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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 鄧哲明(Che-Ming Teng),潘秀玲(Shiow-Lin Pan) | |
| dc.contributor.author | Ho-Ying Wu | en |
| dc.contributor.author | 吳和穎 | zh_TW |
| dc.date.accessioned | 2021-06-16T06:34:18Z | - |
| dc.date.available | 2024-12-31 | |
| dc.date.copyright | 2014-10-15 | |
| dc.date.issued | 2014 | |
| dc.date.submitted | 2014-08-04 | |
| dc.identifier.citation | Ai J, Wang Y, Dar JA, Liu J, Liu L, Nelson JB, et al. (2009a). HDAC6 Regulates Androgen Receptor Hypersensitivity and Nuclear Localization via Modulating Hsp90 Acetylation in Castration-Resistant Prostate Cancer. Molecular Endocrinology 23(12): 1963-1972.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/57076 | - |
| dc.description.abstract | 國人十大死因中癌症致死率始終居高不下，而前列腺癌為男性癌症死亡率中的第七位，雖然一開始給予賀爾蒙療法可以讓前列腺癌獲得有效的控制，但是病患通常會在18~24個月有復發形成castration-resistant prostate cancer (CRPC)，其中與過度活化HDAC與Hsp90蛋白有關。因此本篇論文目的為評估一個新合成的HDAC與Hsp90雙重抑制劑MPT0G314對於前列腺癌的抗癌機轉。實驗結果顯示，MPT0G314相較於已核准上市的HDAC抑制劑SAHA有相當的pan-HDAC抑制活性，且擁有比17AAG強的Hsp90抑制效果，並利用fluorogenic HDAC assay kit偵測MPT0G314對於不同HDAC isoforms的抑制力，顯示MPT0G314選擇性抑制HDAC6的能力相對於抑制其他Class I HDAC isoforms有5~19倍的優勢，且利用西方墨點法也發現MPT0G314對於HDAC6 biomarker (Ac-tubulin) 有呈濃度依賴性增加蛋白表現，相對的MPT0G314只有在高濃度(10μM)才可以增加p21, AcH3蛋白表現，證實MPT0G314雖然為一個pan-HDAC抑制劑，卻特別具有良好的HDAC6選擇抑制的能力。進一步實驗證實MPT0G314可以在12小時誘發cleaved PARP，卻在24小時才有caspase 9, caspase 3的活化，暗示MPT0G314可能可以透過caspase-independent pathway誘發cleaved PARP。接著也發現MPT0G314可以透過多條路徑干擾前列腺癌細胞生長，包括: (1) 抑制Akt/mTOR 4E-BP1/eIF4E路徑或者Akt/mTOR p70S6K路徑抑制癌細胞合成蛋白，(2) 抑制MEK/ERK路徑並直接或間接抑制c-MYC蛋白表現，最後抑制survivin並防止survivin抑制caspases，(3) 影響細胞週期G1/S以及G2/M中的調控蛋白正常表現，干擾正常細胞週期的進行，防止癌細胞過度生長，(4) 可以減少Bcl-2, Mcl-1蛋白表現、增加Bim蛋白表現，接著活化caspase 9, caspase 3將PARP切割，促進內生性細胞凋亡路徑的進行。在腫瘤移植的動物模式中也看到MPT0G314能抑制PC3異種移植腫瘤生長，MPT0G314會活化caspase 3與增加PARP cleavage、抑制HDAC6、MEK與代償性增加Hsp70蛋白表現，這些作用與in vitro的結果相符合。最後，抗藥性的發生一直以來都是癌症治療的大難題，尤其是CRPC已被發現會藉由過度活化HDAC與Hsp90來逃避傳統化療藥物造成的細胞凋亡，因此將MPT0G314合併五種會使用在前列腺癌的傳統化療藥物，包括: irinotecan, etoposide, doxorubicin, carboplatin, and docetaxel，結果顯示以topoisomerase抑制劑irinotecan與etoposide具有最好的加乘作用，並初步證明MPT0G314與irinotecan併用能增加DNA斷裂的指標r-H2A的表現，與增加effector caspase 3、PARP cleavage、Ac-tubulin蛋白表現，並抑制EGFR, MEK, Akt蛋白表現。總結來說，新穎性HDAC與Hsp90雙重抑制劑MPT0G314在人類前列腺癌細胞中，能有效地抑制HDAC與Hsp90，並透過多條路徑促進內生性的細胞凋亡路徑，迄今尚未有HDAC/Hsp90雙重抑制劑進入臨床使用或被核准用來治療前列腺癌，因此盼望MPT0G314成為新一代的前列腺癌治療藥物。 | zh_TW |
| dc.description.abstract | Cancer is the top one leading cause of death and prostate cancer is the seventh cause of cancer-related death in Taiwan. Although androgen deprivation therapy (ADT) makes tumors under control, cancer will relapse to be castration-resistant prostate cancer (CRPC) after a median of 18-24 months. Recent data showed that the progression of CRPC was related to overexpression of HDAC and Hsp90 proteins. The purpose of this study is to evaluate the anti-cancer effects of a novel synthetic HDAC and Hsp90 dual inhibitor, MPT0G314, in prostate cancer. Our data suggested that HDAC-inhibitory effects of MPT0G314 was equal to SAHA and Hsp90-inhibitory effects of MPT0G314 was more potent than 17AAG. By fluorogenic HDAC assay kit, we found that MPT0G314 was a pan-HDAC inhibitor but demonstrated potent and selective inhibitory activity against HDAC6. MPT0G314 is 5-, 19-, 7-, and 6- folds less active against HDAC1, HDAC2, HDAC3, and HDAC8 (class I HDACs), respectively. Moreover, MPT0G314 