2003 年度実績報告書

がん増殖環境修飾物質の研究

研究課題

研究課題/領域番号	12217157
研究機関	独立行政法人理化学研究所
研究代表者	長田裕之独立行政法人理化学研究所, 抗生物質研究室, 主任研究員 (80160836)
研究分担者	川田学財団法人微生物化学研究会, 微生物化学研究センター, ユニット長 (20300808)
キーワード	血管新生阻害剤 / 分子標的 / PP2A / Bcl-2 / アポトーシス / 転移
研究概要	がん征圧を目指した薬剤開発には、がん細胞を直接攻撃する抗がん剤の転移を抑制する薬剤の開発が必要である。本研究では、薬剤開発のための標的分子の開拓と、それに対する微生物代謝産物からの阻害剤探索を目的とした。 1.腫瘍血管の新生を阻害する薬剤は、固形腫瘍の栄養を遮断する効果が期待されると同時に、腫瘍細胞が血管内に浸潤し転移することを抑制する有効が期待できる。これまでの探索研究で見出した新規化合物ICMO301が、ラット大動脈を用いたin vitro血管新生モデルで有効性を示した。さらに、血管内皮細胞の増殖阻害剤epoxyqunol Bの標的分子を同定するためにcDNAマイクロアレー解析およびプロテオーム解析を行った。いくつかの標的分子候補を見出したので、今後薬効との関連で詳細な評価を行う予定である。 2.セリンスレオニンホスファターゼPP2Aが、転移および抗がん剤の耐性機構に関わっていることが次第に明らかになってきた。今年度は、アポトーシス抑制たんぱく質Bcl-2がPP2Aで脱リン酸化されること、および低リン酸化型Bcl-2を発現している細胞は抗がん剤に耐性傾向を示すことを明らかにした。PP2Aの特異的阻害剤として新規harzianic acid類縁体homoharzianic acidおよびdemethylharzianic acidを見出した。 3.微小管作用薬が血管新生阻害剤として有効であることが知られている。pironetinがα-tubulinに共有結合することを明らかにしたので、再評価を行う予定である。

研究成果

(24件)

すべてその他

すべて文献書誌 (24件)

