1998 Fiscal Year Annual Research Report

新規天然制癌物質の探索とその作用機序の解明

Research Project

Project/Area Number	09255105
Research Institution	Microbial Chemistry Research Foundation
Principal Investigator	石塚雅章財団法人微生物化学研究所, 化学療法研究所, 副所長 (80159722)
Co-Investigator(Kenkyū-buntansha)	長田裕之理化学研究所, 抗生物質, 主任研究員 (80160836) 小林淳一北海道大学, 大学院・薬学研, 教授 (90221241) 上村大輔名古屋大学, 大学院・理学研究科, 教授 (00022731) 伏谷伸宏東京大学, 大学院・農学生命科学研, 教授 (70012010) 瀬戸治男東京大学, 分子細胞生物学研, 教授 (10013335)
Keywords	アポトーシス誘導物質 / 細胞接着阻害物質 / 細胞周期阻害物質 / PP2A / 微小管重合 / caspase-3
Research Abstract	1.新規物質の探索 (1)caspase-3の誘導活性を指標に微生物生産物中にアポトーシス誘導物質を探索し、FE35A、その類縁物質FE35Bおよび6-hydroxytetrangulolを発見した。これらの化合物はU937細胞に対するIC50は各々280nM、3.7nMおよび4.7nMを示し、300-500nM以上でcaspase-3を誘導した。 (2)放線菌の生産するりポペプチドAmamistatinはMCF-7、A549あるいはMKN48などのヒト培養癌細胞に0.24μM-0.56μMで細胞毒性を示した。(3)海藻イギスよりTribromoacetamideを単離、類縁体を合成し活性を検討したところ、N-methyl-N-benzyltribromoacetamideがP388に対して0.11μg/mlのIC50を示し、チューブリン重合阻害並びにアポトーシス誘導活性を示した。 (4)海綿由来、新規mycalolide、30-hydroxymycalolide A、32-hydroxymyca1olide Aおよび38一hydroxymica1olide BのL1210細胞に対するIC50は13-19ng/mlでIC50は骨格部分の立体化学は同一であった。2.作用機序の研究 (1)癌細胞の細胞外マトリックスへの接着阻害物質として得たCytostatinが接着因子インテグリンのシグナル伝達に重要なパキシリンのセリン・スレオニン脱リン酸化酵素、PP2Aを阻害し細胞接着を阻害していることを明らかにした。CalyculinやOkadaic acidなど他のPP2A阻害剤について接着阻害活性を調べたところ活性が認められ、PP2Aがインテグリンを介した細胞接着に重要な役割を果たしていることを示した。 (2)細胞周期阻害剤Tryprostatin Aは細胞内で微小管重合を阻害して細胞周期をM期で停止させることを明らかにした。この重合は微小管結合蛋白質、MAPあるいはTauに依存した重合を特異的に阻害した。

Research Products
(18 results)

All Other

All Publications (18 results)

[Publications] M.Chino: "Effect of a novel antibiotic, heliquinomycin, on DNA helicase and cell growth." J.Antibiotics. 51. 480-486 (1998)
[Publications] M.Kawada: "Differential induction of apoptosis in B16 melanoma and EL-4 lymphoma cells by cytostatin and bactobolin." Jpn.J.Cancer Res.90. 219-225 (1999)
[Publications] N.Yamashita: "6-Hydroxytetrangulol, a new CPP32 protease inducer produced by Streptomyces sp." J.Antibiotics. 51. 79-81 (1998)
[Publications] N.Yamashita: "New ravidomycin analogues, FE35A and FE35B, apoptosis inducers produced by streptomyces rochei." J.Antibiotics. 51. 1105-1108 (1998)
[Publications] Y.Masuoka: "A novel substance with TGF-β like activity, diheteropeptin, produced by a fungus, Diheterospora sp." J.Antibiotics. 50. 1058-1060 (1997)
[Publications] S.Matsunaga: "Thiomycalolides:new cytotoxic trisoxazole-containing macrolides isolated from a marine sponge Mycale sp." J.Nat.Prod.61. 663-666 (1998)
[Publications] S.Matsunaga: "New mycalolides from the marine sponge Mycale magellanica and their interconversion." J.Nat.Prod.61. 1164-1167 (1998)
[Publications] S.Wada: "Actin-binding specificity of marine macrolide toxins, mycalolide B and kabiramide D." J.Biochem.123. 946-952 (1998)
[Publications] H.Arimoto: "Absolute stereostructure of halichlorine;a potent inhibitor of VCAM-1 induction." Tetrahedron Lett.39. 861-862 (1998)
[Publications] X.Wang: "Taxezopidines B〜H, new texoids from Japanese yew Taxus cuspidata." J.Nat.Prod.61. 474-479 (1998)
[Publications] J.Kobayashi: "Modulation of multidrug resistance by taxuspine C and other taxoids from Japanese yew." Bioorg.Med.Lett.8. 1555-1558 (1998)
[Publications] A.Ogawa: "A sulfated glycoglycerolipid from archaebacterium inhibits eukaryotic DNA polymerase α, β and retroviral reverse transcriptase and affects the methyl metanesulfonate cytotoxicity." Int.J.Cancer. 76. 512-518 (1998)
[Publications] S.W.Ki: "Identification of radicicol as an inhibitor of in vivo Ras/Raf interaction by the yeast two-hybrid screen system." J.Antibiotics. 51. 936-944 (1998)
[Publications] H.Nakajima: "FR901228, a potent antitumor antibiotics, is a novel histone deacetylase inhibitor." Exp.Cell Res.241. 126-133 (1998)
[Publications] M.-C.Rho: "Enhancement of drug accumulation by andrastin A produced by penicilium sp.F0-3929 in bincristine-resistant KB cells." J.Antibiotics. 51. 68-72 (1998)
[Publications] T.Usui: "Tryprostatin A, a specific and novel inhibitor of microtubule assembly." Biochem.J.333. 543-548 (1998)
[Publications] H.Osada: "Bioprobes for investigating mammalian cell cycle control." J.Antibiotics. 51. 973-981 (1998)
[Publications] M.Kondoh: "Effects of tryprostatin derivatives on microtubule assembly in vitro and in situ." J.Antibiotics. 51. 801-804 (1998)

