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系統識別號 U0026-1807201714192400
論文名稱(中文) 探討LCL161在MDR-1表達且具有多重抗藥性的癌症細胞中的效果及其分子作用機轉
論文名稱(英文) Investigation of the potency and the molecular mechanism of actions of LCL161 in MDR1-expressing multidrug-resistant cancer cells
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 105
學期 2
出版年 106
研究生(中文) 楊宗翰
研究生(英文) Tsung-Han Yang
學號 S26044133
學位類別 碩士
語文別 英文
論文頁數 71頁
口試委員 指導教授-張雋曦
口試委員-張俊彥
口試委員-呂增宏
中文關鍵字 LCL161  多重抗藥性蛋白質  多重抗藥性 
英文關鍵字 LCL161  MDR1  Multi-drug resistance 
學科別分類
中文摘要 當癌症患者接受長期化療藥物治療後,經常觀察到多重抗藥性蛋白質(multidrug resistance protein 1, MDR1)的基因有高度表現的情形,多重抗藥性蛋白質- MDR1的基因高度表現的腫瘤被認為是造成臨床上化療藥物治療失敗的一個主要原因,因此,對於探討臨床試驗階段的新穎抗癌藥物是否屬於多重抗藥性蛋白質的受質以及是否能夠導致多重抗藥性蛋白質高度表現的癌細胞死亡是極具臨床重要意義;Smac類似物 - LCL161目前已經經歷第一和第二期臨床試驗,然而目前對於 LCL161的分子作用機制目前仍尚未被完整的了解,此外,針對 LCL161是否能夠用於治療多重抗藥性蛋白質高度表現的具有多重抗藥性癌細胞目前也尚未有被研究,因此,本研究的目的著重於探討 LCL161在多重抗藥性蛋白質高度表達的癌細胞中的藥物作用情形及詳細的分子作用機制,本研究中,在 MTT 細胞存活率試驗中發現 LCL161能有效的降低無論多重抗藥性蛋白質表現多寡的癌細胞的存活率,令人感到驚訝的是,多重抗藥性蛋白質活性試驗及 MTT細胞存活率試驗證實 LCL161具有抑制多重抗藥性蛋白質將藥物排到細胞外的活性,並且恢復多重抗藥性蛋白質高度表現的 KB-TAX50、KB-VIN10 和 NTU0.017細胞對於 MDR1受質的敏感性。細胞內 ATP檢測分析實驗及多重抗藥性蛋白酶冷光檢測的分析結果揭露 LCL161會減少細胞內 ATP的含量以及刺激多個多重抗藥性蛋白質的ATP 酶的活性。另外,在探討LCL161的分子機制中,發現 LCL161在多重抗藥性蛋白質高度表現以及多重抗藥性蛋白質未表現的癌細胞中,會藉由增加 LC3B-II的轉換,以及提高 p62/SQSTM1的蛋白質表現和蛋白質穩定度來改變細胞的自噬作用。有趣的是,西方墨點法證實 LCL161在多重抗藥性蛋白質高度表現以及多重抗藥性蛋白質未表現的癌細胞中會下調節存活素的表現;綜合上述結果,我們的研究顯示 LCL161 具有抗癌能力的新穎藥物,並且不受到多重抗藥性蛋白質的影響,有趣的是,LCL161 能抑制多重抗藥性蛋白質的幫補功能以恢復因多重抗藥性蛋白質而產生的多重抗藥性。因此,LCL161對於各種癌症皆是具有前景的新穎抗癌藥物,特別是對於具多重抗藥性蛋白質高度表現的癌症患者而言。
英文摘要 Up-regulation of multidrug resistance protein 1 (MDR1), also known as P-glycoprotein (P-gp), in cancer cells has frequently been observed in patients after prolonged chemotherapeutic treatments and MDR1-expressing tumor is widely accepted as one of the most difficult cancers to treat in clinical situations. Therefore, it is of clinical importance to find or to develop a drug that is not a substrate of MDR1 and also capable of inducing the death of MDR1-expressing cancer cells. LCL161 is a Smac mimetic currently undergoing various Phase I/II clinical trials in cancer patients. However, the molecular mechanism of actions of LCL161 is still incompletely understood. In addition, it is still unclear on whether LCL161 is capable of targeting MDR1-expressing multidrug resistant cancer cells. The aims of this study are to determine the effectiveness of LCL161 in targeting MDR1-expressing cancer cells and to explore its mechanism of actions in cancer cells in details. In this study, results of the MTT cell viability assay revealed that LCL161 is potent in targeting cancer cells regardless to the expression of MDR1. Surprisingly, LCL161 inhibited the drug efflux activity of MDR1 and also restored the sensitivity to MDR1 substrate drugs in MDR1-expressing KB-TAX50, KB-VIN10 and NTU0.017 cancer cells. Results of cellular ATP detection assay and MDR1 ATPase activity assay revealed that LCL161 decreased the amount