[文献書誌] Watanabe, N.et al.: "M-phase kinases induce phospho-dependent ubiquitination of somatic Weel by SCFbTrCP."Proc.Natl.Acad.Sci., USA.. (in press). (2004)
[文献書誌] Minamiguchi, K.et al.: "Ectopic expression of the amino-terminal peptide of androgen receptro leads to androgen receptro dysfunction and inhibition of androgen receptor-mediated prostate cancer growth."Mol.Cell.Endocrinol.. (in press). (2004)
[文献書誌] Simizu, S.et al.: "Secretion of heparanase protein is regulated by glycosylation in human tumor cell lines."J.Biol.Chem.. 279. 2697-2703 (2004)
[文献書誌] Woehlecke, H.et al.: "Reversal of breast cancer resistance protein-mediated drug resistance by tryprostatin A."Int.J.Cancer.. 107. 721-728 (2003)
[文献書誌] Ganesh, S.et al.: "The lafora disease gene product laforin interacts with HIRIP5, a phylogenetically conserved protein containing a Nifu-like domain."Hum.Mol.Genet.. 12. 2359-2368 (2003)
[文献書誌] Kanoh, N.et al.: "Immobilization of natural products on glass slides by using a photoaffinity reaction and the detection of protein-small molecule interactions."Angew.Chem.Int.Ed.. 42. 5584-5587 (2003)
[文献書誌] Kakeya, H.et al.: "Novel non-peptide inhibitors targeting death receptor-mediated apoptosis."Bioorg.Med.Chem.Lett.. 13. 3743-3746 (2003)
[文献書誌] Su, S.et al.: "Synthesis and cell cycle inhibition of the peptide enamide natural products terpeptin and the aspergillamides."Tetrahedron. 59. 8931-8946 (2003)
[文献書誌] Maruyama, M.et al.: "Renal abnormalities in mice Caused by insufficiency of p38 α."J.Rec.Sig.Trans.. 23. 173-183 (2003)
[文献書誌] Shoji, M.et al.: "Reaction modes of oxidative dimerization of epoxycyclohexenols."Tetrahedron Lett.. 44. 7205-7207 (2003)
[文献書誌] Palaniappan, N.et al.: "Enhancement and selective production of phoslactomycin B, a protein phosphatase iia inhibitor, through identification and engineering of the corresponding biosynthetic gene cluster."Planta Medica. 69. 377-379 (2003)
[文献書誌] Sekiyama, Y.et al.: "Biosynthesis of phoslactomycins : cyclohexanecarboxylic acid as the starter unit."Tetrahedron. 59. 7465-7471 (2003)
[文献書誌] Nagashima, F.et al.: "Apoptosis-inducing properties of ent-kaurene-type diterpenoids from the liverwort jungermannia truncat α."Planta Medica. 69. 377-379 (2003)
[文献書誌] Hayashi, Y.et al.: "Asymmetric total synthesis of pseurotin A."Organic Lett.. 5. 2287-2290 (2003)
[文献書誌] Simizu, S.et al.: "Expression of heparanase in human tumor cell lines and human head and neck tumors."Cancer Lett.. 193. 83-89 (2003)
[文献書誌] Kawatani, M.et al.: "Transmembrane domain of Bcl-2 is required for inhibition of ceramide synthesis, but not cytochrome c release in the pathway of inostamysin-induced apoptosis."Exp.Cell.Res.. 286. 57-66 (2003)
[文献書誌] Osada, H.: "Development and application of bioprobes for mammalian cell cycle analyses."Cur.Med.Chem.. 10. 727-732 (2003)
[文献書誌] Miyake, Y.et al.: "Epoxycyclohexenone inhibits fas-mediated apoptosis by blocking activation of pro-caspase-8 in the death-inducing signaling complex."J.Biol.Chem.. 278. 11213-11220 (2003)
[文献書誌] Nakazawa, J.et al.: "A novel action of terpendole E on the motor activity of mitotic kinesin Eg5."Chem.& Biol.. 10. 131-137 (2003)
[文献書誌] Nakamura, M.et al.: "Nordihydroguaiaretic acid, of a new family of microtubule-stabilizing agents, shows effects differentiated from paclitaxel."Biosci.Biotechnol.Biochem.. 67. 151-157 (2003)
[文献書誌] Takamoto, K.et al.: "Aminoglycoside antibiotics reduce glucose reabsorption in kidney through down-regulation of SGLT1."Biochem.Biophys.Res.Commun.. 308. 866-871 (2003)
[文献書誌] Kawada, M., Ishizuka, M.: "Inhibition of CTP : Phosphocholine cytidylyltransferase activity by 15-deoxyspergualin."J.Antibiot.. 56. 725-726 (2003)
[文献書誌] Minamiguchi, K.et al.: "Androgen-independent prostate cancer DU-145 cells suppress androgen-dependent growth of prostate stromal cells through production of inhibitory factors for androgen responsiveness."Biochem.Biophys.Res.Commun.. 306. 629-636 (2003)
[文献書誌] Kawada, M.et al.: "Specific inhibitors of protein phosphatase 2A inhibit tumor metastasis through augmentation of natural killer cells."Int.Immunopharmacol.. 3. 179-188 (2003)

2003 年度 実績報告書

がん増殖環境修飾物質の研究

研究代表者

長田 裕之 独立行政法人理化学研究所, 抗生物質研究室, 主任研究員 (80160836)

研究成果

[文献書誌] Watanabe, N.et al.: "M-phase kinases induce phospho-dependent ubiquitination of somatic Weel by SCFbTrCP."Proc.Natl.Acad.Sci., USA.. (in press). (2004)

[文献書誌] Minamiguchi, K.et al.: "Ectopic expression of the amino-terminal peptide of androgen receptro leads to androgen receptro dysfunction and inhibition of androgen receptor-mediated prostate cancer growth."Mol.Cell.Endocrinol.. (in press). (2004)

[文献書誌] Simizu, S.et al.: "Secretion of heparanase protein is regulated by glycosylation in human tumor cell lines."J.Biol.Chem.. 279. 2697-2703 (2004)

[文献書誌] Woehlecke, H.et al.: "Reversal of breast cancer resistance protein-mediated drug resistance by tryprostatin A."Int.J.Cancer.. 107. 721-728 (2003)

