Screening for microbial metabolites that regulate cellular stress response

• Project/Area Number: 17390031
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: Tokyo University of Science
• Principal Investigator: 早川 洋一 Tokyo University of Science, 薬学部, 教授 (20208606)
• Co-Investigator(Kenkyū-buntansha): SHIN-YA Kazuo 産業技術総合研究所, 生物情報解析研究センター, 主任研究員 (20251481) ; KAWASAKI Takashi 東京理科大学, 薬学部, 助教 (00408733)
• Co-Investigator(Renkei-kenkyūsha): SHIN-YA Kazuo 独立行政法人産業技術総合研究所, 生物情報解析研究センター, 主任研究員 (20251481) ; KAWASAKI Takashi 東京理科大学, 薬学部, 助教 (00408733)
• Project Period (FY): 2005 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥16,420,000 (Direct Cost: ¥15,100,000、Indirect Cost: ¥1,320,000); Fiscal Year 2008: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2007: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2006: ¥2,200,000 (Direct Cost: ¥2,200,000); Fiscal Year 2005: ¥8,500,000 (Direct Cost: ¥8,500,000)
• Keywords: 小胞体ストレス / 分子シャペロン / GRP78 / アデノウイルスがん遺伝子 / versipelostatin / piericidin / efrapeptin / thioviridamide / ammocidin / IGF / tyroscherin / 立体異性体 / 構造活性相関 / レポーターアッセイ / prunustatin A / Tolypocladium / 固形癌 / 呼吸阻害剤 / アポトーシス / アデノウイルス / がん遺伝子 / チオアミド

Research Abstract

微生物由来の細胞ストレス応答制御物質を探索した結果、土壌放線菌からversipelostatin、thioviridamide、海洋放線菌からpiericidin C_7およびC-8、海洋糸状菌からefrapeptin Jを単離し、その構造を決定した。Versipelostatin、efrapeptin J は小胞体ストレスを抑制する分子シャペロンGRP78の発現を阻害し、小胞体ストレス下でがん細胞に対して選択的細胞死を誘導した。Thioviridamideは、細胞ストレス感受性を上昇させるアデノウイルスE1Aがん遺伝子を導入した細胞に対して選択的にアポトーシスを誘導した。Piericidin C_7およびC_8は、呼吸阻害剤oligomycinによるストレス下で、がん細胞に対して選択的に細胞死を誘導した

