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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 林辰栖 | |
| dc.contributor.author | Yi-Jhen Hsieh | en |
| dc.contributor.author | 謝宜臻 | zh_TW |
| dc.date.accessioned | 2021-07-10T21:34:43Z | - |
| dc.date.available | 2021-07-10T21:34:43Z | - |
| dc.date.copyright | 2016-11-02 | |
| dc.date.issued | 2016 | |
| dc.date.submitted | 2016-08-18 | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/76665 | - |
| dc.description.abstract | 犬黑色素瘤是犬常見罹患的癌症之一，約佔所有癌症的4-7%。目前犬黑色素瘤的治療方式以手術切除為主，然而惡性的黑色素瘤在術後依然有很高的復發率，因此也期望能發展出新興的治療方式來更有效的治療犬黑色素瘤。Sorafenib為酪胺酸激酶抑制劑(tyrosine kinase inhibitor) ，能阻斷RAS/RAF/MEK/ERK 訊息傳導路徑與轉錄訊息傳遞及活化子蛋白3 (Signal transducer and activator of transcription 3, STAT3) ，並且已核准用於治療人類晚期肝癌及腎細胞癌的小分子標靶藥物。近來，許多文獻也指出在人與犬的多種癌細胞中，STAT3 都呈現過度表現的現象，而STAT3 調控了細胞增生、存活及細胞凋亡，因此也被認為與癌症的形成有關。本篇研究的目的為探討Sorafenib 的衍生物SC-43 於犬黑色素瘤中的抗癌效果與其分子機制。由實驗結果發現， SC-43 在犬黑色素瘤細胞株中顯現出誘導細胞凋亡的能力，達到抑制腫瘤細胞生長的效果皆優於Sorafenib ，此效應是藉由SC-43 透過調降STAT3的活化進而影響下游相關蛋白Survivin 及 Cyclin D1 的表現量，進而影響細胞的生長與存活。SC-43 不僅能夠誘導細胞進行細胞凋亡，更發現到SC-43 能藉由活化細胞自噬造成犬黑色素瘤細胞的死亡。此外，利用SHP-1 抑制劑以抑制SHP-1 的活性，能夠反轉SC-43 所誘導的細胞凋亡，顯示出SC-43 是透過增加SHP-1 的活性，達到調降p-STAT3 的表現量。總結而言， SC-43 在犬黑色素瘤細胞中，藉由活化SHP-1 的活性來抑制STAT3 的磷酸化，進而誘導細胞凋亡與細胞自噬效應，達到更優於Sorafenib 的效果。更重要的是在小鼠的動物模式中，給予小鼠SC-43 10 毫克/公斤/天的劑量治療30天，腫瘤的大小僅為控制組的32% ，顯示出SC-43 具有顯著的抗癌效果。 | zh_TW |
| dc.description.provenance | Made available in DSpace on 2021-07-10T21:34:43Z (GMT). No. of bitstreams: 1 ntu-105-R03629010-1.pdf: 2605166 bytes, checksum: 3e9331aa6789ff635174414c0c54287d (MD5) Previous issue date: 2016 | en |
| dc.description.tableofcontents | 口試委員審定書 I
誌謝 II 中文摘要 III Abstract IV Contents VI Chapter 1 Introduction 1 Chapter 2 Background and Literature Review 3 2.1 Canine melanoma 3 2.1.1 Epidemiology of canine melanoma 3 2.1.2 Etiology 4 2.1.3 Treatment and prognosis for canine melanoma 5 2.2 Human melanoma 7 2.2.1 Epidemiology of human melanoma 7 2.2.2 Etiology 8 2.2.3 Types of human melanoma 11 2.2.4 Treatment and prognosis for human melanoma 14 2.3 Signal Transducer and Activator of Transcription 3 (STAT3) 17 2.3.1 The STAT family of proteins 17 2.3.2 Overactive STAT3 in cancer 19 2.3.3 STAT3 in cell proliferation and apoptosis 20 2.3.4 STAT3 as targets for cancer therapy 20 2.4 Molecular Targeting Strategies in Cancer Therapies 21 2.4.1 Overview of targeted therapies for cancer 21 2.4.2 Tyrosine kinase inhibitors 22 2.4.3 Tyrosine kinase inhibitors in veterinary medicine 23 2.4.4 SC-43 and sorafenib 25 Chapter 3 Materials and Methods 27 3.1 Cell culture 27 3.2 Cell viability analysis 28 3.3 Cell cycle sub-G1 phase analysis 29 3.4 Western blotting 29 3.5 Acridine orange staining 31 3.6 Canine melanoma cells with ectopic expression of STAT3 31 3.7 Xenograft model 32 3.8 Statistical analysis 33 Chapter 4 Results 34 4.1 SC-43 reduced cell viability in canine melanoma cells 34 4.2 SC-43 demonstrated more potent apoptotic activity than sorafenib in canine