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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 顧記華 | |
dc.contributor.author | Wei-Ling Chang | en |
dc.contributor.author | 張瑋凌 | zh_TW |
dc.date.accessioned | 2021-06-08T07:22:17Z | - |
dc.date.copyright | 2008-08-08 | |
dc.date.issued | 2008 | |
dc.date.submitted | 2008-07-24 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/26717 | - |
dc.description.abstract | RFLC021是benzimidazole的衍生物,可抑制多種癌細胞的生長活性,包括攝護腺癌細胞(PC-3, DU145, LNCaP)、肝癌細胞(Hep3B, HepG2)、非小細胞肺癌(A549),與表現大量p-glycoprotein的乳癌細胞 (NCI/ADR-RES),其IC50濃度大約介於1.7到3.7 μM。由於RFLC021也抑制NCI/ADR-RES細胞的生長,因此,此化合物可能非p-glycoprotein的受質。RFLC021隨著濃度與時間的增加,造成PC-3、DU-145與LNCaP細胞的細胞週期停止在G2/M時期;在長時間的作用下,RFLC021引起hypodiploid之DNA增加,表示細胞凋亡的發生。由in vitro 微小管試驗與免疫螢光試驗可知,RFLC021於PC-3細胞中會抑制微小管聚合,並造成不正常的有絲分裂紡錘體。此化合物會造成cyclin B1與MPM-2的表現量增加、使CDK1的Thr161與Tyr15位置磷酸化。這些結果顯示RFLC021使細胞停止在G2/M phase。此外,粒線體相關的訊息傳遞也受到RFLC021的影響,包括Mcl-1減少與Bad的斷裂、Bcl-2與Bcl-xL的磷酸化、caspase-9與-3的活化以及poly(ADP-ribose) polymerase (PARP)的斷裂。此外,RFLC021也造成DNA 損傷。有趣的是,JNK抑制劑 SP600125可顯著的降低由RFLC021引起的細胞凋亡,且降低Bcl-2、Bcl-xL磷酸化的表現及caspase-3, -9和PARP的活化,同時也減少了型態異常的紡錘絲形成。另外,SP600125也影響了RFLC021對細胞週期的調控,包括減少MPM-2與cyclin B的表現量,增加cyclin E與p27表現量,使細胞通過Mitotic phase,以2N或4N的形式回到G1 phase。總言之,這些實驗結果顯示出由RFLC021引發之抗生長活性與細胞凋亡作用是透過抑制微小管聚合、使得細胞週期停止在G2/M時期,引發JNK相關的細胞凋亡。 | zh_TW |
dc.description.abstract | RFLC021, a benzimidazole derivative, inhibited cell growth in various cancer cell lines, including prostate cancer PC-3, DU-145 and LNCaP, hepatocellular carcinoma Hep3B and HepG2, non-small cell lung cancer A549, chronic myeloid leukemia K562, acute promyelocytic leukemia HL-60 and P-glycoprotein-rich NCI/ADR-RES cells with IC50 values ranging from 1.7 to 3.7 μM. NCI/ADR-RES cells were susceptible to RFLC021-mediated anticancer effect suggesting that this compound is not a substrate for P-glycoprotein transporter. In flow cytometry analysis, PC-3, DU-145 and LNCaP cells were arrested at G2/M phases in a time- and concentration-dependent manner, followed by a sequential increase of hypodiploid phase (apoptosis). In vitro tubulin turbidity and immunofluorescence assays showed that RFLC021 inhibited tubulin polymerization and caused abnormal mitotic spindles in PC-3 cells. This compound also activated the up-regulation of cyclin B1 expression, Cdk1 phosphorylation at Thr161 as well as Cdc25C phosphorylation and elevation of MPM-2 levels. The data indicate the occurrence of mitotic arrest to RFLC021 action. Moreover, several mitochondria-related signals were modified by RFLC021, including the cleavage of Mcl-1 and Bad, phosphorylation of Bcl-2 and Bcl-xL, activation of