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研究生:李蘭蕙
研究生(外文):Lan-Hui Li
論文名稱:克服治療傳染病與癌症抗藥性之新策略
論文名稱(外文):New Strategies to Overcome Drug Resistance on Infectious Disease and Cancer
指導教授:陳惠文陳惠文引用關係
口試委員:陳健尉陳璿宇林泰元周涵怡何肇基
口試日期:2014-07-25
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:毒理學研究所
學門:醫藥衛生學門
學類:其他醫藥衛生學類
論文種類:學術論文
論文出版年:2014
畢業學年度:102
語文別:英文
論文頁數:86
中文關鍵詞:淋菌多重抗藥性奈米材料奈米銀細胞毒性肺腺癌表皮生長因子接受器突變精油扁柏醇DNA損傷自噬衰老
外文關鍵詞:Neisseria gonorrhoeaemultidrug resistancenanomaterialsAg NPscytotoxicitylung adenocarcinomaEGFR mutationessential oilshinokitiolp53-independent DNA damageautophagysenescencexenograft
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低毒性奈米材料增強Cefmetazole對多重抗藥性淋菌的抑菌效果

淋菌的多重抗藥性是目前臨床治療上棘手的挑戰,因此找出具預防或治療淋病效果的新策略是迫切的。本研究的目的為從各式奈米材料中找出具抗淋菌效果的奈米材料並探討其抑菌機轉。本研究共測試了21種包括矽類、碳類、金屬類及金屬氧化物類等各式奈米材料,結果顯示大部分的奈米材料皆有不錯的抗淋菌效果,其中金屬類的奈米銀(120 nm)抑菌效果最佳(MIC:12.5 μg/ml),若進一步測試不同尺寸的金屬銀粒子抗淋菌效果則可發現,120 nm奈米銀與20 nm奈米銀抑菌效果相近(MIC:12.5 μg/ml),但1 μm銀粒子抑菌效果最差(MIC:500 μg/ml)。進一步測試120 nm與20 nm奈米銀對細胞毒性可發現,120 nm奈米銀抑制90%淋菌生長的劑量對於人類纖維細胞株及上皮細胞株皆不會產生毒性,因此將針對120 nm奈米銀進行機轉探討。進一步以掃描式電子顯微鏡觀察可發現,經奈米銀處理的淋菌菌體外觀尺寸變小且細胞膜皺縮破損,而穿透式電子顯微鏡切面顯示細胞壁/膜變薄且細胞質空泡化。奈米銀除了可有效抑制淋菌標準菌株的生長外,對於臨床分離的多重抗藥性淋菌菌株也具有同樣效果,而且當奈米銀與抗生素cefmetazole合併使用時具有協同的抑菌作用,可有效降低抗生素使用劑量,讓菌株對cefmetazole從具抗性轉變為具感受性。而透過抗生素與奈米銀的結合試驗可證明,cefmetazole可有效攜帶奈米銀離子,且經感應耦合電漿質譜分析儀(Inductively Coupled Plasma-Mass Spectrometer)分析證實,奈米銀抗菌作用主要來自奈米結構而不是解離後的銀離子。本篇是第一篇探討奈米材料抗淋菌的研究,結果顯示奈米銀(120 nm)可輔助抗生素的作用且對細胞毒性小,預期未來在外用藥膏或衛生用品敷料具應用價值,以達到預防或治療多重抗藥性淋菌。