1998 Fiscal Year Annual Research Report

新規天然制癌物質の探索とその作用機序の解明

Principal Investigator

石塚 雅章 財団法人微生物化学研究所, 化学療法研究所, 副所長 (80159722)

Research Products

[Publications] M.Chino: "Effect of a novel antibiotic, heliquinomycin, on DNA helicase and cell growth." J.Antibiotics. 51. 480-486 (1998)

[Publications] M.Kawada: "Differential induction of apoptosis in B16 melanoma and EL-4 lymphoma cells by cytostatin and bactobolin." Jpn.J.Cancer Res.90. 219-225 (1999)

[Publications] N.Yamashita: "6-Hydroxytetrangulol, a new CPP32 protease inducer produced by Streptomyces sp." J.Antibiotics. 51. 79-81 (1998)

[Publications] N.Yamashita: "New ravidomycin analogues, FE35A and FE35B, apoptosis inducers produced by streptomyces rochei." J.Antibiotics. 51. 1105-1108 (1998)

[Publications] Y.Masuoka: "A novel substance with TGF-β like activity, diheteropeptin, produced by a fungus, Diheterospora sp." J.Antibiotics. 50. 1058-1060 (1997)

[Publications] S.Matsunaga: "Thiomycalolides:new cytotoxic trisoxazole-containing macrolides isolated from a marine sponge Mycale sp." J.Nat.Prod.61. 663-666 (1998)

[Publications] S.Matsunaga: "New mycalolides from the marine sponge Mycale magellanica and their interconversion." J.Nat.Prod.61. 1164-1167 (1998)

[Publications] S.Wada: "Actin-binding specificity of marine macrolide toxins, mycalolide B and kabiramide D." J.Biochem.123. 946-952 (1998)

[Publications] H.Arimoto: "Absolute stereostructure of halichlorine;a potent inhibitor of VCAM-1 induction." Tetrahedron Lett.39. 861-862 (1998)

[Publications] X.Wang: "Taxezopidines B〜H, new texoids from Japanese yew Taxus cuspidata." J.Nat.Prod.61. 474-479 (1998)

[Publications] J.Kobayashi: "Modulation of multidrug resistance by taxuspine C and other taxoids from Japanese yew." Bioorg.Med.Lett.8. 1555-1558 (1998)

[Publications] A.Ogawa: "A sulfated glycoglycerolipid from archaebacterium inhibits eukaryotic DNA polymerase α, β and retroviral reverse transcriptase and affects the methyl metanesulfonate cytotoxicity." Int.J.Cancer. 76. 512-518 (1998)

[Publications] S.W.Ki: "Identification of radicicol as an inhibitor of in vivo Ras/Raf interaction by the yeast two-hybrid screen system." J.Antibiotics. 51. 936-944 (1998)

[Publications] H.Nakajima: "FR901228, a potent antitumor antibiotics, is a novel histone deacetylase inhibitor." Exp.Cell Res.241. 126-133 (1998)

[Publications] M.-C.Rho: "Enhancement of drug accumulation by andrastin A produced by penicilium sp.F0-3929 in bincristine-resistant KB cells." J.Antibiotics. 51. 68-72 (1998)

[Publications] T.Usui: "Tryprostatin A, a specific and novel inhibitor of microtubule assembly." Biochem.J.333. 543-548 (1998)

[Publications] H.Osada: "Bioprobes for investigating mammalian cell cycle control." J.Antibiotics. 51. 973-981 (1998)

[Publications] M.Kondoh: "Effects of tryprostatin derivatives on microtubule assembly in vitro and in situ." J.Antibiotics. 51. 801-804 (1998)

石塚雅章財団法人微生物化学研究所, 化学療法研究所, 副所長 (80159722)