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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 陳信銘 | |
dc.contributor.author | Po-Ya Chang | en |
dc.contributor.author | 張博雅 | zh_TW |
dc.date.accessioned | 2021-06-08T03:29:31Z | - |
dc.date.copyright | 2019-08-26 | |
dc.date.issued | 2019 | |
dc.date.submitted | 2019-08-15 | |
dc.identifier.citation | 1. Ackroyd R, Kelty C, Brown N, Reed M. The History of Photodetection and Photodynamic Therapy. Photochemistry and Photobiology 2001;74(5):656-69 doi:10.1562/0031-8655(2001)0740656thopap2.0.Co2
2. Hong EJ, Choi DG, Shim MS. Targeted and effective photodynamic therapy for cancer using functionalized nanomaterials. Acta Pharm Sin B 2016;6(4):297-307 doi:10.1016/j.apsb.2016.01.007 3. Castano AP, Mroz P, Hamblin MR. Photodynamic therapy and anti-tumour immunity. Nature reviews. Cancer 2006;6(7):535-45 doi: 10.1038/nrc1894 4. Moan J, Berg K. THE PHOTODEGRADATION OF PORPHYRINS IN CELLS CAN BE USED TO ESTIMATE THE LIFETIME OF SINGLET OXYGEN. Photochemistry and Photobiology 1991;53(4):549-53 doi:10.1111/j.1751-1097 .1991.tb03669.x 5. Kennedy JC, Pottier RH. New trends in photobiology: Endogenous protoporphyrin IX, a clinically useful photosensitizer for photodynamic therapy. Journal of Photochemistry and Photobiology B: Biology 1992;14(4):275-92 doi:10.1016/ 1011-1344(92)85108-7 6. Dougherty TJ, Kaufman JE, Goldfarb A, Weishaupt KR, Boyle D, Mittleman A. Photoradiation Therapy for the Treatment of Malignant Tumors. Cancer Research 1978;38(8):2628 7. Kennedy JC, Pottier RH, Pross DC. Photodynamic therapy with endogenous protoporphyrin: IX: Basic principles and present clinical experience. Journal of Photochemistry and Photobiology B: Biology 1990;6(1):143-48 doi:10.1016/ 1011-1344(90)85083-9 8. Dailey HA, Smith A. Differential interaction of porphyrins used in photoradiation therapy with ferrochelatase. Biochem J 1984;223(2):441-45 doi:10.1042/bj2230441 9. Gibson SL, Cupriks DJ, Havens JJ, Nguyen ML, Hilf R. A regulatory role for porphobilinogen deaminase (PBGD) in delta-aminolaevulinic acid(delta-ALA) -induced photosensitization? Br J Cancer 1998;77(2):235-42 doi:10.1038/bjc.1998.39 10. Takahashi K, Ikeda N, Nonoguchi N, et al. Enhanced expression of coproporphyrinogen oxidase in malignant brain tumors: CPOX expression and 5-ALA-induced fluorescence, 2011. 11. Cerrati EW, Nguyen SA, Farrar JD, Lentsch EJ. The Efficacy of Photodynamic Therapy in the Treatment of Oral Squamous Cell Carcinoma: A Meta-Analysis. Ear, Nose & Throat Journal 2015;94(2):72-79 doi:10.1177/014556131509400208 12. Vohra F, Al-Kheraif AA, Qadri T, et al. Efficacy of photodynamic therapy in the management of oral premalignant lesions. A systematic review. Photodiagnosis and Photodynamic Therapy 2015;12(1):150-59 doi:10.1016/j.pdpdt.2014.10.001 13. Jonker JW, Buitelaar M, Wagenaar E, et al. The breast cancer resistance protein protects against a major chlorophyll-derived dietary phototoxin and protoporphyria. Proceedings of the National Academy of Sciences of the United States of America 2002;99(24):15649-54 doi: 10.1073/pnas.202607599 14. Robey RW, Steadman K, Polgar O, Bates SE. ABCG2-mediated transport of photosensitizers: potential impact on photodynamic