2002 Fiscal Year Annual Research Report

がん増殖環境修飾物質の研究

Research Project

Project/Area Number	12217157
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, 所長 (80159722)
Co-Investigator(Kenkyū-buntansha)	長田裕之理化学研究所, 抗生物質研究室, 主任研究員 (80160836)
Keywords	血管内皮細胞遊走阻害 / 血管内皮細胞増殖阻害 / がん-間質相互作用 / PP2A阻害剤 / 前立腺がん / アンドロゲン受容体
Research Abstract	平成14年度がん特定領域研究補助金によって以下の成果を得た。 1.VEGFによって誘導される血管内皮細胞遊走阻害剤として、糸状菌の生産する新規化合物azaspireneおよびepoxyquinolAを発見した。いずれの化合物も既存の血管新生阻害剤とは化学構造が大きく異なり、その詳細な作用機構を解析中である。昨年度の本研究で発見した血管内皮細胞増殖を特異的に阻害するf7436物質の生産菌より新たに6種の類縁体を見いだした。 2.がんの増殖に間質との接着や分泌因子が密接に関わっていることから、がん-間質相互作用を調節することでがんを抑制できる可能性がある。我々は新たな実験系として、ヒト正常前立腺間質細胞PrSCと前立腺がん細胞を共培養し、Rhodanile blueを用いてがん細胞を選択的に定量する方法を確立した。この共培養系で増殖が促進されるDU145およびLNCaP細胞の増殖は5-FUおよびBleomycinによって抑制された。 3.NK活性化物質を求めPP2A阻害物質の探索を行った結果、糸状菌培養液に特異的活性を見出し、harzianic acidにZnイオンが配位したものが活性物質と同定された。Zn配位harzianic acidはPP2AをIC50 10μg/mlで阻害したが、1000μg/mlでも他のフォスファターゼPP1を阻害しなかった。 4.抗アンドロゲン剤非依存性前立腺がんにおいてもアンドロゲン受容体(AR)阻害が増殖阻害に作用することを確認し、AR阻害剤の探索系を構築した。

Research Products

(13 results)

All Other

All Publications (13 results)

[Publications] M.Kawada: "Specific inhibitors of protein phosphatase 2A inhibit tumor metastasis through augmentation of natural killer cells"Int.Immunopharmacol.. 3. 179-188 (2003)
[Publications] M.Kawada: "Hygrolidin induces p21 expression and abrogates cell cycle progression at G1 and S phases"Biochem.Biophys.Res.Commun.. 298. 178-183 (2002)
[Publications] M.Kawada: "15-deoxyspergualin inhibits Akt kinase activation and phosphatidylcholine synthesis"J.Biol.Chem.. 277. 27765-27771 (2002)
[Publications] M.Shintani: "Overexpression of cyclin D1 contributes to malignant properties of esophageal tumor cells by increasing VEGF production and decreasing Fas expression"Anticancer Res.. 22. 639-647 (2002)
[Publications] K.Machida: "A novel adenine nucleotide translocase inhibitor, MT-21, induces cytochrome C release by a mitochondrial permeability transition-independent mechanism"J.Biol.Chem.. 277. 31243-31248 (2002)
[Publications] Y.Miyamoto: "Identification of Saccharomyces cerevisiae isoleucyl-tRNA synthetase as target of G1-specific inhibitor reveromycin A"J.Biol.Chem.. 277. 28810-28814 (2002)
[Publications] A.Matsuyama: "In vivo destabilization of dynamic microtubules by HDAC6-mediated deacetylation"EMBO J.. 24. 6820-6831 (2002)
[Publications] Y.Hayashi: "Asymmetric total synthesis of (-)-azaspirene, a nevel angiogenesis inhibitor"J.Am.Chem.Soc.. 124. 12078-12079 (2002)
[Publications] H.Kakeya: "Epoxyquinol A, a highly functionalized pentaketide dimmer with antiangiogenic activity isolated from fungal metabolites"J.Am.Chem.Soc.. 124. 3496-3497 (2002)
[Publications] M.Shoji: "Total synthesis of (+)-epoxyquinols A and B"Angew.Chem.Int.Ed.. 41. 3192-3194 (2002)
[Publications] Y.Asami: "Azaspirene : a novel angiogenesis inhibitor containing a 1-oxa-7-azaspiro [4.4]non-2-ene-4,6-dione skeleton produced by a fungi Neosartorya sp."Orgainc Lett.. 4. 2845-2848 (2002)
[Publications] K.Ueda: "4-isoavenaciolide covalently binds and inhibits VHR, a dual-specificity phosphatase"FEBS Lett.. 525. 48-52 (2002)
[Publications] N.Takahashi-Ando: "A novel lactonohydrolase responsible the detoxification of zearalenone. -Enzyme purification and gene cloning"Biochem.J.. 365. 1-6 (2002)

2002 Fiscal Year Annual Research Report

がん増殖環境修飾物質の研究

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, 所長 (80159722)

Research Products

[Publications] M.Kawada: "Specific inhibitors of protein phosphatase 2A inhibit tumor metastasis through augmentation of natural killer cells"Int.Immunopharmacol.. 3. 179-188 (2003)

[Publications] M.Kawada: "Hygrolidin induces p21 expression and abrogates cell cycle progression at G1 and S phases"Biochem.Biophys.Res.Commun.. 298. 178-183 (2002)

[Publications] M.Kawada: "15-deoxyspergualin inhibits Akt kinase activation and phosphatidylcholine synthesis"J.Biol.Chem.. 277. 27765-27771 (2002)

[Publications] M.Shintani: "Overexpression of cyclin D1 contributes to malignant properties of esophageal tumor cells by increasing VEGF production and decreasing Fas expression"Anticancer Res.. 22. 639-647 (2002)

[Publications] K.Machida: "A novel adenine nucleotide translocase inhibitor, MT-21, induces cytochrome C release by a mitochondrial permeability transition-independent mechanism"J.Biol.Chem.. 277. 31243-31248 (2002)

[Publications] Y.Miyamoto: "Identification of Saccharomyces cerevisiae isoleucyl-tRNA synthetase as target of G1-specific inhibitor reveromycin A"J.Biol.Chem.. 277. 28810-28814 (2002)

[Publications] A.Matsuyama: "In vivo destabilization of dynamic microtubules by HDAC6-mediated deacetylation"EMBO J.. 24. 6820-6831 (2002)

[Publications] Y.Hayashi: "Asymmetric total synthesis of (-)-azaspirene, a nevel angiogenesis inhibitor"J.Am.Chem.Soc.. 124. 12078-12079 (2002)

[Publications] H.Kakeya: "Epoxyquinol A, a highly functionalized pentaketide dimmer with antiangiogenic activity isolated from fungal metabolites"J.Am.Chem.Soc.. 124. 3496-3497 (2002)

[Publications] M.Shoji: "Total synthesis of (+)-epoxyquinols A and B"Angew.Chem.Int.Ed.. 41. 3192-3194 (2002)

[Publications] Y.Asami: "Azaspirene : a novel angiogenesis inhibitor containing a 1-oxa-7-azaspiro [4.4]non-2-ene-4,6-dione skeleton produced by a fungi Neosartorya sp."Orgainc Lett.. 4. 2845-2848 (2002)

[Publications] K.Ueda: "4-isoavenaciolide covalently binds and inhibits VHR, a dual-specificity phosphatase"FEBS Lett.. 525. 48-52 (2002)

[Publications] N.Takahashi-Ando: "A novel lactonohydrolase responsible the detoxification of zearalenone. -Enzyme purification and gene cloning"Biochem.J.. 365. 1-6 (2002)

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