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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 林亮音 | zh_TW |
| dc.contributor.advisor | LiangIn Lin | en |
| dc.contributor.author | 何錦海 | zh_TW |
| dc.contributor.author | Kam Hoi HO | en |
| dc.date.accessioned | 2023-10-02T16:14:27Z | - |
| dc.date.available | 2023-11-10 | - |
| dc.date.copyright | 2023-10-02 | - |
| dc.date.issued | 2023 | - |
| dc.date.submitted | 2023-08-11 | - |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/90443 | - |
| dc.description.abstract | 急性骨髓性白血病 (acute myeloid leukaemia, AML) 的主要治療挑戰是復發或難治性，有高達57％的患者在完全緩解後出現此情況。而Disulfiram (DSF) 雖然於臨床前試驗中，在癌症治療方面取得令人鼓舞的結果，但其後發現，它在臨床上的應用會受到其不穩定性而影響，導致在血液中無法形成足夠的濃度的diethyldithiocarbamate-copper complex (CuET)。而DSF之所以可以抗癌，就是依賴這一含銅(copper, Cu)代謝物。因此，在本篇論文中會嘗試找出合適的藥物與DSF/Cu進行合併，以增強其在低濃度下的細胞毒殺作用，並從而增加DSF的臨床價值。
首先，我們分別評估了低濃度和高濃度DSF/Cu對兩種AML細胞株 (OCI AML 3和HEL) 的影響。低濃度組的作用是模擬臨床上可達到的CuET水平，而高濃度組則用來比較。結果顯示低濃度組的細胞毒殺作用輕微或不確定，而高濃度則表現出強大的細胞毒殺作用。此外，我們發現DSF/Cu的細胞死亡機制比較複雜，會誘導不同類型的細胞死亡。因此，我們認為於這方面進行更探入的探討可能不會對找出合適的藥物有所幫助。所以我們轉移焦點，探討DSF/Cu的藥物一開始的作用機制，即產生氧化壓力。結果如預期，我們發現能夠對細胞產生足夠的氧化壓力是DSF/Cu可以導致細胞死亡至關重要的一個機制。 得知這個機制後和經實驗室一些轉錄組的數據分析，我們選出PIM447作為第一個合併的候選藥物。然而，結果顯示與DSF/Cu合併後，其細胞毒殺效果不佳，僅表現出細胞生長的抑制效應，而非導致細胞死亡。 為更清楚瞭解DSF/Cu的分子機制，我們對OCI AML 3細胞進行了RNA定序分析 (RNA sequencing, RNA-seq)。基因集豐富分析(GSEA)結果與目前的研究結果一致，上調的基因路徑包括氧化壓力的反應、金屬或銅有關的反應，以及蛋白質錯誤摺疊的反應。而下調的路徑包括DNA複製的路徑和粒線體功能的路徑。 為了找到合適的藥物合併，我們利用RNA-seq數據構建了蛋白質交互作用(protein-protein interaction, PPI)網路。並從中得出49個關鍵基因相信是與DSF/Cu所誘導的細胞死亡有關。通過檢索不同藥物數據庫，結果得出了三種候選藥物，rapamycin (sirolimus), zinc protoporphyrin (ZnPP)，以及APR-246 (Eprenetapopt)，適合與低濃度的DSF/Cu 合併。 在這三種候選藥物中，APR-246表現出較好的效果，在對細胞死亡和誘導粒線體ROS的產生的測試中都得出有協同效應。進一步的分析顯示，這兩個結果是可以通過影響硫醇/二硫化物(thiol/disulfide)的平衡和誘導未折疊蛋白反應（UPR）來連結，產生因果關係。 | zh_TW |
| dc.description.abstract | A major challenge in treating acute myeloid leukaemia (AML) is relapsed or refractory, which affects up to 57% of patients after complete remission (CR). Despite promising preclinical results in cancer therapy, the clinical application of disulfiram (DSF) was limited by its poor stability and the inability to form the diethyldithiocarbamate-copper complex (CuET), an ultimate anticancer copper-containing metabolite of DSF, at sufficient concentrations. Hence, combining DSF/Cu with an appropriate drug to enhance its cytotoxicity at low concentration may be a way to enhance the clinical value of DSF.
