RGD小分子藥物合併低劑量紫杉醇誘導人類神經膠母細胞瘤凋亡

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研究生：	張明偉 Chang, Ming-Wei
論文名稱：	RGD小分子藥物合併低劑量紫杉醇誘導人類神經膠母細胞瘤凋亡 Combination of RGD Compound and Low-Dose Paclitaxel Induces Apoptosis in Human Glioblastoma Cells
指導教授：	莊淳宇 Chuang, Chun-Yu
口試委員:	江啟勳羅建苗黃鈺軫洪雪芬
學位類別：	博士 Doctor
系所名稱：	原子科學院 - 生醫工程與環境科學系 Department of Biomedical Engineering and Environmental Sciences
論文出版年：	2014
畢業學年度：	103
語文別：	英文
論文頁數：	112
中文關鍵詞：	人類神經膠母細胞瘤、RGD小分子藥物、紫杉醇、細胞凋亡
外文關鍵詞：	Glioblastoma, RGD peptide, Paclitaxel, Caspase
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查詢本校圖書館目錄查詢臺灣博碩士論文知識加值系統勘誤回報

根據世界衛生組織最新公布的癌症報告，腦癌發生率占所有癌症的1.8%(直腸癌9.2%，乳癌25.2%)，看似不高的發生率，但是將近100%的最終致死率佔癌症前10名。行政院衛生署癌病登記統計，台灣每年約有600位原發性惡性腦瘤新病例，佔所有惡性腫瘤發生個案的1.03%。人類多型性神經膠母細胞瘤(glioblastoma multiforme, GBM)，約佔所有惡性腦瘤60%，是最常見的成人原發惡性腦瘤。目前，臨床對於人類多型性神經膠母細胞瘤的治療方式為放射線治療、外科手術切除，以及合併化學藥物治療。然而，人類多型性神經膠母細胞瘤生長速率快，具高度組織浸潤性(infiltrative)，導致治療效率不佳。
組合蛋白(integrin)表現在細胞表面，負責細胞訊號傳遞的穿膜蛋白質受器，由α及β鏈組成的蛋白二聚體。Integrin-αvβ3活化主要參與腫瘤組織血管新生(neovasculature / angiogenesis)及腫瘤細胞轉移。目前已知生化合成的RGD (Arg-Gly-Asp)胜肽小分子藥物可以與integrin-αvβ3專一性結合，進而達到抑制血管新生的效果。但是，腫瘤細胞專一性受體-integrin-αvβ3的表現量不足會影響RGD小分子藥物的標靶治療效率。本研究以低劑量癌症治療藥物紫杉醇(Paclitaxel, PTX)進行人類多型性神經膠母細胞瘤U87MG細胞株前處理，以誘導integrin-αvβ3在腫瘤細胞上的表現增加，接著應用單環結構c(RGDyK)與雙環結構E[c(RGDyK)]2兩種生化合成之RGD小分子藥物進行標靶治療，以期達到增加RGD小分子藥物的治療效率。
人類多型性神經膠母細胞瘤U87MG細胞，給予12小時10 nM低劑量紫杉醇前處理，顯著增加integrin-αvβ3受器表現，提供更多與RGD胜肽結合位置。接著給予RGD胜肽處理後，可觀察到U87MG細胞存活率下降。另外，在低劑量紫杉醇前處理合併RGD胜肽處理之組別，參與細胞凋亡的半胱天蛋白酶(caspase) -3，-8，-9基因表現量明顯高於單一給予紫杉醇或RGD胜肽處理的組別。給予caspase抑制劑，觀察到U87MG細胞經由合併PTX及E[c(RGDyK)]2處理後的外在細胞凋亡路徑caspase-3，-8，-9被專一性抑制。
本研究發現低劑量紫杉醇的前處理可以促進人類多型性神經膠母細胞瘤U87MG細胞integrin-αvβ3表現，進而增加與RGD胜肽專一性鍵結，提高RGD胜肽小分子標靶藥物促進U87MG細胞凋亡之成效。