of cellular ATP present in MDR1-expressing cancer cells and stimulated the ATPase activity of the recombinant MDR1 in vitro. Further mechanistic investigations revealed that LCL161 altered cellular autophagy as indicated by of the increased conversion of LC3B-II and increased expression and protein stability of p62/SQSTM1 in both MDR1-expressing and MDR1-nonexpressing cancer cells. Interestingly, LCL161 also down-regulated the expression of survivin in both MDR1-expressing and MDR1-nonexpressing cancer cells, as revealed by the Western blot analysis. In conclusion, LCL161 is a potent anti-cancer compound and its potency is unaffected by the expression of MDR1 in cancer cells. Intriguingly, LCL161 reverses MDR1-mediated multi-drug resistance by directly inhibiting the efflux function of MDR1. Therefore, LCL161 is a promising anti-cancer compound that has potential for the management of various malignancies, particularly for patients with MDR1-related drug resistance after prolonged chemotherapeutic treatments.
論文目次 中文摘要 I
ABSTRACT IV
誌謝 VII
Abbreviation VIII
List of Tables X
List of Figures XI
List of Appendices XII
INTRODUCTION 1
1.1. Multidrug resistance protein 1 (MDR1) 2
1.1.1. Overview of drug resistance in cancer cells 2
1.1.2. Multidrug resistance protein 1 (MDR1) in cancer 3
1.1.3. MDR1 inhibitors as potential tumor chemo-sensitizers 4
1.2. Inhibitor of Apoptosis Proteins (IAPs) 5
1.2.1. Overview. 5
1.2.2. IAPs and human cancers 6
1.3. General introduction to the Second mitochondrial activator of caspase (Smac) mimetic LCL161 in cancer treatment 7
1.4. Autophagy 8
1.5. Aims of this study 9
MATERIALS AND METHODS 10
2.1. Materials 11
2.1.1 Chemicals and enzyme 11
2.1.2 Kits 13
2.2 Recipes 13
2.3. Methods 15
2.3.1. Cells and culture 15
2.3.2. MTT cell viability assay 16
2.3.3. Western blot analysis 16
2.3.4. Protein stability Assay 17
2.3.5. LysoTracker® Red staining 17
2.3.6. Semi quantitative-PCR 18
2.3.7. MDR1 activity assay 18
2.3.8. Luminescent ATP Detection Assay 18
2.3.9. MDR1 ATPase assay 19
2.3.10. Statistic analysis 20
RESULTS 21
3.1. LCL161 exhibits similar potency in both MDR1-expressing and MDR1-nonexpressing cancer cells in vitro 22
3.2. LCL161 is not a substrate of MDR1 in cancer cells 22
3.3. LCL161 inhibits the drug efflux ability of MDR1 in cancer cells 23
3.4. LCL161 decreases MDR1 drug efflux activity through a protein expression-independent mechanism. 24
3.5. LCL161 induces cellular ATP depletion and alters the ATPase activity of MDR1 in MDR1-expressing cancer cells. 24
3.6. LCL161 downregulates survivin expression and alters the autophagic process in both MDR1-expressing and MDR1-nonexpressing cancer cells. 25
3.7. LCL161 increases p62/SQSTM1 protein stability in cancer cells. 27
DISCUSSION & 29
CONCLUSIONS 29
4.1. Discussion 30
4.2. Conclusion 32
REFERENCES 33
TABLES 50
FIGURES 54
APPENDICES 69
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