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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 林淑萍(Shwu-Bin Lin) | |
dc.contributor.author | Su-Yu Chen | en |
dc.contributor.author | 陳書語 | zh_TW |
dc.date.accessioned | 2021-06-15T12:29:47Z | - |
dc.date.available | 2021-08-26 | |
dc.date.copyright | 2016-08-26 | |
dc.date.issued | 2016 | |
dc.date.submitted | 2016-08-05 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/50103 | - |
dc.description.abstract | 本研究自Ganoderma colossum子實體中分離出已知化合物schisanlactone A、colossolactone G與新穎化合物colossolactone H ( colo H)。Colo H對肺癌、肝癌、大腸癌與乳癌細胞具有細胞毒性,其IC50為32.8至68.5 microM。利用基因晶片分析colo H對於肺癌H1650細胞整體基因表現的影響,發現colo H上調的基因顯著地參與在氧化還原中,而被下調的基因則顯著地參與在細胞週期相關調控。進一步發現,colo H引發活性氧化物(reactive oxygen species, ROS)上升、損壞DNA並增加抑癌基因p53,導致細胞生長停滯與細胞凋亡。Colo H與艾瑞莎合併使用於H1650 (具艾瑞莎抗藥性之肺癌細胞株)時發現,ROS上升與細胞凋亡程度加劇。動物實驗也顯示,colo H合併艾瑞莎使用顯著地抑制腫瘤生長。另一方面,colo H抑制12-O-Tetradecanoyl-phorbol-13-acetate引發的ERK、JNK、c-Jun與matrix metalloproteinases 9活化,進而抑制H1650細胞之侵襲能力。此外,在具高度轉移性肺癌細胞CL1-5中,colo H透過引發ROS上升、活化Rb造成了間質-表皮細胞轉型與爬行、侵襲能力的下降。這些實驗結果顯示新穎化合物colo H具有發展為抗癌藥物與輔助療法之潛力。本論文系統性地分析colo H對癌細胞整體基因表現的影響,有助於釐清藥物的作用機制。 | zh_TW |
dc.description.abstract | In this study, three triterpene dilactones, including two known compounds, schisanlactone A and colossolactone G, as well as a novel compound, colossolactone H (colo H), were isolated from Ganoderma colossum. Colo H exhibited cytotoxicity to lung, liver, colon and breast cancer cell lines, with the IC50 between 32.8~68.5 microM. By gene chip analysis, we determined the colo H-affected gene expression changes. The colo H-upregulated genes were significantly enriched in oxidation reduction and the downregulated genes were significantly enriched in cell cycle. Furthermore, colo H was found to arrest cell growth or induce cell apoptosis via increasing cellular reactive oxygen species (ROS) to cause DNA damage, and the induction of the tumor suppressor p53 protein. Combination of colo H and gefitinib significantly enhanced ROS level and apoptosis in H1650 cells (a gefitinib resistant cell line). Colo H combined with gefitinib significantly inhibited tumor growth in vivo. On the other hand, colo H suppressed the invasiveness of H1650 induced by 12-O-Tetradecanoyl-phorbol-13-acetate via inhibiting phosphorylation of ERK and JNK, and reducing the expression of c-Jun and matrix metalloproteinases 9. Besides, colo H inhibited migration, invasion, and induced mesenchymal-to-epithelial transition through modulating intracellular ROS and induction of Rb in CL1-5 (a highly metastatic cancer cell line). These results suggest that the novel compound colo H is a potential anti-cancer drug and could be useful in complementary medicine for cancer therapy. This thesis systematically analyzed the colo H-affected gene expression changes helping us clarify the drug mechanism. | en |