therapy. Cancer biology & therapy 2005;4(2):187-94 15. Keyse SM, Tyrrell RM. Heme oxygenase is the major 32-kDa stress protein induced in human skin fibroblasts by UVA radiation, hydrogen peroxide, and sodium arsenite. Proceedings of the National Academy of Sciences of the United States of America 1989;86(1):99-103 doi: 10.1073/pnas.86.1.99 16. Lin HY, Shen SC, Chen YC. Anti-inflammatory effect of heme oxygenase 1: glycosylation and nitric oxide inhibition in macrophages. Journal of cellular physiology 2005;202(2):579-90 doi: 10.1002/jcp.20160 17. Araujo J, Zhang M, Yin F. Heme Oxygenase-1, Oxidation, Inflammation, and Atherosclerosis. Frontiers in Pharmacology 2012;3(119) doi: 10.3389/fphar.2012. 00119 18. Chau L-Y. Heme oxygenase-1: emerging target of cancer therapy. Journal of Biomedical Science 2015;22(1):22 doi: 10.1186/s12929-015-0128-0 19. Lee PJ, Jiang BH, Chin BY, et al. Hypoxia-inducible factor-1 mediates transcriptional activation of the heme oxygenase-1 gene in response to hypoxia. J Biol Chem 1997;272(9):5375-81 20. Dean M, Rzhetsky A, Allikmets R. The human ATP-binding cassette (ABC) transporter superfamily. Genome Res 2001;11(7):1156-66 doi: 10.1101/gr.184901 21. Allikmets R, Schriml LM, Hutchinson A, Romano-Spica V, Dean M. A human placenta-specific ATP-binding cassette gene (ABCP) on chromosome 4q22 that is involved in multidrug resistance. Cancer Res 1998;58(23):5337-9 22. Miyake K, Mickley L, Litman T, et al. Molecular Cloning of cDNAs Which Are Highly Overexpressed in Mitoxantrone-resistant Cells. Cancer Research 1999;59(1):8 23. Doyle LA, Yang W, Abruzzo LV, et al. A multidrug resistance transporter from human MCF-7 breast cancer cells. Proceedings of the National Academy of Sciences 1998;95(26):15665 doi: 10.1073/pnas.95.26.15665 24. Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP– dependent transporters. Nature Reviews Cancer 2002;2(1):48-58 doi: 10.1038/ nrc706 25. Robey RW, Polgar O, Deeken J, To KW, Bates SE. ABCG2: determining its relevance in clinical drug resistance. Cancer metastasis reviews 2007;26(1):39-57 doi: 10.1007/s10555-007-9042-6 26. Leonard GD, Fojo T, Bates SE. The role of ABC transporters in clinical practice. The oncologist 2003;8(5):411-24 27. Diestra JE, Scheffer GL, Catala I, et al. Frequent expression of the multi-drug resistance-associated protein BCRP/MXR/ABCP/ABCG2 in human tumours detected by the BXP-21 monoclonal antibody in paraffin-embedded material. The Journal of pathology 2002;198(2):213-9 doi: 10.1002/path.1203 28. Wakabayashi K, Tamura A, Saito H, Onishi Y, Ishikawa T. Human ABC transporter ABCG2 in xenobiotic protection and redox biology. Drug metabolism reviews 2006;38(3):371-91 doi: 10.1080/03602530600727947 29. Tamura A, Watanabe M, Saito H, et al. Functional validation of the genetic polymorphisms of human ATP-binding cassette (ABC) transporter ABCG2: identification of alleles that are defective in porphyrin transport. Molecular pharmacology 2006;70(1):287-96 doi: 10.1124/mol.106.023556 30. Desuzinges-Mandon E, Arnaud O, Martinez L, Huche F, Di Pietro A, Falson P. ABCG2 transports and transfers heme to albumin through its large extracellular loop. The Journal of biological chemistry 2010;285(43):33123-33 doi: 10.1074/ jbc.M110.139170 31. Krishnamurthy P, Ross DD, Nakanishi T, et al. The stem cell marker Bcrp/ABCG2 enhances hypoxic cell survival through interactions with heme. The Journal of biological chemistry 2004;279(23):24218-25 doi: 10.1074/jbc.M313599200 32. Ishikawa T, Nakagawa H, Hagiya Y, Nonoguchi N, Miyatake S-I, Kuroiwa T. Key Role of Human ABC Transporter ABCG2 in Photodynamic Therapy and Photodynamic Diagnosis, 2010. 