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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/36619完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 鄧哲明博士 | |
| dc.contributor.author | Yao-Ting Huang | en |
| dc.contributor.author | 黃耀霆 | zh_TW |
| dc.date.accessioned | 2021-06-13T08:08:07Z | - |
| dc.date.available | 2015-12-25 | |
| dc.date.copyright | 2005-08-02 | |
| dc.date.issued | 2005 | |
| dc.date.submitted | 2005-07-21 | |
| dc.identifier.citation | Adams,J.M. and Cory,S. (1998). The Bcl-2 protein family: arbiters of cell survival. Science 281, 1322-1326.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/36619 | - |
| dc.description.abstract | 本論文闡明Alisol B acetate、CIL-102以及YC-1在PC-3前列腺癌細胞株之抗癌作用機轉。
中草藥具備許多抗癌活性成份。本論文的第一部份，我們發現澤瀉中的一種主成份Alisol B acetate可造成PC-3細胞濃度與時間相依性的細胞凋亡。且此一凋亡作用與粒線體膜電位的變化，呈現良好的相關性，顯示粒線體調控之細胞凋亡途徑，參與Alisol B acetate引起的凋亡作用。Alisol B acetate引起Bax蛋白質表現增加且轉置到細胞核，並可觀察到啟始caspase-8、caspase-9及執行caspase-3的活化，顯示外在與內在細胞凋亡途徑均參與Alisol B acetate引起的凋亡作用。研究証實，Alisol B acetate引起粒線體調控的細胞凋亡，伴隨caspase-8、caspase-9、caspase-3之活化，而Bax的表現量增加及其細胞位置的轉變，可能為此一系列作用之重要關鍵步驟。 本論文的第二部份，以一系列的實驗，闡明系列衍生物CIL-102於賀爾蒙抗性前列腺癌細胞株的抗腫瘤作用。以3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenylte-trazolium bromide和sulforhodamine B分析法發現，CIL-102具備很強之抗癌活性。免疫螢光染色法及微細蛋白聚點分析法，顯示CIL-102會與微管蛋白結合並擾亂微小管組織化。流式細胞儀分析法顯示CIL-102造成G2/M細胞週期停滯及凋亡細胞增加。此外，CIL-102造成PC-3細胞中cyclin B1蛋白表現增加及p34cdc2激酶活性增加。而p34cdc2抑制劑olomoucine則明顯減少CIL-102造成的有絲分裂細胞週期蓄積。此外，CIL-102也引起Bcl-2蛋白、Cdc25C蛋白磷酸化以及survivin蛋白表現增加。雖然CIL-102引起的細胞凋亡與caspase-3的活化有關，但廣效型caspase抑制劑僅能部份減低CIL-102引起的細胞凋亡，另一方面，AIF由粒線體釋放到細胞質，顯示存在一條caspase非依賴的訊息傳遞途徑。綜合而言，CIL-102藉由與微小管蛋白結合，擾亂微小管組織化，進而引起細胞週期停滯及細胞凋亡。此外，CIL-102所造成之細胞週期停滯，部分藉由調控細胞週期激酶而來；CIL-102所造成的細胞凋亡，則由caspase與non-caspase兩者所貢獻。 雖然已知indazole衍生物YC-1具抗腫瘤作用，然而其作用標的與機轉仍未被充份研究。本論文第三部份，即在探討YC-1是否直接作用在前列腺癌細胞並引起細胞凋亡，並進一步闡明其抗腫瘤機轉。實驗發現，YC-1可濃度及時間相依性地抑制PC-3細胞增長。以4’,6-diamidino-2-phe-nylindole染色，可發現經YC-1處理的PC-3細胞，其染色質有濃縮現象且sub-G1期細胞增加，這此証據指出細胞凋亡的發生。進一步檢測亦發現，YC-1造成PC-3細胞之caspase-3及poly(ADP-ribose) polymerase裂解。免疫螢光染色法及Enzyme-Linked Immunosorbent Assay分析可發現NF-κB的分佈及活性受到YC-1的抑制。此外，可觀察到磷酸態IκBα蛋白減少及IκBα蛋白蓄積。以腫瘤移植動物模式評估YC-1之抗腫瘤作用，可發現YC-1能有效抑制腫瘤的增大。綜合來說，YC-1在in vitro及in vivo模式均具有效抗腫瘤活性，且YC-1抑制NF-κB活化的作用，或可說明YC-1的抗腫瘤作用機轉。 | zh_TW |
| dc.description.abstract | In the present studies we elucidate the anti-tumour mechanisms of Alisol B acetate, CIL-102 and YC-1 in the androgen-refractory human prostate adenocarcinoma cell line PC-3 cells.