Research Products

• [Journal Article] Synthesis and structure revision of tyroscherin, and bioactivities of its stereoisomers against IGF-1-dependent tumor cells (2009)
  • Author(s): Ishigami, K., Katsuta, R., Shibata, C., Hayakawa, Y., Watanabe, H., Kitahara, T.
  • Journal Title: Tetrahedron 65 Pages: 3629-3638
  • Peer Reviewed
• [Journal Article] Ammocidins B, C and D, new cytotoxic 20-membered macrolides from Saccharothrix sp (2009)
  • Author(s): Murakami, R., Shinozaki, J., Kajiura, T., Kozone, I., Takagi, M., Shin-ya, K., Seto, H., Hayakawa, Y.
  • Journal Title: AJ9571. J. Antibiot. 62 Pages: 123-127
  • Peer Reviewed
• [Journal Article] Ammocidins B, C and D, new cytotoxic 20-membered macrolides from Saccharothrix sp. AJ9571 (2009)
  • Author(s): Ryo Murakami
  • Journal Title: The Journal of Antibiotics 62 Pages: 123-127
  • Peer Reviewed
• [Journal Article] Synthesis and structure revision of tyroscherin, and bioactivities of its stereoisomers against IGF-1-dependent tumor cells (2009)
  • Author(s): Ken Ishigami
  • Journal Title: Tetrahedron 65 Pages: 3629-3638
  • Peer Reviewed
• [Journal Article] Relative and absolute stereochemistry of quinadoline B, an inhibitor of lipid droplet synthesis in macrophages (2008)
  • Author(s): Koyama, N., Inoue, Y., Sekine, M., Hayakawa, Y., Homma, H., Omura, S., Tomoda H.
  • Journal Title: Org. Lett. 10 Pages: 5273-5276
  • Peer Reviewed
• [Journal Article] A prodigiosin from the roseophilin producer Streptomyces griseoviridis (2008)
  • Author(s): Kawasaki, T., Sakurai, F., Hayakawa, Y.
  • Journal Title: J. Nat. Prod. 71 Pages: 1265-1267
  • Peer Reviewed
• [Journal Article] Efrapeptin J, a new down-regulator of the molecular chaperone GRP78 from a marine Tolypocladium sp (2008)
  • Author(s): Hayakawa, Y., Hattori, Y., Kawasaki, T., Kanoh, K., Adachi, K., Shizuri, Y., Shin-ya, K.
  • Journal Title: J. Antibiot. 61 Pages: 365-371
  • NAID: 10021927947
  • Peer Reviewed
• [Journal Article] Efrapeptin J, a new down-regulator of the molecular chaperone GRP78 from a marine Tolypocladium sp. (2008)
  • Author(s): Yoichi Hayakawa
  • Journal Title: The Journal of Antibiotics 61 Pages: 365-371
  • NAID: 10021927947
  • Peer Reviewed
• [Journal Article] Burkholone, a new cytotoxic antibiotic against IGF-I dependent cells from Burkholderia sp (2007)
  • Author(s): Mori, T., Yamashita, T., Furihata, K., Nagai, K., Suzuki, K., Hayakawa, Y., Shin-ya, K.
  • Journal Title: J. Antibiot. 60 Pages: 713-716
  • NAID: 10019972488
  • Peer Reviewed
• [Journal Article] Relative and absolute configuration of versipelostatin, a down-regulator of molecular chaperone GRP78 expression (2007)
  • Author(s): Park, H.-R., Chijiwa, S., Furihata, K., Hayakawa, Y., Shin-ya, K.
  • Journal Title: Org. Lett. 9 Pages: 1457-1460
  • Peer Reviewed
• [Journal Article] Structures of new cytotoxic antibiotics, piericidins C_7 and C_8 (2007)
  • Author(s): Hayakawa, Y., Shirasaki, S., Kawasaki, T., Matsuo, Y., Adachi, K., Shizuri, Y.
  • Journal Title: J. Antibiot. 60 Pages: 201-203
  • NAID: 10018875732
  • Peer Reviewed
• [Journal Article] Piericidins C7 and C8, new cytotoxic antibiotics produced by a marine Streptomyces sp (2007)
  • Author(s): Hayakawa, Y., Shirasaki, S., Shiba, S., Kawasaki, T., Matsuo, Y., Adachi, K., Shizuri, Y.
  • Journal Title: J. Antibiot. 60 Pages: 196-200
  • Peer Reviewed
• [Journal Article] Relative and absolute configuration of versipelostatin, a down-regulator of molecular chaperone GRP78 expression. (2007)
  • Author(s): Hae-Ryong Park
  • Journal Title: Organic Letters 9 Pages: 1457-1460
  • Peer Reviewed
• [Journal Article] Absolute structure of prunustatin A, a novel GRP78 molecular chaperone down-regulator. (2007)
  • Author(s): Yukiko Umeda
  • Journal Title: Organic Letters 9 Pages: 4239-4242
  • Peer Reviewed
• [Journal Article] Burkholone, a new cytotoxic antibiotic against IGF-I dependent cells from Burkholderia sp. (2007)
  • Author(s): Toshiya Mori
  • Journal Title: The Journal of Antibiotics 60 Pages: 713-716
  • Peer Reviewed
• [Journal Article] Glucose-deprived HT-29 human colon carcinoma cells are sensitive to verrucosidin as a GRP78 down-regulator. (2007)
