がん細胞のアポトーシス抵抗性を標的とする抗がん物質の探索

• Project/Area Number: 12217030
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Tokyo University of Science (2004); The University of Tokyo (2000-2003)
• Principal Investigator: 早川 洋一 東京理科大学, 薬学部, 教授 (20208606)
• Project Period (FY): 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥37,900,000 (Direct Cost: ¥37,900,000); Fiscal Year 2004: ¥7,200,000 (Direct Cost: ¥7,200,000); Fiscal Year 2003: ¥7,300,000 (Direct Cost: ¥7,300,000); Fiscal Year 2002: ¥7,200,000 (Direct Cost: ¥7,200,000); Fiscal Year 2001: ¥8,200,000 (Direct Cost: ¥8,200,000); Fiscal Year 2000: ¥8,000,000 (Direct Cost: ¥8,000,000)
• Keywords: 小胞体ストレス / 分子シャペロン / GRP78 / versipelostatin / アポトーシス / FL29 / アデノウイルス / チオアミド / 増殖因子 / IGF / QN23319 / Gymnasterol / QN5727 / p21 / ras / Rasfonin / Byssochlamysol / ヒトパピローマウイルス / Oximidine I / 液胞型H^+-ATPase / スポトーシス / がん遺伝子 / Ras / マクロライド / ヒストンデアセチラーゼ / PAI-1 / HDAC1 / MAPK

Research Abstract

小胞体ストレスに呼応して発現上昇する分子シャペロンGRP78は固形がんのアポトーシス抵抗性に関与することが知られている。Streptomyces versipellisと同定した放線菌から得られた新規物質versipelostatin (VST)は、低グルコースや2-デオキシグルコース処理した固形がん細胞に対してGRP78の発現をmRNAレベルで抑制し、選択的細胞死を誘導した。VSTは小胞体ストレス応答の転写活性化因子であるXBP1およびATF4の産生を抑制した。また、MKN74ヒト胃がんを移植したヌードマウスにおいて、VSTは単独で抗腫瘍活性を示し、シスプラチンとの併用ではさらに高い抗腫瘍効果が認められた。
がん遺伝子導入細胞に対して選択的にアポトーシスを誘導する物質を探索した結果、Streptomyces olivoviridisと同定した放線菌の培養物中に新規活性物質FL29を見いだした。各種機器分析により、FL29は分子式(イオン)C_<56>H_<93>N_<14>O_<10>S_7+のペプチド化合物であり、多数のチオアミド結合を有する極めてユニークな構造であることが判明した。各種がん遺伝子で形質転換したラット3Y1線維芽細胞に対する作用を調べたところ、FL29はアデノウイルスE1A遺伝子を有する細胞に対して選択的にアポトーシスを誘導し、特に12型アデノウイルスで形質転換したAd12-3Y1細胞に対して高い活性を示した(IC_<50>3.9ng/ml)。