increased HDAC6 biomarker (Ac-tubulin) with a concentration-dependent and time-dependent manner while increased p21 and AcH3 protein level at 10μM in PC3 cells. Both of enzyme kit assay and western blot assay suggested MPT0G314 has a potent and selective inhibitory activity against HDAC6. Furthermore, MPT0G314 may induces apoptosis of PC3 cells by multiple pathways, such as inhibition of Akt/mTOR pathway, inhibition of MEK/ERK pathway, regulation of G1/S and G2/M transition protein, down-regulation of Bcl-2, Mcl-1, and up-regulation of caspase9, caspase3, cleaved PARP protein expression. Interestingly, we observed that the short-term treatment of PC3 cells with MPT0G314 upregulated cleaved PARP without caspases induction. It may suggests that MPT0G314 induces cleaved PARP through a caspase-independent pathway. Moreover, MPT0G314 exhibited the tumor-inhibitory activity in PC3 xenografted models. MPT0G314 activated caspase 3, increased cleaved PARP, decreased MEK and HDAC6 in vivo. These data were consistent with in vitro results. Prostate cancer is hard to cure because multiple pathway lead to drug resistance. Our data observed the synergic effect of growth inhibition between MPT0G314 and chemoagents, especially irinotecan or etoposide. Combination of MTP0G314 and irinotecan increased DNA damage marker r-H2A expression and up-regulated caspase 3, cleaved PARP, actubulin, and downregulated EGFR, MEK, Akt protein expression. In conclusion, MPT0G314, a novel synthetic HDAC and Hsp90 dual inhibitor, potently inhibits HDAC, Hsp90 and triggers intrinsic apoptotic pathways in PC3 cells. So far, there is no HDAC and Hsp90 dual inhibitor in clinical trial or approved for prostate cancer. After further development on MPT0G314, it may be a new candidate drug of prostate cancer in the future. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T06:34:18Z (GMT). No. of bitstreams: 1 ntu-103-R01443016-1.pdf: 15301656 bytes, checksum: 49af3b171117572e71edaa4549d65966 (MD5) Previous issue date: 2014 | en |
| dc.description.tableofcontents | 目錄
口試委員審定書.........................I 致謝.........................................II 縮寫表.....................................IV 中文摘要..................................V 英文摘要.................................VII 第一章 研究動機與目的..............1 第二章 文獻回顧........................2 第三章 實驗材料與方法 第一節 實驗材料........................44 第二節 實驗方法........................46 第四章 實驗結果........................54 第五章 討論 ..............................63 第六章 結論與展望.....................74 參考文獻...................................95 | |
| dc.language.iso | zh-TW | |
| dc.subject | 前列腺癌 | zh_TW |
| dc.subject | prostate cancer | en |
| dc.title | 探討新合成Alkylamides衍生物MPT0G314誘導細胞凋亡於人類前列腺癌細胞之體外及體內的作用機轉 | zh_TW |
| dc.title | MPT0G314, a novel synthetic alkylamides derivative, induces cell apoptosis in human prostate cancer cells in vitro and in vivo. | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 102-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 顏茂雄(Mao-Hsiung YEN),楊春茂(Chuen-Mao Yang),黃德富(Tur-Fu Huang) | |
| dc.subject.keyword | 前列腺癌, | zh_TW |
| dc.subject.keyword | prostate cancer, | en |
| dc.relation.page | 108 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2014-08-04 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 藥理學研究所 | zh_TW |
| 顯示於系所單位： | 藥理學科所 | |
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