扁柏醇引起Gefitinib抗藥性肺腺癌DNA損傷自噬細胞週期停滯及衰老

根據2013年全美癌症統計報告,肺癌死亡率排名第1;而在台灣,肺癌也是國人十大癌症死因的第1名。肺癌治療除了傳統的手術切除搭配化學或放射治療外,亞洲人肺腺癌細胞特有的表皮生長因子接受器(Epidermal Growth Factor Receptor,EGFR)突變,對標把藥物也有良好感受性,但在標把藥物使用後的9個月內,病人通常會產生抗藥性,因此發展新的抗肺癌策略是迫切的。本研究的目的是從40種台灣特有植物萃取精油,找出對肺癌具有療效的精油並探討其機轉。研究結果發現台灣肖楠心材精油的活性成分扁柏醇(hinokitiol),具有抑制一系列肺癌細胞株生長的能力,同時也包括抑制對標把藥物具有抗性的PC9-IR與 H1975細胞株的聚落生長能力。進一步以基因微陣列分析及預測受到扁柏醇調控的基因及訊息傳遞路徑發現,DNA損傷(DNA damage)、自噬(autophagy)及細胞週期(cell cycle)是主要受到影響的層面。在H1975細胞株驗證也證實了扁柏醇(5 μM, 72 h)會引起DNA損傷指標γ-H2AX蛋白質的表現增加,且與p53無關;引起自噬指標LC3-II、p62、ATG5蛋白質的表現增加;引起細胞週期停滯在S期;引起細胞衰老等機轉導致細胞生長受到抑制。有趣的是,扁柏醇處理下,正常的肺臟纖維細胞在DNA損傷、自噬、細胞週期停滯現象皆不顯著。而動物實驗進一步證明了扁柏醇具有抑制腫瘤生長的效果,且免疫組織化學染色法也證實了DNA損傷及自噬現象相較於對照組皆有顯著增加與細胞實驗呼應。這篇研究發現了扁柏醇抑制肺腺癌腫瘤細胞生長的機轉,對於標把藥物具有抗性的肺腺癌具有治療潛力。

Non-cytotoxic Nanomaterials Enhance Antimicrobial Activities of Cefmetazole against Multidrug-Resistant Neisseria Gonorrhoeae

The emergence and spread of antibiotic-resistant Neisseria gonorrhoeae has led to difficulties in treating patients, and novel strategies to prevent and treat this infection are urgently needed. Here, we examined 21 different nanomaterials including Si, carbons, metals and metal oxides for their potential activity against N. gonorrhoeae (ATCC 49226). The data showed good antibacterial activity among most nanomaterials. Specifically, silver nanoparticles (Ag NPs, 120 nm) showed the greatest potency for reducing N. gonorrhoeae colony formation (MIC: 12.5 μg/ml). We further test the size effects of silver nanoparticles and found 120 nm and 20 nm (MIC: 12.5 μg/ml) had better activity than 1 μm (MIC: 500 μg/ml) against N. gonorrhoeae. Ag NPs in 120 nm within a concentration range that did not induce cytotoxicity in human fibroblasts or epithelial cells compared with smaller size of 20 nm. Thus we focused on the antibacterial mechanisms of Ag NPs in 120 nm in the following experiments. Scanning electron microscopy revealed that the Ag NPs significantly reduced bacterial size and cell membrane integrity; transmission electron microscopy revealed that Ag NPs significantly reduced bacterial cell wall/ membrane thickness and simulated cytoplasm disorganization. Besides ATCC N. gonorrhoeae, Ag NPs possessed similar effects against multidrug-resistant N. gonorrhoeae in clinical isolates. Furthermore, combined treatment with 120 nm Ag NPs and cefmetazole produced additive effects. The modes of action probably due to the zeta potential of Ag NPs that might form complex with cefmetazole to enhance the susceptibility. Based on the ICP-MASS analysis, Ag NPs possessed the dominant influence on the antibacterial activity with their properties of the nanoparticles. This is the first report to screen the effectiveness of nanomaterials against N. gonorrhoeae, and our results indicate that 120 nm Ag NPs deliver low levels of toxicity to human epithelial cells and could be used as an adjuvant with antibiotic therapy, either for topical use or as a coating for biomaterials, to prevent or treat multidrug-resistant N. gonorrhoeae..


Hinokitiol Induces DNA Damage and Autophagy Followed by Cell Cycle Arrest and Senescence in Gefitinib-Resistant Lung Adenocarcinoma Cells

According to the cancer statistics in 2013, lung cancer remains the top one leading cause of cancer death in USA and also in Taiwan. Despite of the good response initially following standard treatment options, most of the lung adenocarcinoma patients with EGFR mutations took EGFR-tyrosine kinase inhibitors (TKIs) might develop resistance within 9 months. To explore the new anti-cancer strategy is urgent. In this study, we investigated 40 Taiwan indigenous essential oils, these essential oils from plants were used as alternative treatments for a wide range of illnesses; however its’ anti-cancer effects and underlying mechanisms are less evaluated. In this study, we found hinokitiol, a natural monoterpenoid from the heartwood of Calocedrus formosana, exhibited potent anticancer effects. Here, we demonstrated that hinokitiol inhibited a series of lung adenocarcinoma cells proliferation and colony formation as well as corresponding EGFR-TKI resistant cell lines (PC9-IR and H1975). The transcriptomic analysis and pathway prediction indicated that DNA damage, autophagy, and cell cycle pathways were majorly affected. Further validations confirmed that hinokitiol could inhibit cell proliferation without inducing apoptosis but autophagy; induced p53-independent DNA damage, arrested cell cycle in S phase and senescence, whereas had less effects in lung stromal fibroblasts. Furthermore, hinokitiol inhibited the growth of xenograft tumors and increaseed DNA damage and autophagy evidenced by IHC staining. Taken together, we first demonstrated the novel mechanisms of hinokitiol from essential oils as a promising anticancer agent to overcome the EGFR-TKI resistant lung cancer.

