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系統識別號 U0026-2707201623361800
論文名稱(中文) 探討YM155合併Amiodarone治療應用於未來YM155抗癌臨床試驗之可能性
論文名稱(英文) Evaluation of the possibility of combining YM155 with Amiodarone for the future YM155-based anticancer clinical trials
校院名稱 成功大學
系所名稱(中) 藥理學研究所
系所名稱(英) Department of Pharmacology
學年度 104
學期 2
出版年 105
研究生(中文) 蔡如雅
研究生(英文) Ju-Ya Tsai
學號 S26031041
學位類別 碩士
語文別 英文
論文頁數 78頁
口試委員 口試委員-張俊彥
口試委員-呂增宏
口試委員-陳韻雯
指導教授-張雋曦
中文關鍵字 存活素  YM155  胺碘酮  癌症 
英文關鍵字 survivin  YM155  MDR1  amiodarone  cancer 
學科別分類
中文摘要 存活素(Survivin)是一個抗細胞凋亡蛋白,其在大多數的腫瘤高度表現,並使癌細胞對凋亡刺激及化學治療產生抗藥性。在許多癌症中,存活素的表達與癌症惡化,及較低的存活率有關。儘管存活素是具吸引力的抗癌標靶,因其難以發展藥物的特性,而只有少數的選擇性抑制劑。在過去十年裡,只有一個小分子存活素抑製劑,YM155,在人體中顯示良好的藥物動力學特性,並進入第二期臨床試驗。然而,在第二期臨床試驗YM155單獨治療或合併療法的結果都令人失望。多重耐藥性蛋白MDR1常在惡化的癌症中過度表達,而YM155是多重耐藥性蛋白的受質,因此,我們旨在探討YM155與能抑制多重耐藥性蛋白的臨床用藥合併使用,是否能為YM155標靶存活素的治療帶來更好的結果。
胺碘酮(amiodarone)是臨床使用的抗心律不整藥物,用於預防心房顫動。最近的研究顯示,它可誘導自噬(autophagy),抑制腫瘤發展。胺碘酮具有抑制多重耐藥性蛋白的能力。本篇研究中,以人類子宮頸癌KB細胞和KB衍生、表達多重耐藥性蛋白的KB-TAX50和KB-VIN10細胞作為模型。多重耐藥性蛋白活性試驗證實,在KB-TAX50和KB-VIN10細胞中,胺碘酮於臨床使用濃度範圍內,能抑制多重耐藥性蛋白的活性。重要的是,MTT細胞活性試驗和LDH細胞毒殺性試驗結果顯示,併用YM155與2微莫爾胺碘酮,顯著的使KB-TAX50和KB-VIN10細胞恢復對YM155的敏感性。西方墨點法分析顯示,合併療法增加了細胞凋亡蛋白表達,例如半胱天冬酶-3 (caspase-3) 和PARP蛋白的活化,表示表現多重耐藥性蛋白的癌細胞進行細胞凋亡。我們先前的研究指出,YM155能透過調控自噬和自噬誘導的DNA損傷使得癌細胞死亡。本篇研究中,在表現多重耐藥性蛋白的癌細胞給予YM155與胺碘酮合併治療,增加酸性小泡胞器(AVOs)的生成,並使自噬作用指標p62 / SQSTM1蛋白減少,顯示自噬作用增加。有趣的是,逆轉錄聚合酶鏈式法 (RT-PCR) 揭露,合併治療減少多重耐藥性蛋白轉錄的總量。
由於參與第二期臨床試驗的病人,常於癌症較後期且具有多重耐藥性,我們的研究或許可以提供YM155臨床試驗新的治療選擇。
英文摘要 Survivin, an inhibitor-of-apoptosis protein, is highly expressed in vast majority of tumors and contributes to their resistance to apoptotic stimuli and chemotherapies. Survivin expression also correlates with an advanced carcinoma and poor survival rate in several cancers. Despite survivin is an attractive target for anticancer treatment, there are few selective inhibitors available due to its “semi- druggable” properties. In the past ten years, only one small molecule survivin inhibitor, YM155, shows favorable human pharmacokinetic properties and has reached phase II clinical trial. However, phase II clinical studies of YM155 monotherapy and YM155-combination therapy show disappointing results. Because YM155 is a substrate of the multi-drug resistant protein, MDR1, which is frequently overexpressed in patients with advanced cancer; therefore in this study, we aimed to investigate whether combining YM155 with a clinically used drug that exhibits MDR1 inhibitory property can bring better outcome for the YM155 survivin-targeted therapy in the future.
