新規天然制癌物質の探索とその作用機序の解明

• Project/Area Number: 09255105
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas (A)
• Allocation Type: Single-year Grants
• Research Institution: Microbial Chemistry Research Foundation
• Principal Investigator: 石塚 雅章 財団法人 微生物化学研究会, 化学療法研究所, 副所長 (80159722)
• Co-Investigator(Kenkyū-buntansha): 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) ; 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・薬学研究科, 教授 (90221241) ; 林 正彦 (社)北里研究所, 基礎研究所, 室長 (20164965)
• Project Period (FY): 1999
• Project Status: Completed (Fiscal Year 1999)
• Budget Amount: ¥111,000,000 (Direct Cost: ¥111,000,000); Fiscal Year 1999: ¥37,000,000 (Direct Cost: ¥37,000,000); Fiscal Year 1998: ¥37,000,000 (Direct Cost: ¥37,000,000); Fiscal Year 1997: ¥37,000,000 (Direct Cost: ¥37,000,000)
• Keywords: テロメラーゼ阻害剤 / 海洋生物由来細胞毒物質 / 細胞接着阻害剤 / 血管新生阻害剤 / 神経突起伸長 / 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 / DNAポリメラーゼβ阻害物質 / チロシンキナーゼ阻害物質 / 多剤耐性克服物質 / IL-6阻害物質 / TGF-β活性調節物質 / サイトカイン調節物質 / 消化管毒性軽減物質

Research Abstract

1.細胞増殖阻害物質:微生物代謝産物よりきわめて選択性に優れたテロメラーゼ阻害活性を示す新規物質GM95物質を発見した。本物質による癌細胞ならびに宿主におけるテロメラーゼ機能の解明が期待される。TGF-β様活性を指標にヒト癌細胞に制癌活性を示す新規物質Q71576 AおよびB物質を発見した。植物由来物質として、微小管脱重合阻害活性を示す新規タキサン化合物Taxezopidine KおよびL、環状ペプチドMoroidin、タンパク合成阻害物質で細胞毒性を示すCephalezomine A-F、海洋生物由来細胞毒性物質、Theopederin類、Hterumalide、Attenol類などの新規物質を発見した。これらの物質については制癌活性の検討が行われる。
2.作用機構の解明:a)微生物生産物より接着因子ビトロネクチンの受容体でヒト血管内皮細胞に分布するαVβ3結合阻害物質としてPyrrothine群抗生物質が同定され、Thiolutinが接着シグナルに深く関与するパキシリンの減少に作用することを示した。b)ヒト腫瘍細胞のG1ならびにG2期特異的停止作用を有するHerboxidineがP27の翻訳を上昇させ、CDK結合活性を持つP27フラグメントを蓄積させることを明らかにした。c)液胞型プロトンポンプATPsaseの阻害剤DestruxinがPC12神経芽腫細胞のカテプシンB活性を阻害して神経突起伸長を誘導することを見出した。神経芽腫ならびに神経線維の研究への展開が期待される。

