアペプチドの同定とその応用 (2010)
  • Author(s): 國安明彦
  • Organizer: 特定領域研究「バイオ操作」公開シンポジウム
  • Place of Presentation: 九州大学医学部(福岡県福岡市)
  • Year and Date: 2010-03-05
• [Presentation] Notch-1 Fragment Peptide Induces Autophagy and Caspase-independent Cell Death in Leukemia Cell Lines (2010)
  • Author(s): Akihiko Kuniyasu, Shinpei Nishimura, Hitoshi Nakayama
  • Organizer: AACR Special Conference"Cell Death Mechanisms and Cancer Therapy"
  • Place of Presentation: San Diego Omni Hotel (San Diego, 米国)
  • Year and Date: 2010-02-03
• [Presentation] Notch-1 Fragment Peptide Induces Autophagy and Caspase-independent Cell Death in Leukemia Call Lines (2010)
  • Author(s): Akihiko Kuniyasu, Shinpei Nishimura, Hitoshi Nakayama
  • Organizer: AACR Special Conference "Cell Death Mechanisms and Cancer Therapy"
  • Place of Presentation: San Diego Omni Hotel(米国)
  • Year and Date: 2010-02-03
• [Presentation] 白血病細胞株におけるオートファジー活性を規定する因子の同定 (2009)
  • Author(s): 瀬戸口誠, 佐藤直哉, 黒木愛, 西村真平, 中山仁, 國安明彦
  • Organizer: 第26回日本薬学会九州支部大会
  • Place of Presentation: 九州大学医学部(福岡県福岡市)
  • Year and Date: 2009-12-13
• [Presentation] ペプチドを利用したミクログリアへの特異的物質導入 (2009)
  • Author(s): 山中暢人, 谷口尊子, 川原浩一, 中山仁, 國安明彦
  • Organizer: 第26回日本薬学会九州支部大会
  • Place of Presentation: 九州大学医学部(福岡県福岡市)
  • Year and Date: 2009-12-13
• [Presentation] 白血病細胞株におけるオートファジー活性を規定する因子の同定 (2009)
  • Author(s): 瀬戸口誠, 佐藤直哉, 黒木愛, 西村真平, 中山仁, 國安明彦
  • Organizer: 第26回日本薬学会九州支部大会
  • Place of Presentation: 九州大学(福岡市)
  • Year and Date: 2009-12-13
• [Presentation] ペプチドを利用したミクログリアヘの特異的物質導入 (2009)
  • Author(s): 山中暢人, 谷口尊子, 川原浩一, 中山仁, 國安明彦
  • Organizer: 第26回日本薬学会九州支部大会
  • Place of Presentation: 九州大学(福岡市)
  • Year and Date: 2009-12-13
• [Presentation] 細胞内導入キャリアとしてのミクログリア選択的ペプチドリガンド (2009)
  • Author(s): 山中暢人, 谷口尊子, 中山仁, 川原浩一, 杉本幸彦, 國安明彦
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸ポートアイランド(兵庫県神戸市)
  • Year and Date: 2009-10-24
• [Presentation] 細胞内導入キャリアとしてのミクログリア選択的ペプヂドリガンド (2009)
  • Author(s): 山中暢人, 谷口尊子, 中山仁, 川原浩一, 杉本幸彦, 國安明彦
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸ポートアイランド(兵庫県)
  • Year and Date: 2009-10-24
• [Presentation] 白血病細胞株におけるNotch1由来ペプチド断片による非アポトーシス性細胞死誘導 (2009)
  • Author(s): 國安明彦, 佐藤直哉, 高橋俊輔, 杉本幸彦, 西村真平, 中山仁
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸ポートアイランド(兵庫県神戸市)
  • Year and Date: 2009-10-23
• [Presentation] 白血病細胞株におけるNotch1由来ペプチド断片による非アポトーシス性細胞死誘導 (2009)
  • Author(s): 國安明彦, 佐藤直哉, 高橋俊輔, 杉本幸彦, 西村真平, 中山仁
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸ポートアイランド(兵庫県)
  • Year and Date: 2009-10-23
• [Presentation] Notch-1由来ペプチドによる白血病細胞における非アポトーシス性細胞死誘導 (2009)
  • Author(s): 國安明彦
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜(神奈川県横浜市)
  • Year and Date: 2009-10-03
• [Presentation] Notch-1由来ペプチドによる白血病細胞における非アポトーシス性細胞死誘導 (2009)
