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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳基旺 | zh_TW |
| dc.contributor.advisor | Ji-Wang Chern | en |
| dc.contributor.author | 劉佳蓉 | zh_TW |
| dc.contributor.author | Jia-Rong Liu | en |
| dc.date.accessioned | 2021-07-10T22:14:05Z | - |
| dc.date.available | 2024-02-28 | - |
| dc.date.copyright | 2018-10-11 | - |
| dc.date.issued | 2018 | - |
| dc.date.submitted | 2002-01-01 | - |
| dc.identifier.citation | 1. Batash, R.; Asna, N.; Schaffer, P.; Francis, N.; Schaffer, M. Glioblastoma Multiforme, Diagnosis and Treatment; Recent Literature Review. Curr Med Chem 2017, 24, 3002-3009.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/77656 | - |
| dc.description.abstract | 膠質母細胞瘤是惡性腦癌中最致命、也是復發性最高的癌症。目前對膠質母細胞瘤的治療主要有手術切除，放射線治療及合併使用化療藥物治療等方式。但這些治療只能延緩病患平均存活率約六個月，無法有效治癒。因此，開發更有效的抗腦癌藥物及治療策略有其迫切的需求。研究指出，第六亞型組蛋白去乙醯酶(HDAC6)在膠質母細胞瘤中有異常地過度表達，而且若藉由siRNA誘導的HDAC6 基因敲除來減少HDAC6的蛋白量可以有效抑制膠質母細胞瘤的增殖。在本論文中，我們證實在實驗室中新合成出來的高選擇性HDAC6抑制劑，J22352，它可以促使在膠質母細胞瘤細胞中異常過度表達的HDAC6蛋白水解，顯著減少HDAC6蛋白的表現量，進而減少癌細胞轉移，抑制癌細胞的自噬能力，達到顯著的腫瘤生長抑制。在動物實驗中，有90%腫瘤生長抑制率。值得注意的是，J22352更降低了PD-L1的免疫抑制活性，增加抗癌免疫反應的T細胞活性。總而言之，這些實驗結果表明J22352可以有效促進HDAC6蛋白降解，同時藉由抑制細胞自噬效果並增加T細胞的抗癌免疫反應來達到抗癌作用。 | zh_TW |
| dc.description.abstract | Glioblastoma is the most fatal type of primary brain cancer, and current treatments for glioblastoma are insufficient. HDAC6 is overexpressed in glioblastoma, and siRNA-mediated knockdown of HDAC6 inhibits glioma cell proliferation. Herein, we report a high-selective HDAC6 inhibitor, J22352, which decreased the abundance of overexpressed HDAC6 in glioblastoma. The consequences of decreased HDAC6 expression in response to J22352 inhibited cell migration, increased autophagic cancer cell death and significant tumor growth inhibition in xenograft mouse model. Notably, J22352 reduced the immunosuppressive activity of PD-L1, leading to the restoration of host anti-tumor activity such as increased levels of CD8+ T cells, interferon-gamma (IFN-γ) and tumor-associated inflammatory cytokines IL-2 as well as reduced levels of IL-6. Taken together, these results demonstrate that J22352 can significantly target glioblastoma by not only inhibiting autophagy associated with enhanced anticancer immunity but also evoking PROTAC-like proteolytic degradation of HDAC6. Therefore, this highly selective HDAC6 inhibitor can be considered a potential therapeutic for the treatment of glioblastoma and provide an insight into the mechanisms of this therapy. | en |
| dc.description.provenance | Made available in DSpace on 2021-07-10T22:14:05Z (GMT). No. of bitstreams: 1 ntu-107-D01423201-1.pdf: 4194678 bytes, checksum: 5c75c29b284e6eccfa1862d5cdd0267c (MD5) Previous issue date: 2018 | en |
| dc.description.tableofcontents | 中文摘要 i
Abstract ii List of Tables iv List of Figures v List of Abbreviations vi Chapter 1 Introduction 1 Chapter 2 Materials and methods 6 2.1 Chemical synthesis of the compounds 6 2.2 Enzymatic assay 7 2.3 Cell Lines and culture conditions 8 2.4 Cell proliferation assay 8 2.5 In vitro scratch assay 9 2.6 Immunoblot analysis 9 2.7 Apoptosis-Caspase assay 11 2.8 Immunofluorescence autophagy flux assay 11 2.9 Characterization of T cell subsets 12 2.10 Cytokine measurements 13 2.11 Animal studies 13 Chapter 3 Results 15 3.1 J22352 is an effective HDAC6 inhibitor 15 3.3 HDAC6: overexpression, proliferation and degradation 24 3.4 J22352 inhibits autophagosome-lysosome fusion 32 3.5 In vivo anticancer activity of J22352 40 3.6 J22352 enhances the immune response 42 Chapter 4 Discussion and perspectives 52 References 63 Supplementary Figures 70 | - |
| dc.language.iso | en | - |
| dc.title | 新穎性第六亞型組蛋白去乙醯酶抑制劑在膠質母細胞瘤之抗癌作用機轉探討 | zh_TW |
| dc.title | Investigation of the anticancer mechanisms of a novel HDAC6 inhibitor in glioblastoma | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 106-2 | - |
| dc.description.degree | 博士 | - |
| dc.contributor.oralexamcommittee | 顧記華;忻凌偉;梁碧惠;陳香惠 | zh_TW |
| dc.contributor.oralexamcommittee | Jih-Hwa Guh;Ling-Wei Hsin;Pi-Hui Liang;Shiang-Huei Chen | en |
| dc.subject.keyword | 膠質母細胞瘤,第六亞型組蛋白去乙醯?,細胞自噬,抗癌免疫力,蛋白水解, | zh_TW |
| dc.subject.keyword | glioblastoma,HDAC6,autophagy,anticancer immunity,proteolysis, | en |
| dc.relation.page | 87 | - |
| dc.identifier.doi | 10.6342/NTU201800889 | - |
| dc.rights.note | 未授權 | - |
| dc.date.accepted | 2018-06-04 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 藥學研究所 | - |
| 顯示於系所單位： | 藥學系 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-106-2.pdf 目前未授權公開取用 | 4.1 MB | Adobe PDF |
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