caspase-9 and -3, and cleavage of poly(ADP-ribose) polymerase (PARP). Interestingly, the JNK inhibitor SP600125 significantly blunted RFLC021-induced apoptotic cell death associated with an inhibition Bcl-2 and Bcl-xL phosphorylation, caspase-3 activity and PARP cleavage, as well as blocking the formation of abnormal mitotic spindle. In addition, SP600125 also inhibited RFLC021-induced G2/M arrest through the regulation of various cell cycle regulators, including the decrease of MPM-2 and cyclin B levels, increase of cyclin E and p27 levels. It suggests that cells escape from mitotic arrest and re-enter the cell cycle with 2N or 4N (hyperdiploid) DNA content. In summary, the data suggest that RFLC021 induces the anti-proliferative and apoptotic effects through the inhibition of tubulin polymerization, induction of mitotic arrest and triggering of JNK-dependent apoptotic cell death. | en |
dc.description.provenance | Made available in DSpace on 2021-06-08T07:22:17Z (GMT). No. of bitstreams: 1 ntu-97-R95423004-1.pdf: 4989734 bytes, checksum: 1e97403cb12685672f9e16bac4976285 (MD5) Previous issue date: 2008 | en |
dc.description.tableofcontents | 縮寫表 I
中文摘要 III 英文摘要 IV 研究動機 1 文獻回顧 2 實驗材料與方法 12 實驗材料 12 細胞培養 13 細胞計數 13 細胞生長測定法 13 流式細胞儀( flow cytometry )測定細胞凋亡與細胞週期 14 粒線體膜電位(MMP, ∆Ψm)測定 15 西方點墨法 15 微小管體外聚合實驗 17 細胞內微小管聚合試驗 17 HDAC活性assay 17 Ras活性測試 18 共軛焦顯微鏡 18 Benign prostatic hyperplasia (BPH)組織培養 19 資料分析 19 實驗結果 20 RFLC021對於腫瘤細胞生長的抑制作用 20 RFLC021造成細胞型態的改變 20 RFLC021對於腫瘤細胞之細胞週期的作用情形 20 RFLC021對於tubulin/microtubule的影響 21 RFLC021對細胞週期的調控 21 RFLC021引起內生性之細胞凋亡作用 22 RFLC021 對 DNA damage 途徑相關蛋白的影響 23 RFLC021對MAPK kinase 的調控 23 JNK 活化參與RFL021引發之細胞凋亡路徑 23 併用JNK 抑制劑造成細胞產生mitotic slippage與multiploid 24 併用JNK 抑制劑後可減少型態異常的紡錘絲形成 24 RFLC021無法抑制HDAC之活性 24 RFLC021 對良性攝護腺肥大之細胞的影響 25 討論 26 結論 37 圖表 38 參考文獻 61 | |
dc.language.iso | zh-TW | |
dc.title | 探討 Benzimidazole 衍生物在人類荷爾蒙不依賴型前列腺癌細胞
的抗癌作用機轉 | zh_TW |
dc.title | Investigation of the Anti-Tumor Mechanism of Benzimidazole
Derivative in Human Androgen-Independent Prostate Cancer Cells | en |
dc.type | Thesis | |
dc.date.schoolyear | 96-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 黃聰龍,楊家榮,林君榮,孔繁璐 | |
dc.subject.keyword | 細胞凋亡,細胞週期停止於G2/M時期,抗微管蛋白作用,JNK抑制劑, | zh_TW |
dc.subject.keyword | apoptosis,G2/M arrest,anti-microtubule,JNK inhibitor, | en |
dc.relation.page | 68 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2008-07-24 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 藥學研究所 | zh_TW |
顯示於系所單位: | 藥學系 |
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ntu-97-1.pdf 目前未授權公開取用 | 4.87 MB | Adobe PDF |
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