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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳惠文(Huei-Wen Chen) | |
| dc.contributor.author | Pei-Jung Lee | en |
| dc.contributor.author | 李佩蓉 | zh_TW |
| dc.date.accessioned | 2021-06-16T07:02:00Z | - |
| dc.date.available | 2019-07-16 | |
| dc.date.copyright | 2014-10-09 | |
| dc.date.issued | 2014 | |
| dc.date.submitted | 2014-07-15 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/57759 | - |
| dc.description.abstract | 肺癌是影響國人重大的疾病之一，根據行政院衛生福利部統計資料顯示，癌症病人中因肺癌死亡的人數佔所有癌症的第一名，若能找出治療肺癌的藥物對病人來說是一大福祉。目前治療肺癌的第一線用藥為Cisplatin，然而病人治療後癒後不佳，且常有復發的情況。近年來研究發現，癌症細胞中存在一群癌症幹細胞(Cancer stem cell)，與抗藥性、遠端轉移和癌症復發有關。現有的化療藥物只能針對分裂比較快速的癌症細胞，對癌症幹細胞並沒有明顯治療效果，而導致癌症抗藥性與復發。因此，精確尋找出對癌症幹細胞有效之藥物，是目前癌症醫學研究當務之急。本研究目的即在發展針對肺癌幹細胞之抗癌藥物，單獨或合併現有化療藥物，找出更適合治療肺癌的治療方式。我們在in vitro實驗中，利用影像高速篩選系統 (Image-based high content screening system)來進行初步篩選，找尋能抑制肺癌幹細胞的藥物，我們在227種藥物中篩選出AE1024在1 μM 即能降低細胞幹細胞特性，並專一性的針對癌細胞(Cancer stem cell IC50 < 1 μM; cancer cells IC50 < 20 μM, BEAS2B: 26.77 μM, normal fibroblast: 39.13 μM)，故選之為候選藥物；利用qPCR來發現細胞給予AE1024後，幹細胞標誌Nanog、Oct3/4、Sox2 mRNA的表現量下降。在in vivo實驗中，透過Xenograft模式來探討AE1024抑制腫瘤生成的能力，結果顯示，AE1024相較於控制組較能抑制腫瘤生長。綜合上述，AE1024為具有潛力針對肺癌幹細胞的藥物。未來也將繼續探討AE1024抑制肺癌幹細胞可能的機轉。 | zh_TW |
| dc.description.abstract | Lung cancer is the leading cause of cancers. Cisplatin is one of the first line chemotherapy for lung cancer currently. However, most of the patients have tumor relapse after therapy. Recently, cancer stem cells (CSCs) have been proposed to be responsible for drug resistance, tumor recurrence and metastasis. Conventional therapy targets at proliferative cells rather than CSCs. Therefore, we aim to find out potential compounds targeting on lung cancer stem cells. Using the image–based high content screening system to screen 227 compounds, we have identified AE1024 shows higher potency targeting on lung cancer stem cells (1 μM) and high specificity targeting on cancer stem cell (IC50 < 1 μM) and cancer cell lines (IC50 < 20 μM); compared to normal human bronchial epithelium cells and human normal fibroblast represented by IC50 (26.77 μM versus 39.13 μM). The level of stemness markers, Nanog, Oct3/4 and Sox2 were down-regulated after AE1024 treatment compared to cisplatin treatment. AE1024 could also suppress tumor initiating abilities and self-renew capacities represented by the ability to grow as tumors spheres. Furthermore, we found that AE1024 could inhibit tumor growth as comparing to control or cisplatin treatment in subcutaneous models in severe combined immunodeficient (NOD/SCID) mice. To sum up, AE1024 is a potential compound targeting on lung cancer stem cells. To discover the pharmacological mechanism of AE1024 on cancer stem cells will be helpful to develop new strategy for lung cancer therapy in the future. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T07:02:00Z (GMT). No. of bitstreams: 1 ntu-103-R01447006-1.pdf: 4341041 bytes, checksum: 902afda7618181fa3ee48f37de68df04 (MD5) Previous issue date: 2014 | en |
| dc.description.tableofcontents | Table of contents
誌謝 I 中文摘要 II Abstract IV Introduction 1 Lung cancer 1 Current treatments to non-small cell lung cancer (NSCLC) 2 Cancer stem cells (CSCs) 2 Natural herbal compounds 4 High-through put screening 6 Materials and methods 8 Cell lines and chemicals 8 Proliferation assay 9 Immunofluorescence microscopy 9 Image-based high-content assay 10 Image acquisition and analysis 11 Ultra-low sphere-forming assay 11 ALDEFLUOR assay 12 Real-time reverse transcriptase (RT) Q-PCR 12 Gene expression profiling 13 In vivo study protocol 13 Immunohistochemistry 14 Statistical analysis 15 Results 16 Image–based high content screening identifies CSCs/CAFs forming colonies and other parameters. 16 CSCs/CAFs serve as a screening platform for anti-CSCs/CAF compounds. 17 High-throughput screening reveals AE1024 inhibit CSCs stemness expression. 17 AE1024 inhibits cell proliferation and suppresses lung cancer stemness. 18 AE1024 inhibits tumor growth and nanog expression in pretreatment xenografts model. 20 AE1024 inhibit tumor metastasis in xenografts model. 21 Transcriptomic analysis reveals possible mechanisms of AE1024 23 Discussion 25 Reference 55 | |
| dc.language.iso | en | |
| dc.subject | 抗藥性 | zh_TW |
| dc.subject | 癌症幹細胞 | zh_TW |
| dc.subject | 高速篩選 | zh_TW |
| dc.subject | 藥物開發 | zh_TW |
| dc.subject | Cancer stem cells | en |
| dc.subject | Drug resistance | en |
| dc.subject | High content screening | en |
| dc.subject | Drug discovery | en |
| dc.title | 以高速篩選平台發展肺癌幹細胞專一性藥物-AE1024 | zh_TW |
| dc.title | High-throughput screening identified AE1024 as a potential lead targeting lung cancer stem cells | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 102-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 楊泮池(Pan-Chyr Yang),林泰元(Thai-Yen Ling),陳健尉(Jeremy J.W. Chen) | |
| dc.subject.keyword | 癌症幹細胞,抗藥性,高速篩選,藥物開發, | zh_TW |
| dc.subject.keyword | Cancer stem cells,Drug resistance,High content screening,Drug discovery, | en |
| dc.relation.page | 63 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2014-07-15 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 毒理學研究所 | zh_TW |
| 顯示於系所單位： | 毒理學研究所 | |
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