  • Author(s): Hae-Ryong Park
  • Journal Title: Toxicology 229・3 Pages: 253-261
• [Journal Article] Piericidins C_7 and C_8, new cytotoxic antibiotics produced by a marine Streptomyces sp. (2007)
  • Author(s): Yoichi Hayakawa
  • Journal Title: The Journal of Antibiotics 60・3 Pages: 196-200
  • NAID: 10018875713
• [Journal Article] Structures of new cytotoxic antibiotics, piericidins C7 and C8. (2007)
  • Author(s): Yoichi Hayakawa
  • Journal Title: The Journal of Antibiotics 60・3 Pages: 201-203
• [Journal Article] Relative and absolute configuration of versipelostatin, down-regulator of molecular chaperone GRP78 expression. (2007)
  • Author(s): Hae-Ryong Park
  • Journal Title: Organic Letters 9・8 Pages: 1457-1460
• [Journal Article] Structure of thioviridamide, a novel apoptosis inducer from Streptomyces olivoviridis (2006)
  • Author(s): Hayakawa, Y., Sasaki, K., Nagai, K., Shin-ya, K., Furihata, K.
  • Journal Title: J. Antibiot. 59 Pages: 6-10
  • NAID: 10017147062
  • Peer Reviewed
• [Journal Article] Thioviridamide, a novel apoptosis inducer in transformed cells from Streptomyces olivoviridis (2006)
  • Author(s): Hayakawa, Y., Sasaki, K., Adachi, H., Furihata, K., Nagai, K., Shin-ya, K.
  • Journal Title: J. Antibiot. 59 Pages: 1-5
  • NAID: 10017147044
  • Peer Reviewed
• [Journal Article] Selective cytotoxic activity of valinomycin against HT-29 human colon carcinoma cells via down-regulation of GRP78. (2006)
  • Author(s): In-Ja Ryoo
  • Journal Title: Biological and Pharmaceutical Bulletin 29・4 Pages: 817-820
• [Journal Article] Thioviridamide, a novel apoptosis inducer in transformed cells from Streptomyces olivoviridis. (2006)
  • Author(s): Yoichi Hayakawa
  • Journal Title: The Journal of Antibiotics 59・1 Pages: 1-5
  • NAID: 10017147044
• [Journal Article] Structure of thioviridamide, a novel apoptosis inducer from Streptomyces olivoviridis. (2006)
  • Author(s): Yoichi Hayakawa
  • Journal Title: The Journal of Antibiotics 59・1 Pages: 6-10
  • NAID: 10017147062
• [Journal Article] Mevashuntin, a novel metabolite produced by inhibition of the mevalonate pathway in Streptomyces prunicolor (2005)
  • Author(s): Shin-ya, K., Umeda, Y., Chijiwa, S., Furihata, K., Furihata, K., Hayakawa, Y., Seto, H.
  • Journal Title: Tetrahedron Lett. 46 Pages: 1273-1276
  • Peer Reviewed
• [Journal Article] Prunustatin A, a novel GRP78 molecular chaperone downregulator isolated from Streptomyces violaceoniger. (2005)
  • Author(s): Yukiko Umeda
  • Journal Title: The Journal of Antibiotics 58・3 Pages: 206-209
• [Journal Article] Deoxyverrucosidin, a novel GRP78/BiP down-regulator, produced by Penicillium sp. (2005)
  • Author(s): Soo-Jin Choo
  • Journal Title: The Journal of Antibiotics 58・3 Pages: 210-213
• [Journal Article] Novel antitumor and neuroprotective substances discovered by characteristic screenings based on specific molecular targets. (2005)
  • Author(s): Kazuo Shin-ya
  • Journal Title: Bioscience, Biotechnology, and Biochemistry 69・5 Pages: 867-872
  • NAID: 130000030314
• [Presentation] Streptomyces griseoviridisの新規代謝産物dechlororoseophilin (2009)
  • Author(s): 長塚俊弥
  • Organizer: 日本薬学会
  • Place of Presentation: 京都
  • Year and Date: 2009-03-27
• [Presentation] Streptomyces griseoviridisの新規代謝産物Dechlororoseophilin (2009)
  • Author(s): 長塚俊弥、川崎崇、早川洋一
  • Organizer: 日本薬学会
• [Presentation] IGF-1依存性がん細胞に対し選択的増殖抑制活性を示すTyroscherinの合成と構造訂正 (2009)
  • Author(s): 勝田亮、柴田智恵、石神健、早川洋一、渡邉秀典、北原武
  • Organizer: 日本農芸化学会
• [Presentation] GRP78転写抑制物質Efrapeptin Jの研究 (2008)
  • Author(s): 服部優希
  • Organizer: 日本薬学会
  • Place of Presentation: 横浜
  • Year and Date: 2008-03-26
• [Presentation] Roseophilin生産菌が生産する新規Prodigiosin (2008)
  • Author(s): 櫻井芙美、平島麗子、川崎崇、早川洋一
  • Organizer: 日本薬学会
• [Presentation] GRP78転写抑制物質Efrapeptin Hの研究 (2008)
  • Author(s): 服部優希、川崎崇、加納周雄、足立恭子、志津里芳一、早川洋一
  • Organizer: 日本薬学会
• [Presentation] 海洋放線菌が生産する新規piericidin類の研究 (2007)
  • Author(s): 白崎進吾、柴沙香、川崎崇、松尾嘉英、早川洋一
  • Organizer: 日本薬学会
• [Presentation] アデノウィルス癌遺伝子導入細胞に対して選択的アポトーシスを誘導するthioviridamideの研究 (2006)
  • Author(s): 早川洋一、佐々木佳穂里、足立久、新家一男、降旗一夫、永井浩二
  • Organizer: 日本農芸化学会