Contents

中文摘要 ii/v
Abstract iii/vi
Contents vii
List of Figures ix
List of Tables x
Chapter I. The Impact of Developing Drug Resistance in Clinical Therapy
1. Summary 1
2. Drug resistance on infectious disease 1
3. Drug resistance on cancer 2
4. Motivation and purpose 2
5. References 3
Chapter II. Non-cytotoxic Nanomaterials Enhance Antimicrobial Activities of Cefmetazole against Multidrug-Resistant Neisseria Gonorrhoeae
1. Summary 4
2. Introduction 5
3. Materials and Methods 8
4. Results 12
5. Discussion 17
6. References 21
7. Figures 27
8. Tables 33
Chapter III. Hinokitiol Induces DNA Damage and Autophagy Followed by Cell Cycle Arrest and Senescence in Gefitinib-Resistant Lung Adenocarcinoma Cells
1. Summary 39
2. Introduction 40
3. Materials and Methods 42
4. Results 50
5. Discussion 56
6. References 62
7. Figures 69
8. Tables 84


List of Figures

Non-cytotoxic Nanomaterials Enhance Antimicrobial Activities of Cefmetazole against Multidrug-Resistant Neisseria Gonorrhoeae
Figure 1. The anti-bacterial activity of Ag particles against N. gonorrhoeae. 27
Figure 2. The cytotoxicity of Ag NPs of different sizes. 29
Figure 3. Morphological analysis of N. gonorrhoeae in response to 120-nm Ag NPs 30
Figure 4. Ag NPs form a complex with cefmetazole (CMZ). 31
Figure 5. Schematic representation of the interactions between Ag NPs and cefmetazole against N. gonorrhoeae. 32

Hinokitiol Induces DNA Damage and Autophagy Followed by Cell Cycle Arrest and Senescence in Gefitinib-Resistant Lung Adenocarcinoma Cells
Figure 1. The effects of hinokitiol on cell proliferation. 69
Figure 2. The effect of hinokitiol on gene expression. 70
Figure 3. The effect of hinokitiol on the expression of DNA damage regulatory proteins. 72
Figure 4. The effect of hinokitiol on apoptosis and autophagy. 74
Figure 5. The effect of hinokitiol on cell cycle distribution. 76
Figure 6. Hinokitiol induced cellular senescence in H1975 cells and lung stromal fibroblasts. 78
Figure 7. In vivo antitumor activity of hinokitiol. 80
Figure 8. A schematic representation of the hypothetical mechanisms for the role of hinokitiol in suppressing lung adenocarcinomas. 83


List of Tables

Non-cytotoxic Nanomaterials Enhance Antimicrobial Activities of Cefmetazole against Multidrug-Resistant Neisseria Gonorrhoeae
Table 1. Anti-N. gonorrhoeae activity of the different nanomaterials tested. 33
Table 2. Minimum inhibitory concentration (MIC) values of silver nanoparticles of different sizes against a standard N. gonorrhoeae strain. 35
Table 3. Concentration of Ag+ ions leaching from Ag particles 36
Table 4. The results of a checkerboard assay using Ag NPs and cefmetazole combinations against drug-resistant N. gonorrhoeae clinical isolates. 37

Hinokitiol Induces DNA Damage and Autophagy Followed by Cell Cycle Arrest and Senescence in Gefitinib-Resistant Lung Adenocarcinoma Cells
Table 1. The screening of essential oils on A549 cell proliferation as determined using MTT assay 84
Table 2. The effect of hinokitiol on adenocarcinoma cell proliferation as determined through trypan blue staining. 86








Non-cytotoxic Nanomaterials Enhance Antimicrobial Activities of Cefmetazole against Multidrug-Resistant Neisseria Gonorrhoeae
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Hinokitiol Induces DNA Damage and Autophagy Followed by Cell Cycle Arrest and Senescence in Gefitinib-Resistant Lung Adenocarcinoma Cells

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