請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/93000完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 楊台鴻 | zh_TW |
| dc.contributor.advisor | Tai-Horng Young | en |
| dc.contributor.author | 徐維彤 | zh_TW |
| dc.contributor.author | Wei-Tung HSU | en |
| dc.date.accessioned | 2024-07-12T16:12:49Z | - |
| dc.date.available | 2024-07-13 | - |
| dc.date.copyright | 2024-07-12 | - |
| dc.date.issued | 2024 | - |
| dc.date.submitted | 2024-07-08 | - |
| dc.identifier.citation | 1.Kratzer, T.B., et al., Lung cancer statistics, 2023. Cancer, 2024. 130(8): p. 1330-1348.
2.Siegel, R.L., et al., Cancer statistics, 2023. Ca Cancer J Clin, 2023. 73(1): p. 17-48. 3.Sánchez-Ortega, M., A.C. Carrera, and A. Garrido, Role of NRF2 in lung cancer. Cells, 2021. 10(8): p. 1879. 4.Maemondo, M., et al., Gefitinib or chemotherapy for non–small-cell lung cancer with mutated EGFR. New England Journal of Medicine, 2010. 362(25): p. 2380-2388. 5.Armour, A. and C. Watkins, The challenge of targeting EGFR: experience with gefitinib in nonsmall cell lung cancer. European Respiratory Review, 2010. 19(117): p. 186-196. 6.Rawluk, J. and C.F. Waller, Gefitinib. Small molecules in oncology, 2018: p. 235-246. 7.Chen, Z., et al., Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade. Cancer letters, 2016. 370(1): p. 153-164. 8.Oxnard, G.R., et al., Assessment of resistance mechanisms and clinical implications in patients with EGFR T790M–positive lung cancer and acquired resistance to osimertinib. JAMA oncology, 2018. 4(11): p. 1527-1534. 9.Coleman, N., et al., Beyond epidermal growth factor receptor: MET amplification as a general resistance driver to targeted therapy in oncogene-driven non-small-cell lung cancer. ESMO open, 2021. 6(6): p. 100319. 10.Dong, Y.-Z. and T. Hu, Effects of miR-143 overexpression on proliferation, apoptosis, EGFR and downstream signaling pathways in PC9/GR cell line. European Review for Medical & Pharmacological Sciences, 2018. 22(6). 11.Wang, X., et al., Molecular mechanism and pharmacokinetics of flavonoids in the treatment of resistant EGF receptor‐mutated non‐small‐cell lung cancer: A narrative review. British Journal of Pharmacology, 2021. 178(6): p. 1388-1406. 12.Sequist, L.V., et al., Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Science translational medicine, 2011. 3(75): p. 75ra26-75ra26. 13.Jeyalakshmi, K., et al., Coordination behavior of N, N′, N ″-trisubstituted guanidine ligands in their Ru–arene complexes: synthetic, DNA/protein binding, and cytotoxic studies. Organometallics, 2019. 38(4): p. 753-770. 14.Kim, S.-H., D. Semenya, and D. Castagnolo, Antimicrobial drugs bearing guanidine moieties: A review. European Journal of Medicinal Chemistry, 2021. 216: p. 113293. 15.Li, J., et al., Mechanism of action of isopropoxy benzene guanidine against multidrug-resistant pathogens. Microbiology Spectrum, 2023. 11(1): p. e03469-22. 16.Zamperini, C., et al., Identification, synthesis and biological activity of alkyl-guanidine oligomers as potent antibacterial agents. Scientific reports, 2017. 7(1): p. 8251. 17.Gomes, A.R., et al., Synthetic and natural guanidine derivatives as antitumor and antimicrobial agents: A review. Bioorganic Chemistry, 2023: p. 106600. 18.Ji, Y.-R., et al., Selective regulation of neurons, glial cells, and neural stem/precursor cells by poly (allylguanidine)-coated surfaces. ACS applied materials & interfaces, 2019. 