In this study, we examined the effects of both low and high concentrations of DSF/Cu on two AML cell lines (OCI AML 3 and HEL). The low concentration group (L group) simulated the clinically achievable levels of CuET, while the high concentration group (H group) serving as a direct comparison. The results demonstrated minimal or ambiguous cytotoxicity in the L group, while potent cytotoxic effects were observed in the H group. Furthermore, we revealed a complex cell death mechanism of DSF/Cu that is capable of inducing different types of cell death. Therefore, it prompted us to shift our focus to investigating the drug mechanism of DSF/Cu from the beginning, that is oxidative stress effects. As expected, we found that induction of an overwhelming oxidative stress is a critical mechanism to contribute to the cell death of DSF/Cu. Based on this perspective and transcriptomic analysis, we firstly evaluated PIM447 as a candidate for combination. However, the results indicated suboptimal cytotoxic effects, with only a cytostatic effect rather than cell death. To better understand the mechanism of DSF/Cu, RNA-sequencing (RNA-seq) was performed in OCI AML 3 cells. Gene set enrichment analysis (GSEA) results were consistent with current studies, the upregulated pathways including response to oxidative stress, response to metal or copper ions and protein misfolding response. Additionally, our GSEA results indicated that the DNA replication pathways and mitochondrial function pathways were downregulated. To identify an appropriate druggable target for combination, a protein-protein interaction (PPI) network was constructed using the RNA-seq data. A total of 49 essential genes were identified from PPI network that presumably involved in DSF/Cu-induced cell death. By searching the drug database, three drug candidates were suggested for combination with low concentration of DSF/Cu, which are rapamycin (sirolimus) zinc protoporphyrin (ZnPP) and APR-246 (Eprenetapopt). Among these candidates, APR-246 in combination with a low concentration of DSF/Cu exhibited the most pronounced effectiveness, demonstrating a synergistic effect on the induction of mitochondrial ROS and cell death. Further analysis revealed that these two effects were interconnected through the perturbation of thiol/disulfide homeostasis and the induction of unfolded protein response (UPR). | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2023-10-02T16:14:27Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2023-10-02T16:14:27Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 誌謝 i
摘要 ii Abstract iv Table of content vi List of figures xii List of tables xv List of supplementary figures xvi List of appendices xviii List of abbreviations xix Chapter 1 Introduction 1 1.1 Acute myeloid leukemia (AML) 1 1.1.1 Overview of acute myeloid leukemia (AML) 1 1.1.2 Pathogenesis 2 1.1.3. Classification of AML: WHO 2022 3 1.1.4. Treatment 4 1.1.5. Prognosis 5 1.2 Reactive oxygen species (ROS) and cellular redox homeostasis 6 1.2.1 Reactive oxygen species (ROS) overview 6 1.2.2 Antioxidant defense 7 1.2.3 Biological role of thiol in antioxidant system 9 1.2.4 Oxidative stress and damage 11 1.2.5 ROS in cancer therapy 12 1.3 Endoplasmic reticulum stress (ER stress) and unfolded protein response (UPR) 13 1.4 Disulfiram (DSF) 17 1.4.1 Overview 17 1.4.2 Pharmacokinetics of DSF 19 1.4.3 Anti-cancer mechanisms of DSF: CuET 21 1.5 APR-246 (eprenetapopt / PRIMA-1MET) 23 1.5.1 Overview and the anti-cancer mechanism: mutant p53 reactivation 23 1.5.2 Anti-cancer mechanisms: p53 independent 25 1.5.3 Clinical trials 27 1.6 Rapamycin (sirolimus) 28 1.7 Zinc protoporphyrin (ZnPP) and heme oxygenase-1 (HO-1) 30 Chapter 2 Research purpose, objectives, experimental design 35 2.1 Research purpose 35 2.2 Research objectives 36 Chapter 3 Materials and methods 37 3.1 Material 37 3.1.1 Cell lines 37 3.1.2 Equipment 37 3.1.3 Chemicals 39 3.1.4 Small molecules 41 3.1.5 Antibody 41 3.1.6 Kit 42 3.1.7 Compound and reagent preparation 42 3.2 Method 45 3.2.1 Cell culture 45 3.2.2 MTS assay 45 3.2.3 Cell proliferation curve and cell death recovery test by trypan blue exclusion assay 46 3.2.3 Dead and viable cells by trypan blue exclusion assay 47 3.2.4 Annexin V-PI double staining 48 3.2.5 DCFDA staining 49 3.2.6 C11 Bodipy staining 50 3.2.7 TMRE staining 50 3.2.8 MitoSox staining 51 3.2.9 Cell lysate preparation 52 3.2.10 Protein quantification 53 3.2.11 Western blot 54 3.2.12 Free thiol determination 55 3.2.13 RNA extraction 56 3.2.14 Reverse transcription 57 3.2.15 Real time quantitative PCR (qPCR) 57 3.2.16 RNA-sequencing (RNA-seq) 58 3.2.17 Protein–protein interaction (PPI) network construction and module (sub-network) analysis 59 3.2.18 Identification of hub and bottleneck genes, and essential genes in the PPI network 60 3.2.19 Identification of potential drug candidates via bioinformatics databases 61 3.2.20 Statistical analysis 62 Chapter 4 Result 64 4.1 Cytotoxic effects of disulfiram (DSF) on AML cell lines 64 4.1.1 Copper may enhance the cytotoxic effect of disulfiram (DSF) on