  • Author(s): 國安明彦
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2009-10-03
• [Presentation] 機能ペプチドによる非アポトーシス細胞死の誘導 (2009)
  • Author(s): 國安明彦
  • Organizer: 文部科学省特定領域「バイオ操作」第四回若手研究者ワークショップ
  • Place of Presentation: アークシティホテル(北海道札幌市)
  • Year and Date: 2009-06-10
• [Presentation] 機能ペプチドによる非アポーシス細胞死の誘導 (2009)
  • Author(s): 國安明彦
  • Organizer: 文部科学省特定領域「バイオ操作」第四回若手研究者ワークショップ
  • Place of Presentation: アークシティホテル(北海道)
  • Year and Date: 2009-06-10
• [Presentation] ペプチドリガンドによる白血病細胞における非アポトーシス性細胞死誘導 (2009)
  • Author(s): 國安明彦, 高橋俊輔, 佐藤直哉, 西村真平, 中山仁
  • Organizer: 日本薬学会第129年会
  • Place of Presentation: 京都国際会議場(京都府京都市)
  • Year and Date: 2009-03-27
• [Presentation] ペプチドリガンドによる白血病細胞における非アポトーシス性細胞死誘導 (2009)
  • Author(s): 國安明彦ら
  • Organizer: 日本薬学会第129年会
  • Place of Presentation: 京都
  • Year and Date: 2009-03-27
• [Presentation] ミクログリア選択的に取り込まれる新規ペプチドリガンドの同定 (2008)
  • Author(s): 山中暢人, 山内千絵美, 川原浩一, 國安明彦
  • Organizer: 第31回日本分子生物学会・第81回日本生化学会合同大会
  • Place of Presentation: 神戸ポートピアアイランド(兵庫県神戸市)
  • Year and Date: 2008-12-11
• [Presentation] 白血病細胞におけるミトコンドリア膜破壊ペプチドによる非アポトーシス性細胞死誘導 (2008)
  • Author(s): 高橋俊輔, 佐藤直哉, 西村真平, 中山仁, 國安明彦
  • Organizer: 日本薬学会第15回九州支部大会
  • Place of Presentation: 九州保健福祉大学(宮崎県延岡市)
  • Year and Date: 2008-12-06
• [Presentation] イマチニブ抵抗性慢性骨髄性白血病細胞におけるBCR-ABL非依存的なMAPキナーゼERK の活性化 (2008)
  • Author(s): 南部健, 中川亜衣子, 國安明彦, 川口辰哉, 荒木令江, 濱田哲暢, 齋藤秀之
  • Organizer: 日本薬学会第15回九州支部大会
  • Place of Presentation: 九州保健福祉大学(宮崎県延岡市)
  • Year and Date: 2008-12-06
• [Presentation] 白血病細胞におけるミトコンドリア膜破壊ペプチドによる非アポトーシス性細胞死誘導 (2008)
  • Author(s): 國安明彦ら
  • Organizer: 日本薬学会第15回九州支部大会
  • Place of Presentation: 延岡
  • Year and Date: 2008-12-06
• [Presentation] Microglia targeting peptide ligands with cell-penetrating properties (2008)
  • Author(s): Akhiko Kuniyasu, Masato Yamanaka, Kohichi Kawahara, Hitoshi Nakayama
  • Organizer: Society for Neuroscience Annual Meeting
  • Place of Presentation: Walter E.Washington Convention Center (Washington DC, USA)
  • Year and Date: 2008-11-18
• [Presentation] A cell penetrating peptide ligand for anti-leukemia/lymphoma therapies (2008)
  • Author(s): 國安明彦, 高橋俊輔, 西村真平, Renata Pasqualini, Wadih Arap
  • Organizer: 第67回日本癌学会総会
  • Place of Presentation: 名古屋国際会議場(愛知県名古屋市)
  • Year and Date: 2008-10-28
• [Remarks] ホームページ等
  • URL: http://square.umin.ac.jp/yseika/
• [Remarks]
  • URL: http://square.umin.ac.jp/yseika/
• [Patent(Industrial Property Rights)] オートファジー性細胞死を誘導するペプチド (2009)
  • Inventor(s): 國安明彦, 西村真平
  • Industrial Property Rights Holder: 熊本大学
  • Filing Date: 2009-03-26
• [Patent(Industrial Property Rights)] 特許権 (2009)
  • Inventor(s): 國安明彦
  • Industrial Property Rights Holder: 熊本大学
  • Filing Date: 2009-03-26
  • Overseas