The anti-tumor potential of components from Chinese herbal medicines has been greatly concerned. In the first part, alisol B acetate, a triterpene from Alismatis rhizoma, induced apoptotic cell death in PC-3 cells in a time- and concentration-dependent manner. A good correlation between loss of mitochondrial membrane potential and apoptotic cell death was apparent, indicating the participation of mitochondria-related mechanism. Alisol B acetate induced Bax up-regulation and nuclear translocation; it also induced the activation of initiator caspase-8 and caspase-9, and executor caspase-3, suggesting the involvement of both extrinsic and intrinsic apoptosis pathways. Taken together, it is suggested that alisol B acetate induces apoptosis in PC-3 cells via a mitochondria-mediated mechanism with activation of caspase-8, -9 and -3. Furthermore, the Bax activation and translocation from the cytosol to nucleus might be a crucial response to the apoptotic effect. In the second part, CIL-102, a 4-anilinofuro[2,3-b]quinoline derivative, displayed a potent anti-tumor effect in PC-3 cells by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenylte-trazolium bromide and sulforhodamine B assays. Immunofluorescence microscopy and in vitro tubulin assembly assays indicated that CIL-102 bound to tubulin and disrupted microtubule organization. The data from flow cytometric analysis showed that CIL-102 caused cells to accumulate in G2/M phase and hypodiploid sub-G1 phase of the cell cycle. CIL-102-induced apoptosis was also characterized by immunofluorescence microscopy. Additionally, CIL-102 exposure induced up-regulation of cyclin B1 and p34cdc2 kinase activity while olomoucine, a p34cdc2 inhibitor, profoundly reduced the number of cells accumulated in mitotic phase. Moreover, CIL-102 also induced the increase of Bcl-2 phosphorylation, Cdc25C phosphorylation, and survivin expression. Although CIL-102-induced apoptosis was associated with activation of caspase-3, benzyloxycarbonyl-VAD-fluoromethyl ketone, a pancaspase inhibitor, only partially inhibited the apoptosis, and apoptosis inducing factor（AIF） was translocated from mitochondria to cytosol, suggesting the involvement of a caspase-independent pathway. Taken together, it is suggested that CIL-102 induces mitotic arrest and apoptosis by binding to tubulin and inhibiting tubulin polymerization. CIL-102 causes mitotic arrest, at least partly, by modulating cyclin-dependent kinases and then apoptosis executed by caspase and noncaspase pathways. Although the indazole compound, YC-1, is reported to exert anticancer activities in several cancer cell types, its target and mechanism of action have not been well explored. The objectives of this study were to ascertain whether YC-1 directly induces apoptosis in prostate cancer cells and to explore the anti-tumor mechanism. YC-1 suppressed growth of PC-3 cells in a concentration- and time-dependent manner. Apoptosis was determined using 4’,6-diamidino-2-phe-nylindole staining and cell cycle progression was examined by FACScan flow cytometry. YC-1 treatment showed chromatin condensation and increased the percentage of PC-3 cells in the hypodiploid sub-G1 phase, indicative of apoptosis. Additionally, cells exposed to YC-1 were found to induce activation of caspase-3 and cleavage of PARP. Translocation and activation of NF-κB were determined by immunofluorescent staining and ELISA, respectively. The results demonstrated that YC-1 abolished constitutive nuclear translocation and activation of NF-κB/p65. Furthermore, inhibition of IκBα phosphorylation and accumulation of IκBα were observed. The anti-tumor effects of YC-1 were evaluated by measuring the growth of tumor xenografts in SCID mice. The data demonstrated that the increase of tumor size was significantly inhibited by YC-1. It is suggested that the YC-1 displays potential anti-tumor activity in both in vitro and in vivo models and the suppression of NF-κB activation might explain YC-1-induced anti-tumor effect in PC-3 cells. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-13T08:08:07Z (GMT). No. of bitstreams: 1 ntu-94-D90443005-1.pdf: 3596255 bytes, checksum: 1adbb5b5df0d12c53f6c1b30f2ce84a8 (MD5) Previous issue date: 2005 | en |
| dc.description.tableofcontents | 目錄
縮寫表 - 1 - 中文摘要 - 3 - ABSTRACT - 7 - 研究動機與目的 - 11 - 第一章 - 13 - 文獻回顧 - 13 - 前列腺癌 - 14 - 細胞死亡 - 21 - 細胞凋亡及其機轉 - 25 - 前列腺癌與細胞凋亡 - 32 - 抗癌藥物研發 - 35 - 第二章 - 49 - 實驗材料與方法 - 49 - 第三章 - 65 - ALISOL B MONOACETATE引起前列腺癌細胞凋亡作用的機轉探討 - 65 - 第一節 緒論 - 66 - Alisol B monoacetate - 66 - 第二節 結果 - 66 - 第三節 討論 - 69 - 第四章 - 83 - CIL-102引起前列腺癌細胞之細胞週期停滯與細胞凋亡的機轉探討 - 83 - 第一節 緒論 - 84 - 微小管（Microtubule） - 84 - 抗微小管作用劑及前列腺癌 - 85 - CIL-102 - 86 - 第二節 結果 - 87 - 第三節 討論 - 92 - 第五章 - 113 - YC-1引起前列腺癌細胞之細胞凋亡的機轉探討 - 113 - 第一節 緒論 - 114 - NF-κB - 114 - 前列腺癌之NF-κB活性 - 114 - YC-1 - 115 - 第二節 結果 - 120 - 第三節 討論 - 124 - 第六章 - 139 - 結論與展望 - 139 - REFERENCES - 147 - 著作 與 獎項 壹 | |
| dc.language.iso | zh-TW | |
| dc.subject | 細胞週期 | zh_TW |
| dc.subject | 細胞凋亡 | zh_TW |
| dc.subject | 前列腺癌 | zh_TW |
| dc.subject | apoptosis | en |
| dc.subject | cell cycle | en |
| dc.subject | prostate cancer | en |
| dc.title | 經由調控細胞週期與訊息傳遞途徑之抗前列腺癌藥物作用機轉探討 | zh_TW |
| dc.title | Targeting Cell Cycle and Signaling Pathways by Anticancer Agents in Prostate Cancer | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 93-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.coadvisor | 顧記華博士 | |
| dc.contributor.oralexamcommittee | 黃德富博士,郭盛助博士,楊泮池博士,林建煌博士,顏茂雄博士,楊春茂博士 | |
| dc.subject.keyword | 前列腺癌,細胞凋亡,細胞週期, | zh_TW |
| dc.subject.keyword | prostate cancer,apoptosis,cell cycle, | en |
| dc.relation.page | 164 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2005-07-21 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 藥理學研究所 | zh_TW |
| 顯示於系所單位： | 藥理學科所 | |
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