33. Kazi AA, Gilani RA, Schech AJ, et al. Nonhypoxic regulation and role of hypoxia-inducible factor 1 in aromatase inhibitor resistant breast cancer. Breast cancer research : BCR 2014;16(1):R15 doi: 10.1186/bcr3609 34. He X, Wang J, Wei W, et al. Hypoxia regulates ABCG2 activity through the activivation of ERK1/2/HIF-1alpha and contributes to chemoresistance in pancreatic cancer cells. Cancer biology & therapy 2016;17(2):188-98 doi: 10.1080/15384047.2016.1139228 35. Ma Q. Role of nrf2 in oxidative stress and toxicity. Annual review of pharmacology and toxicology 2013;53:401-26 doi: 10.1146/annurev-pharmtox- 011112-140320 36. Zhang P, Singh A, Yegnasubramanian S, et al. Loss of Kelch-Like ECH- Associated Protein 1 Function in Prostate Cancer Cells Causes Chemoresistance and Radioresistance and Promotes Tumor Growth. Molecular cancer therapeutics 2010;9(2):336 doi: 10.1158/1535-7163.MCT-09-0589 37. Homma S, Ishii Y, Morishima Y, et al. Nrf2 Enhances Cell Proliferation and Resistance to Anticancer Drugs in Human Lung Cancer. Clinical Cancer Research 2009;15(10):3423 doi: 10.1158/1078-0432.CCR-08-2822 38. Hagiya Y, Adachi T, Ogura S, et al. Nrf2-dependent induction of human ABC transporter ABCG2 and heme oxygenase-1 in HepG2 cells by photoactivation of porphyrins: biochemical implications for cancer cell response to photodynamic therapy. Journal of experimental therapeutics & oncology 2008;7(2):153-67 39. Thomlinson RH, Gray LH. The Histological Structure of Some Human Lung Cancers and the Possible Implications for Radiotherapy. Br J Cancer 1955;9(4):539-49 doi: 10.1038/bjc.1955.55 40. Hui L, Chen Y. Tumor microenvironment: Sanctuary of the devil. Cancer Lett 2015;368(1):7-13 doi: 10.1016/j.canlet.2015.07.039 41. Marignol L, Lawler M Fau - Coffey M, Coffey M Fau - Hollywood D, Hollywood D. Achieving hypoxia-inducible gene expression in tumors. (1538-4047 (Print)) 42. Graeber TG, Osmanian C, Jacks T, et al. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 1996;379(6560):88-91 doi:10.1038/379088a0 43. Tatum JL, Kelloff GJ, Gillies RJ, et al. Hypoxia: importance in tumor biology, noninvasive measurement by imaging, and value of its measurement in the management of cancer therapy. International journal of radiation biology 2006;82(10):699-757 doi: 10.1080/09553000601002324 44. Unruh A, Ressel A Fau - Mohamed HG, Mohamed Hg Fau - Johnson RS, et al. The hypoxia-inducible factor-1 alpha is a negative factor for tumor therapy.