Research Products

• [Publications] M. Kawada: "Cytostatin, an inhibitor of cell adhesion to extracellular matrix, selectively inhibits protein phosphatase 2A"Biochem. Biophysica Acta. 1452. 209-217 (1999)
• [Publications] M. Kawada: "Enhancement of antiproliferative effects of interleukin-1β and tumor necrosisi factor-α on human prostate cancer LNCaP cells by coculture with normal fibroblasts through secreted interleukin-6"Jpn. J. Cancer Res.. 90. 546-554 (1999)
• [Publications] J. W.-Kim: "Oximidines I and II : Novel antitumor macrolides from Pseudomonas sp"J. Org. Chem.. 64. 153-155 (1999)
• [Publications] N. Fusetani: "Tokaramide A, a new cathepsin B inhibitor from the marine sponge Theonella aff. mirabilis"Bioorg. Med. Chem. Lett.. 9. 3397-3402 (1999)
• [Publications] N. Fusetani: "Koshikamide A_1, a new cytotoxic linear poptode isolated from a marine sponge, Theonella sp"Tetrahedron Lett.. 40. 4687-4690 (1999)
• [Publications] N. Takada: "Isolation and structures of heterumalides NA, NB, NC, ND, and NE, novel macrolides from an okinawan sponge Ircinia sp"Tetrahedron Lett.. 40. 6309-6312 (1999)
• [Publications] N. Takada: "Isolation and structures of attenols A and B, novel bicyclic triols from the chinese bivalve Pinna attenuata"Chem. Lett.. 10. 1025-1026 (1999)
• [Publications] K. Suenaga: "Isolation and structures of kasarin, a novel azetinone compound, isolated from a marine microorganism"Heterocycles.
• [Publications] H. Hosoyama: "Modulation of multidrug resistance in tumor cells by taxinine derivatives"Bioorg. Med. Chem. Lett.. 9. 389-394 (1999)
• [Publications] H. Shigemori: "Taxezopidines J, K, and L, new taxoids from Taxus cuspodata inhibiting Ca^<2+>-induceddepolymerization of microtubules"Tetrahedron. 55. 2553-2558 (1999)
• [Publications] H. Morita: "Antimitotic activity of moroidin, a bicyclic peptide from the seeds of Celosia argentea"Bioorg. Med. Chem. Lett..
• [Publications] Y. B. Kim: "Oxamflatin is a novel antitumor compound that inhibits mammalian histone deacetylase"Oncogene. 18. 2461-2470 (1999)
• [Publications] A. Fukami: "New members of macrosphelide from Microsphreopsis sp. FO-5050 IV"J. Antibiotics. 52. 501-504 (1999)
• [Publications] M. Watabe: "Activation of MST/Krs and c-Jun-N terminal kinases by different signaling pathways during cytotrienin A-induced apoptosis"J. Biol. Chem..
• [Publications] M. Watabe: "Requirement of protein kinase (Krs/MST) activation for MT-21-induced apoptosis"Oncogene. 18. 5211-5220 (1999)
• [Publications] M. Kondoh: "Apoptosis induction via microtubule deisassembly by an antitumour compound, pironetin"Biochem. J.. 340. 411-416 (1999)
• [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)
• [Publications] Kawatsu,M.: "Modulation by conagenin of inflammatory mediator productions in mice given 5-fluorouracil." Anticancer Res.17. 917-922 (1997)
• [Publications] Masuoka,Y.: "A novel substance with TGF-β like activity,deheteropeptin,produced by a fungus,Diheterospora sp." J.Antibiotics. 50. 1058-1060 (1997)
• [Publications] Kim,J.W.: "Apoptolidin,a new apoptosis inducer in transformed cells from Nocardiopsis sp." J.Antibiotics. 50. 628-630 (1997)
• [Publications] Kuramoto,M.: "Absolute configuration of norzoanthamine,a promising candidate for an osteoporotic drug." Tetrahedron Lett.38. 5683-5686 (1997)
• [Publications] Kobayashi,J.: "Effects of taxoids from taxus cuspidata on microtubule depolymerization and vincristine accumulation in MDR cells." Bioorg.Med.Chem.Lett.7. 393-398 (1997)
• [Publications] Shigemori,H.: "Taxuspines X〜Z, new taxoids from Japanese yew Taxus cuspidata." Chem.Pharm.Bull.45. 1205-1208 (1997)
• [Publications] Kobayashi,J.: "Tauroacidine A and B,new brobopyrrole alkaloids with tyrosine kinase inhibitory activity from sponge Hymeniacidon sp." Tetrahedron. 53. 16679-16682 (1997)
• [Publications] Hayashi,M.: "Madindoline,a novel inhibitor of IL-6 activity from Streptomyces sp.K93-0711.I.taxonomy,fermentation,isolation and biological activities." J.Antibiotics. 49. 1091-1095 (1997)
• [Publications] Sunazuka,T.: "Relative and absolute stereochemistries and total synthesis of (+)-macrosphelides A and B,potent,orally bioavailable inhibitors of cell-cell adhesion." J.Am.Chem.Soc.119. 10247-10248 (1997)
• [Publications] Takamatsu,S.: "Madindoline,a novel inhibitor of IL-6 activity from Streptomyces sp.K93-0711.II.physicochemical properties and structural elusidation." J.Antibiotics.50. 1069-1072 (1997)
• [Publications] Kakeya,H.: "Inhibition of cyclin D1 expression and phosphorylation of retinoblastoma protein by phosmidosine,a nucleotide antibiotic." Cancer Res.58. 650-656 (1998)
• [Publications] Kondoh,M.: "Cell cycle arrest and antitumor activity of pironetin and its derivatives." Cancer Lett.125. 1-4 (1998)