Amiodarone is a clinically used antiarrhythmic drug for the prevention of atrial fibrillation, and recent studies reported that it can induce autophagy to inhibit tumor progression. Amiodarone is also known to exhibit MDR1 inhibitory effects. In this study, human cervical KB carcinoma cells and KB-derived MDR1-expressing multi-drug resistant KB-TAX50 and KB-VIN10 carcinoma cells were used as models. MDR1 activity assay confirmed that amiodarone, within the clinically used concentration range, could inhibit the activity of MDR1 in KB-TAX50 and KB-VIN10 cells. Importantly, results of the MTT cell viability assay and LDH cytotoxicity assay revealed that co-treatment of 2 M amiodarone significantly re-sensitized KB-TAX50 and KB-VIN10 to YM155. Western blot analysis showed that the amiodarone-YM155 combination treatment increased the expression of the apoptotic markers such as caspase-3 and PARP cleavage, indicating the induction of apoptosis in the treated MDR1-expressing cancer cells. Our previous study revealed that YM155 induces cancer cell death in part through induction of autophagy and autophagy-dependent DNA damage. Here, YM155-amiodarone combination treatment showed an enhanced formation of AVOs and reduced expression of p62/SQSTM1, which is an autophagy flux marker, indicating that the combination treatment up-regulates autophagy in KB-TAX50 and KB-VIN10 cells. Interestingly, PCR analysis revealed that the combination treatment synergistically decreased the expression of MDR1 at the transcriptional level in KB-TAX50 and KB-VIN10 cells.
Since a vast majority of patients enrolled in phase II clinical trials are usually at later cancer stages and possess multiple drug resistance, our study may provide a novel YM155 combination alternative for clinical trials in the future.
論文目次 中文摘要 I
ABSTRACT IV
Abbreviation VII
List of Tables X
List of Figures XI
List of Appendices XII
INTRODUCTION 1
1.1 Survivin as a molecular target for human cancers 2
1.1.1 Inhibitor-of-apoptosis proteins (IAPs) and cancer 2
1.1.2 Anti-apoptotic and pro-mitotic roles of survivin in cancer cells 3
1.1.3 Survivin and autophagy 4
1.1.4 Current developments in survivin-targeted therapy 5
1.2 Sepantronium bromide, YM155 6
1.2.1 Mechanism of action of YM155 6
1.2.2 Clinical studies of YM155 7
1.3 Multidrug resistance protein 1, MDR1 8
1.3.1 Phenomenon of multidrug resistance (MDR) 8
1.3.2 Multidrug resistance protein 1 (MDR1) and cancer drug resistance 8
1.4 Amiodarone 9
1.4.1 Drug information of amiodarone 9
1.4.2 Opportunities for drug repurposing 11
1.5 Aims of this study 11
MATERIALS AND METHODS 13
2.1 Materials 14
2.1.1 Chemicals and enzymes 14
2.1.2 Kits 17
2.2 Recipes 17
2.3. Methods 19
2.3.1 Cells and culture 19
2.3.2 Reverse transcription-PCR (RT-PCR) 20
2.3.3 Flow cytometry analysis of MDR1-overexpressing cells 20
2.3.4 [3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide] (MTT) cell viability assay 21
2.3.5 MDR1 activity assay 21
2.3.6 Lactate dehydrogenase (LDH)-cytotoxicity assay 22
2.3.7 Western blot analysis 22
2.3.8 Monodansylcadaverine (MDC) staining of acidic vesicular organelles (AVOs) 23
2.3.9 Gene silencing by siRNA 23
2.3.10 Comet assay 24
2.3.11 Statistic analysis 25
RESULTS 26
3.1 Tumors of patients with advanced clinical cancer stages exhibit higher MDR1 expression. 27
3.2 KB-derived multi-drug resistant KB-TAX50 and KB-VIN10 cells both express MDR1 endogenously. 28
3.3 Amiodarone, at sub-lethal concentrations, exhibits MDR1 inhibitory activity in cancer cells in vitro. 28
3.4 Amiodarone at sub-lethal but MDR1-inhibitory concentrations restores the sensitivity of MDR1-expressing cancer cells to YM155 in vitro. 29
3.5 Amiodarone-YM155 combination treatment decreases survivin expression and induces apoptosis in MDR1-expressing cancer cells 30
3.6 Amiodarone-YM155 combination treatment induces synergistic effects on autophagy induction and DNA damage in MDR1-expressing cancer cells 32
3.7 Down-regulation of survivin decreases MDR1 expression at the transcription level in MDR1-expressing cancer cells 34
DISCUSSION & 35
CONCLUSIONS 35
4.1. Discussion 36
4.2 Conclusion 38
REFERENCES 39
TABLES 53
FIGURES 56
APPENDICES 74
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