(0950-9232 (Print)) 45. Brahimi-Horn MC, Pouyssegur J. The hypoxia-inducible factor and tumor progression along the angiogenic pathway. International review of cytology 2005;242:157-213 doi: 10.1016/s0074-7696(04)42004-x 46. Wang K, Ding R, Ha Y, et al. Hypoxia-stressed cardiomyocytes promote early cardiac differentiation of cardiac stem cells through HIF-1alpha/Jagged1/Notch1 signaling. Acta Pharm Sin B 2018;8(5):795-804 doi: 10.1016/j.apsb.2018.06.003 47. Hussain I, Waheed S, Ahmad KA, Pirog JE, Syed V. Scutellaria baicalensis targets the hypoxia-inducible factor-1alpha and enhances cisplatin efficacy in ovarian cancer. J Cell Biochem 2018;119(9):7515-24 doi: 10.1002/jcb.27063 48. Wang WJ, Sui H, Qi C, et al. Ursolic acid inhibits proliferation and reverses drug resistance of ovarian cancer stem cells by downregulating ABCG2 through suppressing the expression of hypoxia-inducible factor-1alpha in vitro. Oncol Rep 2016;36(1):428-40 doi: 10.3892/or.2016.4813 49. Arsham AM, Plas DR, Thompson CB, Simon MC. Phosphatidylinositol 3-kinase/Akt signaling is neither required for hypoxic stabilization of HIF-1 alpha nor sufficient for HIF-1-dependent target gene transcription. The Journal of biological chemistry 2002;277(17):15162-70 doi: 10.1074/jbc.M111162200 50. Gray LH, Conger AD, Ebert M, Hornsey S, Scott OCA. The Concentration of Oxygen Dissolved in Tissues at the Time of Irradiation as a Factor in Radiotherapy. The British Journal of Radiology 1953;26(312):638-48 doi: 10.1259/0007-1285-26-312-638 51. Harada H. Hypoxia-inducible factor 1-mediated characteristic features of cancer cells for tumor radioresistance. J Radiat Res 2016;57 Suppl 1(Suppl 1):i99-i105 doi: 10.1093/jrr/rrw012. 52. Brown JM, Wilson WR. Exploiting tumour hypoxia in cancer treatment. Nature Reviews Cancer 2004;4(6):437-47 doi: 10.1038/nrc1367. 53. Wu M-Z, Cheng W-C, Chen S-F, et al. miR-25/93 mediates hypoxia-induced immunosuppression by repressing cGAS. Nature Cell Biology 2017;19:1286 doi:10.1038/ncb3615. 54. Weijer R, Broekgaarden M, Krekorian M, et al. Inhibition of hypoxia inducible factor 1 and topoisomerase with acriflavine sensitizes perihilar cholangiocarcinomas to photodynamic therapy. Oncotarget 2016;7(3):3341-56 doi:10.18632/oncotarget.6490. 55. Mitchell JB, McPherson S, DeGraff W, Gamson J, Zabell A, Russo A. Oxygen dependence of hematoporphyrin derivative-induced photoinactivation of Chinese hamster cells. Cancer Res 1985;45(5):2008-11 56. Mabjeesh NJ, Amir S. Hypoxia-inducible factor (HIF) in human tumorigenesis. Histology and histopathology 2007;22(5):559-72 doi: 10.14670/hh-22.559. 57. Ko FN, Wu CC, Kuo SC, Lee FY, Teng CM. YC-1, a novel activator of platelet guanylate cyclase. Blood 1994;84(12):4226-33 58. Sun HL, Liu YN, Huang Y-T, et al. YC-1 inhibits HIF-1 expression in prostate cancer cells: Contribution of Akt/NF-??B signaling to HIF-1?? accumulation during hypoxia, 2007. 59. Alessi DR, Cuenda A, Cohen P, Dudley DT, Saltiel AR. PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo. The Journal of biological chemistry 1995;270(46):27489-94 doi: 10.1074/jbc.270.46.27489. 