11(51): p. 48381-48392. 19.Ji, Y.-R., et al., Poly (allylguanidine)-coated surfaces regulate TGF-β in glioblastoma cells to induce apoptosis via NF-κB Pathway Activation. ACS Applied Materials & Interfaces, 2021. 13(49): p. 59400-59410. 20.Ha, Y., et al., Liposome leakage and increased cellular permeability induced by guanidine-based oligomers: effects of liposome composition on liposome leakage and human lung epithelial barrier permeability. RSC advances, 2021. 11(51): p. 32000-32011. 21.Choi, H., K.-J. Kim, and D.G. Lee, Antifungal activity of the cationic antimicrobial polymer-polyhexamethylene guanidine hydrochloride and its mode of action. Fungal biology, 2017. 121(1): p. 53-60. 22.Onitsuka, T., et al., Acquired resistance to gefitinib: the contribution of mechanisms other than the T790M, MET, and HGF status. Lung Cancer, 2010. 68(2): p. 198-203. 23.Venable, R.M., A. Kramer, and R.W. Pastor, Molecular dynamics simulations of membrane permeability. Chemical reviews, 2019. 119(9): p. 5954-5997. 24.Cheng, R., et al., Influence of fixation and permeabilization on the mass density of single cells: a surface plasmon resonance imaging study. Frontiers in chemistry, 2019. 7: p. 588. 25.Jamur, M.C. and C. Oliver, Permeabilization of cell membranes. Immunocytochemical methods and protocols, 2010: p. 63-66. 26.Ciardiello, F. and G. Tortora, Epidermal growth factor receptor (EGFR) as a target in cancer therapy: understanding the role of receptor expression and other molecular determinants that could influence the response to anti-EGFR drugs. European journal of cancer, 2003. 39(10): p. 1348-1354. 27.Ono, M. and M. Kuwano, Molecular mechanisms of epidermal growth factor receptor (EGFR) activation and response to gefitinib and other EGFR-targeting drugs. Clinical cancer research, 2006. 12(24): p. 7242-7251. 28.McMillen, E., et al., Epidermal growth factor receptor (EGFR) mutation and p-EGFR expression in resected non-small cell lung cancer. Experimental lung research, 2010. 36(9): p. 531-537. 29.Shilova, O.N., et al., Disassembling a cancer puzzle: Cell junctions and plasma membrane as targets for anticancer therapy. Journal of controlled release, 2018. 286: p. 125-136. 30.Hoelzle, M.K. and T. Svitkina, The cytoskeletal mechanisms of cell–cell junction formation in endothelial cells. Molecular biology of the cell, 2012. 23(2): p. 310-323. 31.Choi, I.-K., et al., Strategies to increase drug penetration in solid tumors. Frontiers in oncology, 2013. 3: p. 193. 32.Ma, J., et al., Krüppel‐like factor 4 regulates blood‐tumor barrier permeability via ZO‐1, occludin and claudin‐5. Journal of cellular physiology, 2014. 229(7): p. 916-926. 33.Lemmer, H.J. and J.H. Hamman, Paracellular drug absorption enhancement through tight junction modulation. Expert opinion on drug delivery, 2013. 10(1): p. 103-114. 34.Boyaval, F., et al., N-glycomic signature of stage II colorectal cancer and its association with the tumor microenvironment. Molecular & Cellular Proteomics, 2021. 20. 35.Peixoto, A., et al., Protein glycosylation and tumor microenvironment alterations driving cancer hallmarks. Frontiers in oncology, 2019. 9: p. 380. 36.Jin, S.W., et al., Polyhexamethylene guanidine phosphate damages tight junctions and the f-actin architecture by activating calpain-1 via the P2RX7/Ca2+ signaling pathway. Cells, 2019. 9(1): p. 59. 