According to the latest World Health Organization report, the incidence of brain tumor constitutes 1.8% of all cancer cases lower than other cancers (e.g., colorectal cancer, 9.2%; breast cancer, 25.2%); however, the final mortality close to 100% is firmly in the top 10 cancers. Currently, the standard therapeutic strategies for GBM include palliative care, radiation therapy, and surgery in combination with anti-cancer drugs. However, this malignant brain tumor is well known for its highly invasive behavior and typically responds poorly to conventional cytotoxic therapy.
Integrins are a family of transmembrane adhesion proteins that mediate cell adhesion and intracellular signaling. Integrin-αvβ3 is expressed on the surface of human glioblastoma multiforme (GBM) cells, and can be further induced by chemical or bio-mechanical stress. As a primary receptor of extracellular matrix adhesion molecules, integrin-αvβ3 acts as a crucial transducer to regulate cell signaling to die. The Arg-Gly-Asp (RGD) motif-containing peptides are specifically bound to integrin-αvβ3, and potential to inhibit neovasculature underlying competition to normal extracellular matrix proteins. This study employed two types of RGD peptides, cyclic RGD (c(RGDyK)) and bi-cyclic RGD (E[c(RGDyK)]2), to human GBM U87MG cells with the combination of low-dose Paclitaxel (PTX) pre-treatment to examine augmentation of therapeutic activity for RGD peptide-induced apoptosis. The docking simulation represented that both c(RGDyK) peptide and E[c(RGDyK)]2 peptide had better avidity and specificity to integrin-αvβ3 attachment (Ligscore 296.04 vs. 245.89).
Human GBM U87MG cells were treated with RGD peptides in the absence or presence of initial exposure to low-dose 10 nM PTX. Results showed that integrin-αvβ3 expressing on the surface of U87MG cells was induced by 10 nM PTX pre-treatment for 12 hrs. Additionally, the U87MG cells pretreated with PTX and followed by RGD peptides exhibited greater expression of caspases-3, -8 and -9 genes than those merely treated with single agent of PTX or RGD peptide. Furthermore, the caspase-3, -8 and -9 inhibitor presented significant protection against E[c(RGDyK)]2 peptide induced U87MG programmed cell death. The increased expression of PTX-induced integrin-αvβ3 was correlated with the enhanced apoptosis in U87MG cells.
This study proposes a novel method of targeting integrin-αvβ3 with RGD peptides in combination with low-dose PTX pre-treatment to improve the efficiency of human GBM treatment.

Table of content
標題
授權書
指導教授推薦書
考試委員會審定書
Part I Combination of RGD Compound and Low-Dose Paclitaxel Induces Apoptosis in Human Glioblastoma Cells    1
中文摘要    2
Abstract    4
Chapter 1 Introduction
1.1 Glioblastoma multiforme (GBM)    6
1.2 Current practical therapeutic modalities in clinical application and limitations of GBMs    8
1.2.1 Radiation therapy of GBM    8
1.2.2 Limitations of current used chemodrugs in GBM therapy    9
1.3 Paclitaxel (PTX)    10
1.4 Integrins     11
1.4.1 Integrin-αvβ3 and angiogenesis    14
1.4.2 Integrin-mediated cellular signaling    15
1.4.3 Integrin-αvβ3 signaling and RGD peptide antagonization    17
1.5 Apoptosis pathway    18
1.5.1 Extrinsic caspase pathway (death receptor pathway)    19
1.5.2 Intrinsic caspase pathway (mitochondria pathway)    19
1.6 Summary    21
Chapter 2 Material and methods 
2.1 Cell culture    24
2.2 Docking of RGD peptides    25
2.3 Cell treatment    26
2.4 Determination of integrin-αvβ3 expression    26
2.5 Immunofluorescence staining of integrin-αvβ3    27
2.6 Viability assay    27
2.7 Determination of cell cycle and apoptosis    28
2.8 Reverse transcription polymerase chain reaction (RT-PCR)    29
2.9 Quantitative real time PCR (QPCR)    29
2.10 Neutralized effect of caspase inhibitors on RGD-induced apoptosis in U87MG cells pre-treated with low-dose PTX    30
2.11 Statistical analysis    31
Chapter 3 Results
3.1 RGD peptide docking simulation    32
3.2 PTX induced integrin-αvβ3 expression and cell cycle effect    33
3.3 Cytotoxic and apoptotic effects of PTX and RGD peptides on U87MG cells    37
3.4 Gene expression of caspase signaling regulated by PTX and RGD peptide    40
Chapter 4 Discussion    44
Chapter 5 Conclusion    51
Chapter 6 Recommendation of future work    52
References    55
List of Tables and Figures
Table 1 WHO grading of tumors of central nervous system and current treatments for malignant gliomas    7
Table 2 Chemodrugs of GBM therapy approved by FDA    9
Table 3 Integrins receptors and their ligands    13
Table 4 Primers used in real time PCR analysis    30
Figure 1 Schematic view of fibronectin bound to integrin at the cell surface    12
Figure 2 The process of angiogenesis    15
Figure 3 Apoptosis signaling    20
Figure 4 Flowchart of experimental procedures in the current work    23
Figure 5 Schematic illustration of chemical structures and docking stimulation outlining     33
Figure 6 Expression of surface integrin-αvβ3 in U87MG cells with the treatment of 10 nM PTX     35
Figure 7 Evaluation of cell cycle arrest in low-dose PTX responsive U87MG cells    36
Figure 8 Cytotoxicity of U87MG cells treated with RGD peptide or the combination of PTX and RGD peptide was quantified using MTT assay    38
Figure 9 Cytometric analysis of apoptosis events in U87MG cells treated with PTX, RGD peptides or the combination treatment     39
Figure 10 Quantitative expression of caspase genes in U87MG cells treated with PTX, RGD peptides or the combination treatment    41
Figure 11 Neutralized effect of caspase-3, -8 and -9 inhibitors on the caspase mRNA expression induced by PTX and RGD peptide     43
Figure 12 Apoptotic pathway of the combination treatment     50
 