dc.description.provenance | Made available in DSpace on 2021-06-15T12:29:47Z (GMT). No. of bitstreams: 1 ntu-105-F97424015-1.pdf: 5413596 bytes, checksum: e4a50a2652015559f7556be38edf74ba (MD5) Previous issue date: 2016 | en |
dc.description.tableofcontents | 口試委員會審定書 I
致謝 II 中文摘要 III 英文摘要 IV 圖目錄 IX 表目錄 XI 附圖目錄 XI 附表目錄 XI 縮寫表 XII 1. 前言 1 1.1 Ganoderma colossum 1 1.2肺癌(Lung cancer) 2 1.3 活性氧化物(Reactive oxygen species, ROS) 7 1.4 細胞週期(cell cycle) 8 1.5 研究目標 9 2. 材料與方法 10 2.1 Ganoderma colossum子實體萃取與純化 10 2.2 莫爾吸光係數測定 11 2.3 細胞培養 11 2.4 細胞生存率測定 (Cell viability assay) 12 2.5 基因晶片 (Gene chip) 12 2.6 細胞週期分析 (Cell cycle analysis) 13 2.7 RNA萃取與即時聚合酶鏈反應(RNA extraction and real-time PCR) 13 2.8 西方墨點分析 (Western blot) 14 2.9 Reactive oxygen species (ROS)分析 16 2.10 Fenton reaction 測定 16 2.11 γ-H2AX免疫螢光染色 16 2.12 細胞Annexin V-PI染色分析 17 2.13 異種移植腫瘤動物實驗 (Xenograft tumor model) 17 2.14 細胞透孔移行與侵襲能力試驗 (Cell migration and invasion assay) 18 2.15 MMP2與MMP9活性染色分析(MMP2 & 9 gelatin zymography assay) 19 2.16 細胞傷口癒合試驗 (Wound healing assay) 19 2.17 細胞絲狀肌動蛋白 (F-actin)染色分析 19 2.18 統計分析 (Statistical Analysis) 20 3. 實驗結果 21 3.1 Ganoderma colossum子實體萃取物分離 21 3.2 Colo H之細胞毒性機制探討 21 3.2.1 Triterpene lactones之細胞毒性 21 3.2.2 Colo H 處理H1650細胞之基因晶片分析 22 3.2.3 Colo H引發Nrf2入核與HO-1表現量上升 24 3.2.4 Colo H造成ROS增加並促進H2O2與FeSO4造成之Fenton reaction 25 3.2.5 Colo H引發DNA損傷與活化p53 26 3.2.6 Colo H透過ROS累積造成p53上升與細胞毒性 26 3.2.7 Colo H高濃度處理H1650細胞株引發細胞凋亡 27 3.3 Colo H與艾瑞莎合併使用於肺癌之探討 27 3.3.1 Colo H 與艾瑞莎合併使用增加細胞毒性 27 3.3.2 Colo H促進艾瑞莎處理下之細胞ROS增加 28 3.3.3 Colo H促進艾瑞莎處理下之細胞DNA損傷增加 28 3.3.4 Colo H 合併艾瑞莎處理引發大量細胞凋亡 29 3.3.5 Colo H合併使用艾瑞莎能有效抑制抗藥性腫瘤生長 29 3.4 Colo H對癌細胞抗轉移能力之探討 30 3.4.1 Colo H抑制TPA誘發之細胞侵襲能力 30 3.4.2 HO-1產物CO抑制TPA誘發之細胞侵襲能力 31 3.4.3 Colo H抑制肺癌細胞株之爬行、透孔移行與侵襲之能力 32 3.4.4 Colo H造成CL1-5細胞MET 32 3.4.5 Colo H 透過引發ROS上升造成MET與抑制侵襲能力 33 4. 討論 34 圖 40 表 75 附圖表 82 參考文獻 96 藥品清單 106 抗體列表 110 中英字詞對照表 112 個人履歷表(Curriculum Vitae) 114 擬發表論文 118 | |
dc.language.iso | zh-TW | |
dc.title | Ganoderma colossum之新穎化合物colo H於肺癌之抗癌活性研究 | zh_TW |
dc.title | Investigation on anticancer activity of a new triterpene dilactone, colo H, from Ganoderma colossum in lung cancer | en |
dc.type | Thesis | |
dc.date.schoolyear | 104-2 | |
dc.description.degree | 博士 | |
dc.contributor.coadvisor | 張雅雯(Ya-Wen Chang) | |
dc.contributor.oralexamcommittee | 楊雅倩(Ya-Chien Yang),陳進庭(Chin-Tin Chen),楊鉅文(Chu-Wen Yang) | |
dc.subject.keyword | Ganoderma colossum,colossolactone H,氧化傷害,抗癌,輔助療法,艾瑞莎,抗侵襲能力, | zh_TW |
dc.subject.keyword | Ganoderma colossum,colossolactone H,oxidative damage,anti-cancer,complementary therapy,gefitinib,anti-invasion, | en |
dc.relation.page | 131 | |
dc.identifier.doi | 10.6342/NTU201601927 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2016-08-05 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 醫學檢驗暨生物技術學研究所 | zh_TW |
顯示於系所單位: | 醫學檢驗暨生物技術學系 |
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