AML cell lines 64 4.1.2 “High concentration” of disulfiram with copper (DSF/Cu) can inhibit the cell proliferation and induce cell dead remarkably but is minimal or ambiguous in clinical achievable range 65 4.1.3 The treatment of disulfiram with copper (DSF/Cu) induces a complex cell death mechanism in addition to apoptosis 69 4.2 Oxidative stress effects of disulfiram with copper (DSF/Cu) on AML cell lines 73 4.2.1 The treatment of disulfiram with Cu (DSF/Cu) did not induce reactive oxygen species (ROS) accumulation in both AML cell lines at 6 hours 73 4.2.2 The treatment of disulfiram with Cu (DSF/Cu) did not increase lipid peroxidation level in both AML cell lines at 6 hours 75 4.2.3 The treatment of disulfiram with Cu (DSF/Cu) increased mitochondrial ROS levels in both AML cell lines at 24 hours 76 4.2.4. Oxidative stress is a critical mechanism of cell death in the high concentration group (H group) of disulfiram with Cu (DSF/Cu) 77 4.3 Combination effects of disulfiram with copper (DSF/Cu) and PIM447 78 4.3.1 PIM447 treatment can downregulate the antioxidant genes and antioxidant signaling pathways including Nrf2 pathways in AML cells according to RNA-seq data 79 4.3.2 The combination of PIM447 and the low concentration of disulfiram with copper (DSF/Cu) had at least an additive effect on sensitivity in both AML cell lines 80 4.3.3 Combination of PIM447 and disulfiram with copper (DSF/Cu) did not promote cell death in both AML cell lines 81 4.3.4. Combination of PIM447 and low concentration of disulfiram/copper (DSF/Cu) influenced the expression of antioxidant genes as expected, but the effect may not be sufficient 82 4.4 RNA-sequencing (RNA-seq) transcriptomic analysis after treatment with “high concentration” of disulfiram with Cu (DSF/Cu) in OCI AML 3 cells 83 4.4.1 Differential expression gene (DEGs) after treatment of “high concentration” of disulfiram with Cu (DSF/Cu) 84 4.4.2 Enrichment pathway analysis of the differential expression gene (DEGs) on Kyoto Encyclopedia of Genes and Genomes (KEGG) database 85 4.4.3 Enrichment analysis of the differential expression gene (DEGs) on Gene Ontology (GO) database 87 4.4.4 Gene set enrichment analysis (GSEA) for the six selected categories including oxidative stress response and Nrf2 signaling pathway 89 4.5 Identification of potential candidate for drug combination via bioinformatics analysis of the RNA-seq data 92 4.5.1 Construction of protein–protein interaction (PPI) network and analysis of the modules 93 4.5.2 Identification of essential genes from the PPI network and module 95 4.5.3 Identification of potential drug candidates for combination 95 4.6 Cytotoxic effects of the drug combinations on AML cell lines 98 4.6.1 Screening the cytotoxic effects of the drug combinations on AML cell lines at the clinical achievable concentration 98 4.6.2 Combination of low concentration group of disulfiram with Cu (DSF/Cu) and APR-246 showed syngenetic effects on cell deaths with almost no rebound after drug withdrawal 100 4.7 Oxidative stress effects of the combination of low concentration of disulfiram with Cu (DSF/Cu) and APR-246 on AML cell lines 103 4.7.1 Oxidative stress is associated with the cell death induced by the combination of low concentration of disulfiram with Cu (DSF/Cu) and APR-246 on AML cell lines 103 4.7.2 Combination of low concentration of disulfiram with Cu (DSF/Cu) and APR-246 increased mitochondrial ROS levels in both AML cell lines at 48 hours 104 4.8 Investigation of the mechanism underlying the synergistic effects on cell death 106 4.8.1 Combination of low concentration of disulfiram with Cu (DSF/Cu) and APR-246 disturb the thiol/disulfide homeostasis 106 4.8.2 Combination of low concentration of disulfiram with Cu (DSF/Cu) and APR-246 induced unfolded protein response (UPR) and the cleavage of PARP and caspase 3 108 Chapter 5 Discussion 111 Chapter 6 Conclusion 117 Chapter 7 References 118 Figure 146 Supplementary figure 193 Tables 217 Appendix 253 | - |
| dc.language.iso | en | - |
| dc.title | 從轉錄體分析中發現具潛力的藥物能加強disulfiram對急性骨髓性白血病的抗癌效果並探討其機制 | zh_TW |
| dc.title | Exploring a potential drug that can enhance the anti-cancer effects of disulfiram on AML cells and discuss the underlying mechanism | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 111-2 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 蘇剛毅;歐大諒;郭靜穎;胡忠怡 | zh_TW |
| dc.contributor.oralexamcommittee | KangYi Su;Da-Liang Ou;ChingYing Kuo;ChungYi Hu | en |
| dc.subject.keyword | 急性骨髓性白血病,癌症,生物資訊分析,蛋白質交互作用網路,氧化壓力,硫醇二硫化物穩態,藥物合併, | zh_TW |
| dc.subject.keyword | Acute myeloid leukaemia,Cancer,Bioinformatics analysis,Protein-protein interaction (PPI) network,Oxidative stress,Thiol-disulfide homeostasis,Drug combination, | en |
| dc.relation.page | 262 | - |
| dc.identifier.doi | 10.6342/NTU202304118 | - |
| dc.rights.note | 同意授權(限校園內公開) | - |
| dc.date.accepted | 2023-08-11 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 醫學檢驗暨生物技術學系 | - |
| dc.date.embargo-lift | 2028-08-10 | - |
| 顯示於系所單位： | 醫學檢驗暨生物技術學系 | |
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