2003 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	The Institute of Physical and Chemical Research
Principal Investigator	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)
Co-Investigator(Kenkyū-buntansha)	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)
Keywords	血管新生阻害剤 / 分子標的 / PP2A / Bcl-2 / アポトーシス / 転移
Research Abstract	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。

Research Products
(24 results)

All Other

All Publications (24 results)

[Publications] Watanabe, N.et al.: "M-phase kinases induce phospho-dependent ubiquitination of somatic Weel by SCFbTrCP."Proc.Natl.Acad.Sci., USA.. (in press). (2004)
[Publications] 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)
[Publications] Simizu, S.et al.: "Secretion of heparanase protein is regulated by glycosylation in human tumor cell lines."J.Biol.Chem.. 279. 2697-2703 (2004)
[Publications] Woehlecke, H.et al.: "Reversal of breast cancer resistance protein-mediated drug resistance by tryprostatin A."Int.J.Cancer.. 107. 721-728 (2003)
[Publications] 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)
[Publications] 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)
[Publications] Kakeya, H.et al.: "Novel non-peptide inhibitors targeting death receptor-mediated apoptosis."Bioorg.Med.Chem.Lett.. 13. 3743-3746 (2003)
[Publications] Su, S.et al.: "Synthesis and cell cycle inhibition of the peptide enamide natural products terpeptin and the aspergillamides."Tetrahedron. 59. 8931-8946 (2003)
[Publications] Maruyama, M.et al.: "Renal abnormalities in mice Caused by insufficiency of p38 α."J.Rec.Sig.Trans.. 23. 173-183 (2003)
[Publications] Shoji, M.et al.: "Reaction modes of oxidative dimerization of epoxycyclohexenols."Tetrahedron Lett.. 44. 7205-7207 (2003)
[Publications] 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)
[Publications] Sekiyama, Y.et al.: "Biosynthesis of phoslactomycins : cyclohexanecarboxylic acid as the starter unit."Tetrahedron. 59. 7465-7471 (2003)
[Publications] Nagashima, F.et al.: "Apoptosis-inducing properties of ent-kaurene-type diterpenoids from the liverwort jungermannia truncat α."Planta Medica. 69. 377-379 (2003)
[Publications] Hayashi, Y.et al.: "Asymmetric total synthesis of pseurotin A."Organic Lett.. 5. 2287-2290 (2003)
[Publications] Simizu, S.et al.: "Expression of heparanase in human tumor cell lines and human head and neck tumors."Cancer Lett.. 193. 83-89 (2003)
[Publications] 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)
[Publications] Osada, H.: "Development and application of bioprobes for mammalian cell cycle analyses."Cur.Med.Chem.. 10. 727-732 (2003)
[Publications] 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)
[Publications] Nakazawa, J.et al.: "A novel action of terpendole E on the motor activity of mitotic kinesin Eg5."Chem.& Biol.. 10. 131-137 (2003)
[Publications] 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)
[Publications] Takamoto, K.et al.: "Aminoglycoside antibiotics reduce glucose reabsorption in kidney through down-regulation of SGLT1."Biochem.Biophys.Res.Commun.. 308. 866-871 (2003)
[Publications] Kawada, M., Ishizuka, M.: "Inhibition of CTP : Phosphocholine cytidylyltransferase activity by 15-deoxyspergualin."J.Antibiot.. 56. 725-726 (2003)
[Publications] 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)
[Publications] 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 Fiscal Year Annual Research Report

がん増殖環境修飾物質の研究

Principal Investigator

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)

Research Products

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

[Publications] 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)

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

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

[Publications] 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)

[Publications] 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)

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

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

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

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

[Publications] 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)

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

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

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

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

[Publications] 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)

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

[Publications] 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)

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

[Publications] 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)

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

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

[Publications] 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)

[Publications] 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)

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)