melanoma cells 35 4.3 SC-43 showed more effective p-STAT3 down-regulation than sorafenib in canine melanoma cells 35 4.4 Down-regulation of p-STAT3 mediates by SC-43 contributed to autophagy in UCDK9M5 cells 37 4.5 Overexpression of STAT3 showed protective effects on SC-43 induced apoptosis 39 4.6 SHP-1 was involved in SC-43 induced apoptosis and inhibition of p-STAT3 39 4.7 Therapeutic evaluation of SC-43 on canine melanoma xenograft tumor growth in vivo 40 Chapter 5 Discussion 42 Tables 52 Figures 53 Figure 1. Chemical structure of sorafenib and SC-43. 53 Figure 2. SC-43 showed cytotoxicity in canine melanoma cells. 54 Figure 3. SC-43 demonstrated no toxic effect in MDCK cells. 55 Figure 4. Inhibiting proliferation of canine melanoma cells by sorafenib and SC-43 56 Figure 5. SC-43 inhibited the viability of canine melanoma cells in a time-dependent manner 57 Figure 6. SC-43 induced apoptosis in KMeC, Pu and CM01 cell lines 58 Figure 7. SC-43 inhibited p-STAT3 signaling pathway 59 Figure 8. SC-43 reduced the expression of cyclin D1 and survivin. 60 Figure 9. Effects of SC-43 on STAT3-related protein 61 Figure 10. SC-43 demonstrated more potent p-STAT3 inhibition than sorafenib 62 Figure 11. SC-43 increased the autophagy in UCDK9M5 cell line 63 Figure 12. SC-43 induced acidic vesicular organelles (AVOs) in UCDK9M5 cells 64 Figure 13. SC-43 induced apoptosis was abolished in STAT3- overexpressed canine melanoma cells 65 Figure 14. Inhibition of SHP-1 reverses effects of SC-43 on p-STAT3 and apoptosis 66 Figure 15. Xenograft canine melanoma tumor model on nude mice 67 Figure 16. Therapeutic evaluation of the effect of SC-43 and sorafenib on Pu-bearing mice 68 Figure 17. SC-43 had a suppressive effect on tumor formation in vivo. 69 Figure 18. Western blot analysis of p-STAT3 expression in the Pu xenograft tumors 70 References 71 | |
| dc.language.iso | en | |
| dc.subject | SHP-1 | zh_TW |
| dc.subject | 轉錄訊息傳遞及活化子蛋白3 | zh_TW |
| dc.subject | Sorafenib | zh_TW |
| dc.subject | 犬黑色素瘤 | zh_TW |
| dc.subject | SC-43 | zh_TW |
| dc.subject | Canine melanoma | en |
| dc.subject | SC-43 | en |
| dc.subject | Sorafenib | en |
| dc.subject | STAT3 | en |
| dc.subject | SHP-1 | en |
| dc.title | 探討Sorafenib衍生物在犬黑色素瘤的抗癌效果 | zh_TW |
| dc.title | Investigation of the Anti-tumor Effect of Sorafenib Derivative on Canine Melanoma | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 104-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 廖光文,張仕杰,蔡女滿,廖泰慶 | |
| dc.subject.keyword | 犬黑色素瘤,SC-43,Sorafenib,轉錄訊息傳遞及活化子蛋白3,SHP-1, | zh_TW |
| dc.subject.keyword | Canine melanoma,SC-43,Sorafenib,STAT3,SHP-1, | en |
| dc.relation.page | 93 | |
| dc.identifier.doi | 10.6342/NTU201603227 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2016-08-20 | |
| dc.contributor.author-college | 獸醫專業學院 | zh_TW |
| dc.contributor.author-dept | 獸醫學研究所 | zh_TW |
| 顯示於系所單位： | 獸醫學系 | |
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