37.Rodgers, L.S., et al., Epithelial barrier assembly requires coordinated activity of multiple domains of the tight junction protein ZO-1. Journal of cell science, 2013. 126(7): p. 1565-1575. 38.De Marchi, E., et al., The mitochondrial permeability transition pore is a dispensable element for mitochondrial calcium efflux. Cell calcium, 2014. 56(1): p. 1-13. 39.Doherty, G.J. and H.T. McMahon, Mechanisms of endocytosis. Annual review of biochemistry, 2009. 78: p. 857-902. 40.Schmidt, N., et al., Arginine-rich cell-penetrating peptides. FEBS letters, 2010. 584(9): p. 1806-1813. 41.Futaki, S. and I. Nakase, Cell-surface interactions on arginine-rich cell-penetrating peptides allow for multiplex modes of internalization. Accounts of chemical research, 2017. 50(10): p. 2449-2456. 42.Melikov, K. and L. Chernomordik, Arginine-rich cell penetrating peptides: from endosomal uptake to nuclear delivery. Cellular and Molecular Life Sciences CMLS, 2005. 62: p. 2739-2749. 43.Jobin, M.-L., et al., The role of tryptophans on the cellular uptake and membrane interaction of arginine-rich cell penetrating peptides. Biochimica et Biophysica Acta (BBA)-Biomembranes, 2015. 1848(2): p. 593-602. 44.Sun, D., et al., Effect of arginine-rich cell penetrating peptides on membrane pore formation and life-times: A molecular simulation study. Physical Chemistry Chemical Physics, 2014. 16(38): p. 20785-20795. 45.Liu, B.R., et al., Endocytic trafficking of nanoparticles delivered by cell-penetrating peptides comprised of nona-arginine and a penetration accelerating sequence. PloS one, 2013. 8(6): p. e67100. 46.Wang, F., et al., Combination therapy of gefitinib and miR-30a-5p may overcome acquired drug resistance through regulating the PI3K/AKT pathway in non-small cell lung cancer. Therapeutic Advances in Respiratory Disease, 2020. 14: p. 1753466620915156. 47.Li, L., et al., Metformin sensitizes EGFR-TKI–resistant human lung cancer cells in vitro and in vivo through inhibition of IL-6 signaling and EMT reversal. Clinical cancer research, 2014. 20(10): p. 2714-2726. 48.Kanaji, N., et al., Higher susceptibility of NOD/LtSz-scid Il2rg−/− NSG mice to xenotransplanted lung cancer cell lines. Cancer Management and Research, 2014: p. 431-436. 49.Yuan, R., et al., Cucurbitacin B inhibits non-small cell lung cancer in vivo and in vitro by triggering TLR4/NLRP3/GSDMD-dependent pyroptosis. Pharmacological Research, 2021. 170: p. 105748. | - |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/93000 | - |
| dc.description.abstract | 吉非替尼是針對非小型細胞肺癌的標靶藥物，倘若使用之初未完全殺死癌細胞，幾乎接受過吉非替尼治療的病患都會產生藥物失效的問題，這導致病患後續的治療方式受限且預後不好，因此我們亟需克服這項問題，本文使用聚丙烯弧合併吉非替尼進行治療，提供嶄新治療策略。
在體外實驗中，我們觀察到低濃度的聚丙烯弧合併吉非替尼處理抗藥性肺癌細胞，相較只用吉非替尼處理，更能輕易地殺死癌細胞，為了探討這背後的可能機制，我們透過分析細胞膜的通透性及膜上所受影響之蛋白，發現在不殺死細胞的聚丙烯弧濃度下，細胞通透性會增加，且原因是因為其破壞細胞外的連接蛋白，讓藥物更大量的進入細胞內，成功使被磷酸化的表皮生長因子受體減少，因而抑制細胞增生。 此外，在後續的小鼠動物實驗中，我們也觀察到相同的表現，我們使用免疫缺陷的小鼠作為模型，異種移植人類抗藥性肺癌細胞後再進行治療，在四種不同的治療方式中，同時使用聚丙烯弧及吉非替尼於皮下注射的方式有著最好的抑制腫瘤體積增大的效果，而且在病理組織切片的分析中，結合治療的視野下幾乎看不到任何腫瘤細胞，雖然有留下一些疤痕組織，但這樣的療效對克服抗藥性肺癌的問題，著實是一大進展。 | zh_TW |
| dc.description.abstract | Gefitinib is a targeted therapy for non-small cell lung cancer (NSCLC). However, if the cancer cells are not completely eradicated at the beginning of the treatment, almost all patients will develop resistance to the drug, which limits subsequent treatment options and leads to poor prognosis. Therefore, it is crucial to overcome this issue. In this study, we combined polyallylamine with gefitinib to provide a new therapeutic approach.