Research Products

• [Journal Article] Mevashuntin, a novel metabolite produced by inhibition of the mevalonate pathway in Streptomyces prunicolor (2005)
  • Author(s): Kazuo Shin-ya
  • Journal Title: Tetrahedron Letters 46・8 Pages: 1273-1276
• [Journal Article] Effect on tumor cells of blocking survival response to glucose deprivation (2004)
  • Author(s): Hae-Ryong Park
  • Journal Title: Journal of the National Cancer Institute 96・17 Pages: 1300-1310
• [Journal Article] Legioliulin, a new isocoumarin compound responsible for blue-white autofluor-escence in Legionella (Fluoribacter) dumoffii under long-wave length UV light (2004)
  • Author(s): Junko Amemura-Maekawa
  • Journal Title: Biochemical and Biophysical Research Communications 323・3 Pages: 954-959
• [Journal Article] Structure of tyroscherin, an antitumor antibiotic against IGF-1-dependent cells from Pseudallescheria sp. (2004)
  • Author(s): Yoichi Hayakawa
  • Journal Title: The Journal of Antibiotics 57・10 Pages: 634-638
  • NAID: 10013726826
• [Publications] Yoichi Hayakawa: "Gymnasterol, a new antitumor steroid against IGE-dependent cells from Gymnascella dankaliensis"Tetrahedron Letters. 44. 1165-1166 (2003)
• [Publications] Toshiya Mori: "Byssochlamysol, a new antitumor steroid against IGF-1-dependent cells from Byssochlamys nivea. I.Taxonomy, fermentation, isolation_and_biological_activity"The Journal of Antibiotics. 56. 1-5 (2003)
• [Publications] Toshiya Mori: "Byssochlamysol, a new antitumor steroid against IGF-1-dependent cells from Byssochlamys nivea. II.Physico-chemical properties and structure elucidation"The Journal of Antibiotics. 56. 6-8 (2003)
• [Publications] Yoichi Hayakawa: "Oximidine III, a new antitumor antibiotic against transformed cells from Pseudomonas< sp. I.Taxonomy, fermentation, isolation, physico-chemical properties and biological activity"The Journal of Antibiotics. 56. 899-904 (2003)
• [Publications] Yoichi Hayakawa: "Oximidine III, a new antitumor antibiotic against transformed cells from Pseudomonas sp. II.Structure elucidation"The Journal of Antibiotics. 56. 905-908 (2003)
• [Publications] Taijiro Tomikawa: "Structure of aspochalasin H, a new member of the aspochalasin family"The Journal of Antibiotics. 55. 666-668 (2002)
• [Publications] Hae-Ryong Park: "Versipelostatin, a novel GRP78/Bip molecular chaperone down-regulator of microbial origin"Tetrahedron Letters. 43. 6941-6945 (2002)
• [Publications] Manabu Kawada: "Hygrolidin induces p21 expression and abrogates cell cycle progression at G1 and S phases"Biochemical and Biophysical Research Communications. 298. 178-183 (2002)
• [Publications] Yoichi Hayakawa: "Gymnasterol, a new antitumor steroid against IGF-dependent cells from Gymnascella dankaliensis"Tetrahedron Letters. 44. 1165-1166 (2003)
• [Publications] Toshiya Mori: "Byssochlamysol, a new antitumor steroid against IGF-1-dependent cells from Byssochlamys nivea. I. Taxonomy, fermentation, isolation and biological activity"The Journal of Antibiotics. 56. 1-5 (2003)
• [Publications] Toshiya Mori: "Byssochlamysol, a new antitumor steroid against IGF-1-dependent cells from Byssochlamys nivea. II. Physico-chemical properties and structure elucidation"The Journal of Antibiotics. 56. 6-8 (2003)
• [Publications] Yuhta Masuoka: "Spiruchostatins A and B, novel gene expression-enhancing substances produced by Pseudomonas sp"Tetrahedron Letters. 42. 41-44 (2001)
• [Publications] Kazuo Shin-ya: "Telomestatin, a novel telomerase inhibitor from Strepomyces anulatus"Journal of the American Chemical Society. 123. 1262-1263 (2001)
• [Publications] Michael R. Boyd: "Discovery of a novel antitumor benzolactone enamide class that selectively inhibits mammalian vacuolar-type (H^+)-ATPases"The Journal of Pharmacology and Experimental Therapeutics. 297. 114-120 (2001)
• [Publications] Taijiro Tomikawa: "Selective cytotoxicity and stereochemistry of aspochalasin D"The Journal of Antibiotics. 54. 379-381 (2001)
• [Publications] Ryo Murakami: "Ammocidin, a new apoptosis inducer in Ras-dependent cells from Saccharothrix sp. I. Production, isolation and biological activity"The Journal of Antibiotics. 54. 710-713 (2001)
• [Publications] Ryo Murakami: "Ammocidin, a new apoptosis inducer in Ras-dependent cells from Saccharothrix sp. II. Physico-chemical properties and structure elucidation"The Journal of Antibiotics. 54. 714-717 (2001)
• [Publications] Yoichi Hayakawa: "Trichostatin D, a new inducer of phenotypic reversion in transformed cells."The Journal of Antibiotics. 53. 179-183 (2000)
• [Publications] Yuhta Masuoka: "Diheteropeptin, a new substance with TGF-β-like activity, produced by a fungus, Diheterospora chlamydosporia. I.Production, isolation and biological activities."The Journal of Antibiotics. 53. 788-792 (2000)
• [Publications] Yuhta Masuoka: "Diheteropeptin, a novel substance with TGF-β-like activity, produced by a fungus, Diheterospora chlamydosporia. II.Physico-chemical properties and structure elucidation."The Journal of Antibiotics. 53. 793-798 (2000)
• [Publications] Taijiro Tomikawa: "Rasfonin, a new apoptosis inducer in ras-dependent cells from Talaromyces sp."The Journal of Antibiotics. 53. 848-850 (2000)
• [Publications] Yuhta Masuoka: "Spiruchostatins A and B, novel gene expression-enhancing substances produced by Pseudomonas sp."Tetrahedron Letters. 42. 41-44 (2001)
• [Publications] Yuhta Masuoka: "Phoenistatin, a new gene expression-enhancing substance produced by Acremonium phoenicis."The Journal of Antibiotics. 54. 187-190 (2001)