[文献書誌] Ganesh, S.et al.: "The lafora disease gene product laforin interacts with HIRIP5, a phylogenetically conserved protein containing a Nifu-like domain."Hum.Mol.Genet.. 12. 2359-2368 (2003)

[文献書誌] Kanoh, N.et al.: "Immobilization of natural products on glass slides by using a photoaffinity reaction and the detection of protein-small molecule interactions."Angew.Chem.Int.Ed.. 42. 5584-5587 (2003)

[文献書誌] Kakeya, H.et al.: "Novel non-peptide inhibitors targeting death receptor-mediated apoptosis."Bioorg.Med.Chem.Lett.. 13. 3743-3746 (2003)

[文献書誌] Su, S.et al.: "Synthesis and cell cycle inhibition of the peptide enamide natural products terpeptin and the aspergillamides."Tetrahedron. 59. 8931-8946 (2003)

[文献書誌] Maruyama, M.et al.: "Renal abnormalities in mice Caused by insufficiency of p38 α."J.Rec.Sig.Trans.. 23. 173-183 (2003)

[文献書誌] Shoji, M.et al.: "Reaction modes of oxidative dimerization of epoxycyclohexenols."Tetrahedron Lett.. 44. 7205-7207 (2003)

[文献書誌] Palaniappan, N.et al.: "Enhancement and selective production of phoslactomycin B, a protein phosphatase iia inhibitor, through identification and engineering of the corresponding biosynthetic gene cluster."Planta Medica. 69. 377-379 (2003)

[文献書誌] Sekiyama, Y.et al.: "Biosynthesis of phoslactomycins : cyclohexanecarboxylic acid as the starter unit."Tetrahedron. 59. 7465-7471 (2003)

[文献書誌] Nagashima, F.et al.: "Apoptosis-inducing properties of ent-kaurene-type diterpenoids from the liverwort jungermannia truncat α."Planta Medica. 69. 377-379 (2003)

[文献書誌] Hayashi, Y.et al.: "Asymmetric total synthesis of pseurotin A."Organic Lett.. 5. 2287-2290 (2003)

[文献書誌] Simizu, S.et al.: "Expression of heparanase in human tumor cell lines and human head and neck tumors."Cancer Lett.. 193. 83-89 (2003)

[文献書誌] Kawatani, M.et al.: "Transmembrane domain of Bcl-2 is required for inhibition of ceramide synthesis, but not cytochrome c release in the pathway of inostamysin-induced apoptosis."Exp.Cell.Res.. 286. 57-66 (2003)

[文献書誌] Osada, H.: "Development and application of bioprobes for mammalian cell cycle analyses."Cur.Med.Chem.. 10. 727-732 (2003)

[文献書誌] Miyake, Y.et al.: "Epoxycyclohexenone inhibits fas-mediated apoptosis by blocking activation of pro-caspase-8 in the death-inducing signaling complex."J.Biol.Chem.. 278. 11213-11220 (2003)

[文献書誌] Nakazawa, J.et al.: "A novel action of terpendole E on the motor activity of mitotic kinesin Eg5."Chem.& Biol.. 10. 131-137 (2003)

[文献書誌] Nakamura, M.et al.: "Nordihydroguaiaretic acid, of a new family of microtubule-stabilizing agents, shows effects differentiated from paclitaxel."Biosci.Biotechnol.Biochem.. 67. 151-157 (2003)

[文献書誌] Takamoto, K.et al.: "Aminoglycoside antibiotics reduce glucose reabsorption in kidney through down-regulation of SGLT1."Biochem.Biophys.Res.Commun.. 308. 866-871 (2003)

[文献書誌] Kawada, M., Ishizuka, M.: "Inhibition of CTP : Phosphocholine cytidylyltransferase activity by 15-deoxyspergualin."J.Antibiot.. 56. 725-726 (2003)

[文献書誌] Minamiguchi, K.et al.: "Androgen-independent prostate cancer DU-145 cells suppress androgen-dependent growth of prostate stromal cells through production of inhibitory factors for androgen responsiveness."Biochem.Biophys.Res.Commun.. 306. 629-636 (2003)

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

2003 年度実績報告書

長田裕之独立行政法人理化学研究所, 抗生物質研究室, 主任研究員 (80160836)