In in vitro experiments, we found that low concentrations of poly (allyl guanidine) (PAG) combined with gefitinib were more effective in inhibiting the activity of resistant lung cancer cells compared to gefitinib alone. To investigate the mechanism behind this phenomenon, we analyzed cell membrane permeability and the affected proteins on the membrane. We discovered that at non-cytotoxic concentrations of PAG, cell permeability increased due to the disruption of extracellular junction proteins, allowing a greater amount of the drug to enter the cells. This led to a reduction in phosphorylated epidermal growth factor receptor (P-EGFR), thereby inhibiting cell growth. Furthermore, in subsequent mouse animal experiments, we observed a similar trend. We used immunodeficient mice as models, xenografting them with human resistant lung cancer cells before treatment. Among the four different treatment methods, the combination of subcutaneous injections of PAG and gefitinib exhibited the best tumor growth inhibition. Pathological tissue analysis showed that in the combination treatment group, almost no tumor cells were observed, although some scar tissue remained. This therapeutic effect represents a significant advancement in overcoming drug-resistant lung cancer. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2024-07-12T16:12:49Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2024-07-12T16:12:49Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 口試委員會審定書...I
誌謝...II 中文摘要...III Abstract...IV Contents...VI List of Figures...III List of tables...X Chapter1: Introduction...1 1.1 Lung cancer...1 1.2 Gefitinib treatment...3 1.3 Gefitinib resistance...6 1.4 Guanidine and PAG...8 1.5 Liposome leakage caused by the guanidine family...11 1.6 Purpose and framework of the study...12 Chapter2: Materials and methods...14 2.1 Cell line and culture condition...14 2.2 Cell viability test...14 2.3 Cell membrane morphology assay...15 2.4 DAPI membrane permeability analysis...15 2.5 Western blot...16 2.6 LC MS/MS...17 2.7 Protein array...17 2.8 In vivo antitumor assay...17 2.9 Histological analysis...18 2.10 Statistical analysis...18 Chapter3: Results...19 3.1 Viability of both lung cancer cells...19 3.2 Cell morphology changes in PC9/GR caused by PAG...21 3.3 Staining of plasma membrane and DAPI in PC9/GR...22 3.4 Cell permeability changes in both lung cancer cells...24 3.5 EGFR and phospho-EGFR expression in PC9/GR...26 3.6 Purification of PC9/GR Plasma membrane protein...29 3.7 LC/MS/MS analysis of PC9/GR membrane proteins...30 3.8 Protein array analysis of PC9/GR membrane proteins...31 3.9 In vivo anti-tumor efficiency...34 Chapter4: Discussion...39 4.1 PAG enhances the ability of the gefitinib to kill PC9/GR cells...39 4.2 PAG's impact on cell membranes...39 4.3 The effect of altered membrane permeability on gefitinib efficiency...40 4.4 The interaction between PAG and PC9/GR membrane proteins...41 4.5 Cell junction proteins affected by PAG...42 4.6 In vivo anti-tumor treatment...43 Chapter5: Conclusion...45 Chapter6: Supplementary information...46 Reference...49 | - |
| dc.language.iso | en | - |
| dc.subject | 非小型細胞肺癌 | zh_TW |
| dc.subject | 聚丙烯胍 | zh_TW |
| dc.subject | 小鼠動物實驗 | zh_TW |
| dc.subject | 吉非替尼抗藥性 | zh_TW |
| dc.subject | 細胞連接蛋白 | zh_TW |
| dc.subject | Mice animal model | en |
| dc.subject | Poly (allyl guanidine) | en |
| dc.subject | Cell Adhesion Proteins | en |
| dc.subject | Non-small cell lung cancer | en |
| dc.subject | Gefitinib resistance | en |
| dc.title | 聚烯丙胍應用於克服吉非替尼抗藥性肺癌之研究 | zh_TW |
| dc.title | Application of poly (allyl guanidine) (PAG) in Overcoming Gefitinib Resistance of Human Lung Cancer | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 112-2 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 王大銘;賴君義 | zh_TW |
| dc.contributor.oralexamcommittee | Da-Ming Wang;Juin-Yih Lai | en |
| dc.subject.keyword | 非小型細胞肺癌,聚丙烯胍,吉非替尼抗藥性,細胞連接蛋白,小鼠動物實驗, | zh_TW |
| dc.subject.keyword | Non-small cell lung cancer,Poly (allyl guanidine),Gefitinib resistance,Cell Adhesion Proteins,Mice animal model, | en |
| dc.relation.page | 52 | - |
| dc.identifier.doi | 10.6342/NTU202401569 | - |
| dc.rights.note | 未授權 | - |
| dc.date.accepted | 2024-07-08 | - |
| dc.contributor.author-college | 工學院 | - |
| dc.contributor.author-dept | 醫學工程學系 | - |
| 顯示於系所單位： | 醫學工程學研究所 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-112-2.pdf 未授權公開取用 | 3.14 MB | Adobe PDF |
系統中的文件，除了特別指名其著作權條款之外，均受到著作權保護，並且保留所有的權利。