2000 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 Category	Grant-in-Aid for Scientific Research on Priority Areas (C)
Research Institution	Microbial Chemistry Research Foundation
Principal Investigator	石塚雅章 (財)微生物化学研究会, 化学療法研究所, 副所長 (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	Cuvularol / アポトーシス / NK細胞活性化 / 15-deoxyspergualin / 癌増悪化 / 上皮-間質細胞間反応
Research Abstract	がん増殖環境修飾に関わる最新の分子標的に対する阻害物質あるいは調節物質を天然物中に探索するとともに、それら物質の作用機構を追究し、本年度は以下の成果を得た。 1.新規細胞毒物質の発見:糸状菌培養液よりタンパク合成を阻害し、強い細胞毒性を有する新規セスキテルペン化合物cuvularolを発見した。また、ヒト内皮細胞増殖を特異的に阻害するデカリン骨格を有する新規物質を発見した。 2.作用機構の研究:(1)微小管阻害活性を有する制癌物質が臨床でも効果を挙げているが、微小管ダメージ後のアポトーシス誘導機構については不明の点が多い。本研究で微小管ダメージ後のアポトーシス誘導が微小管結合性キナーゼPlk依存し、その安定化にHsp90が重要であることを見い出した。(2)癌細胞の転移にはNK細胞の活性化が強く関与していることは明らかである。癌転移阻害物質でPP2Aの特異的阻害物質Cytostatinが強いNK細胞の活性化作用を示し、その誘導体でPP2A阻害活性のないdephosphocytostatinに活性化作用のないことからセリン/スレオニンフォスファターゼがNK細胞の活性化に強く関与していることを発見した。(3)強い抗白血病作用を示す15-deoxyspergualinの構造活性相関を調べ、構造中のスペルミジンが細胞の選択性に強く関与し、本物質がフォスファチジルコリンの合成を阻害して細胞毒性を示すことを見い出した。(4)炎症性サイトカインと癌細胞増殖との関係を調べ、前立腺癌細胞LNCapがIL-1βやTNFαに長時間暴露されると増悪化することが分かった。(5)上皮細胞と間質細胞との細胞間反応による探索系を用いて前立腺肥大形成阻害物質を発見した。

Research Products
(12 results)

All Other

All Publications (12 results)

[Publications] Kawada,M.: "The long-lasting antiproliferative effect of 15-deoxyspergulain through its spermidine moiety."J.Antibiot.. 53. 705-710 (2000)
[Publications] Iijima,M.: "Biosynthesis of IC202C, a new siderophore with immunosupressive activity."J.Antibiot.. 53. 1411-1415 (2000)
[Publications] Sudo,T.: "p62 functions as a p38 MAP kinase regulatior."Biochem.Biophys.Res.Commun.. 269. 521-525 (2000)
[Publications] Ganesh,S.: "Laforin, defective in the progressive myoclonus epilepsy of Lafora type, is a dual-specificity phosphatase associated with polyribosomes."Human Mol.Genet.. 9. 2251-2261 (2000)
[Publications] Ko,H.R.: "CRM646-A and -B, novel fungal metabolites that inhibit heparinase."J.Antibiot.. 53. 211-214 (2000)
[Publications] Watanabe,H.: "Synthesis of pironetin and related analogs : Studies on structure-activity relationships as tubulin assembly inhibitors."J.Antibiot.. 53. 540-545 (2000)
[Publications] Watabe,M.: "Activation of MST/Krs and c-Jun N-terminal kinases by different signaling pathways during cytotrienin A-induced apoptosis."J.Biol.Chem.. 275. 8766-8771 (2000)
[Publications] Matsumoto,M.: "Involvement of p38 mitogen-activated protein kinase signaling pathway in osteoclastogenesis mediated by receptor activator of NF-κ BLigand(RANKL)."J.Biol.Chem.. 275. 31155-31161 (2000)
[Publications] Wang,H.: "Synthesis and evaluation of tryprostatin B and demethoxyfumitremorgin C analogs."J.Med.Chem.. 43. 1577-1585 (2000)
[Publications] Simizu,S.: "Bcl-2 inhibits calcineurin-mediated Fas ligand expression in antitumor drug-induced baby hamster kidney cells."Jpn.J.Cancer Res.. 91. 706-714 (2000)
[Publications] Simizu,S.: "Mutations of Plk gene lead to instability of Plk protein in human cancer cell lines."Nature Cell Biol.. 2. 852-854 (2000)
[Publications] Honda,Y.: "Isolation, and biological properties of a new cell cycle inhibitor, curvularol, isolated from Curvularia sp.RK97-F166."J.Antibiot.. 54. 10-16 (2001)

2000 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)微生物化学研究会, 化学療法研究所, 副所長 (80159722)

Research Products

[Publications] Kawada,M.: "The long-lasting antiproliferative effect of 15-deoxyspergulain through its spermidine moiety."J.Antibiot.. 53. 705-710 (2000)

[Publications] Iijima,M.: "Biosynthesis of IC202C, a new siderophore with immunosupressive activity."J.Antibiot.. 53. 1411-1415 (2000)

[Publications] Sudo,T.: "p62 functions as a p38 MAP kinase regulatior."Biochem.Biophys.Res.Commun.. 269. 521-525 (2000)

[Publications] Ganesh,S.: "Laforin, defective in the progressive myoclonus epilepsy of Lafora type, is a dual-specificity phosphatase associated with polyribosomes."Human Mol.Genet.. 9. 2251-2261 (2000)

[Publications] Ko,H.R.: "CRM646-A and -B, novel fungal metabolites that inhibit heparinase."J.Antibiot.. 53. 211-214 (2000)

[Publications] Watanabe,H.: "Synthesis of pironetin and related analogs : Studies on structure-activity relationships as tubulin assembly inhibitors."J.Antibiot.. 53. 540-545 (2000)

[Publications] Watabe,M.: "Activation of MST/Krs and c-Jun N-terminal kinases by different signaling pathways during cytotrienin A-induced apoptosis."J.Biol.Chem.. 275. 8766-8771 (2000)

[Publications] Matsumoto,M.: "Involvement of p38 mitogen-activated protein kinase signaling pathway in osteoclastogenesis mediated by receptor activator of NF-κ BLigand(RANKL)."J.Biol.Chem.. 275. 31155-31161 (2000)

[Publications] Wang,H.: "Synthesis and evaluation of tryprostatin B and demethoxyfumitremorgin C analogs."J.Med.Chem.. 43. 1577-1585 (2000)

[Publications] Simizu,S.: "Bcl-2 inhibits calcineurin-mediated Fas ligand expression in antitumor drug-induced baby hamster kidney cells."Jpn.J.Cancer Res.. 91. 706-714 (2000)

[Publications] Simizu,S.: "Mutations of Plk gene lead to instability of Plk protein in human cancer cell lines."Nature Cell Biol.. 2. 852-854 (2000)

[Publications] Honda,Y.: "Isolation, and biological properties of a new cell cycle inhibitor, curvularol, isolated from Curvularia sp.RK97-F166."J.Antibiot.. 54. 10-16 (2001)

石塚雅章 (財)微生物化学研究会, 化学療法研究所, 副所長 (80159722)