Part II Bioaerosols from a Food Waste Composting Plant Affect Remodeling Genes in Human Airway Epithelial Cells    66
中文摘要    67
Abstract    69
Chapter 1 Introduction
1.1 Bioaerosol    71
1.2 Endotoxin    72
1.3 Aspergillus    73
1.4 Respiratory system and its related remodeling genes    75
Chapter 2 Material and methods
2.1 Field sampling of airborne bioaerosols    79
2.2 Culture of microorganisms from the composting facility    80
2.3 Endotoxin detection    81
2.4 Identification of Aspergillus fumigatus (A. fumigatus)    82
2.5 Cell culture of human airway epithelial cells    83
2.6 Preparation of A. fumigatus / field bioaerosols conditioned medium    83
2.7 Determination of pro-inflammatory cytokine IL-6 protein    84
2.8 Quantitative real time PCR for gene expression    85
2.9 Statistical analysis    86
Chapter 3 Results
3.1 Quantification of A. fumigatus    87
3.2 Microbe concentrations in different areas of the composting plant    88
3.3 Airborne particle concentration and endotoxin levels in the composting plant    90
3.4 IL-6 secretion in NCI-H292 cells exposed to a conditioned medium of field bioaerosol samples    91
3.5 Exposure to bioaerosol or A. fumigatus mediated gene expression    92
Chapter 4 Discussion    94
Chapter 5 Conclusion    99
Chapter 6 Recommendation of future work    102
References    105
List of Tables and Figures
Table 5 Primers used in real time PCR analysis    86
Table 6 Medium concentrations of airborne bacteria detected at various location of the composting plant    89
Table 7 Average concentration of endotoxin in airborne sampled coarse and fine airborne particles    90
Figure 13 Structures of conidiophores, vesicles and conidia of Aspergillus species    74
Figure 14 Flowchart of experimental procedures in the current work    77
Figure 15 Layout of sampling pots of the food waste composting plant    80
Figure 16 Distribution of microorganisms in the composting hall, maintenance and restaurant    89
Figure 17 IL-6 secretion of NCI-H292 cells cultured with field bioaerosol samples    92 
Figure 18 Quantitative expression of remodel genes in NCI-H292 cells treated with control group, standard A. fumigatus or field bioaerosol samples for 24 hrs    93
Figure 19 A possible mechanism of airway remodeling genes in response to bioaersol exposure in the composting hall    101 
                                

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