60. Katiyar S, Mukhtar H. Tea in chemoprevention of cancer. International journal of oncology 1996;8(2):221-38 61. Sang S, Lambert JD, Ho CT, Yang CS. The chemistry and biotransformation of tea constituents. Pharmacological research 2011;64(2):87-99 doi: 10.1016/j.phrs.2011.02.007 62. Lee SH, Nam HJ, Kang HJ, Kwon HW, Lim YC. Epigallocatechin-3-gallate attenuates head and neck cancer stem cell traits through suppression of Notch pathway. European Journal of Cancer 2013;49(15):3210-18 doi: 10.1016/ j.ejca.2013.06.025 63. Chikara S, Nagaprashantha LD, Singhal J, Horne D, Awasthi S, Singhal SS. Oxidative stress and dietary phytochemicals: Role in cancer chemoprevention and treatment. Cancer Lett 2018;413:122-34 doi: 10.1016/j.canlet.2017.11.002 64. Rady I, Mohamed H, Rady M, Siddiqui IA, Mukhtar H. Cancer preventive and therapeutic effects of EGCG, the major polyphenol in green tea. Egyptian Journal of Basic and Applied Sciences 2018;5(1):1-23 doi: 10.1016/j.ejbas.2017.12.001 65. He Y, Zeng Q, Drenning SD, et al. Inhibition of Human Squamous Cell Carcinoma Growth In Vivo by Epidermal Growth Factor Receptor Antisense RNA Transcribed From the U6 Promoter. JNCI: Journal of the National Cancer Institute 1998;90(14):1080-87 doi: 10.1093/jnci/90.14.1080 66. Grandis JR, Melhem MF, Gooding WE, et al. Levels of TGF-α and EGFR Protein in Head and Neck Squamous Cell Carcinoma and Patient Survival. JNCI: Journal of the National Cancer Institute 1998;90(11):824-32 doi: 10.1093/jnci/90.11.824 67. Kolev TM, Velcheva EA, Stamboliyska BA, Spiteller M. DFT and experimental studies of the structure and vibrational spectra of curcumin. International Journal of Quantum Chemistry 2005;102(6):1069-79 doi: 10.1002/qua.20469 68. Campbell FC, Collett GP. Chemopreventive properties of curcumin. Future Oncology 2005;1(3):405-14 doi: 10.1517/14796694.1.3.405 69. Ullah F, Liang A, Rangel A, Gyengesi E, Niedermayer G, Munch G. High bioavailability curcumin: an anti-inflammatory and neurosupportive bioactive nutrient for neurodegenerative diseases characterized by chronic neuroinflammation. Arch Toxicol 2017;91(4):1623-34 doi: 10.1007/s00204-017-1939-4 70. Kunnumakkara AB, Bordoloi D, Harsha C, Banik K, Gupta SC, Aggarwal BB. Curcumin mediates anticancer effects by modulating multiple cell signaling pathways. Clinical science (London, England : 1979) 2017;131(15):1781-99 doi:10.1042/cs20160935 71. Kunnumakkara AB, Bordoloi D, Padmavathi G, et al. Curcumin, the golden nutraceutical: multitargeting for multiple chronic diseases. British journal of pharmacology 2017;174(11):1325-48 doi: 10.1111/bph.13621 72. Petiti J, Rosso V, Lo Iacono M, et al. Curcumin induces apoptosis in JAK2-mutated cells by the inhibition of JAK2/STAT and mTORC1 pathways. Journal of cellular and molecular medicine 2019;23(6):4349-57 doi: 10.1111/jcmm.14326 73. Chearwae W, Shukla S, Limtrakul P, Ambudkar SV. Modulation of the function of the multidrug resistance-linked ATP-binding cassette transporter ABCG2 by the cancer chemopreventive agent curcumin. Molecular cancer therapeutics 2006;5(8):1995-2006 doi: 10.1158/1535-7163.Mct-06-0087 74. Du Y, Long Q, Zhang L, et al. Curcumin inhibits cancer-associated fibroblast- driven prostate cancer invasion through MAOA/mTOR/HIF-1alpha signaling. International journal of oncology 2015;47(6):2064-72 doi: 10.3892/ijo.2015.3202 75. Yang SJ, Pyen J, Lee I, Lee H, Kim Y, Kim T. Cobalt chloride-induced apoptosis and extracellular signal-regulated protein kinase 1/2 activation in rat C6 glioma cells. Journal of biochemistry and molecular biology 2004;37(4):480-6 76. S. Al Okail M. Cobalt chloride, a chemical inducer of hypoxia-inducible factor-1α in U251 human glioblastoma cell line, 2010. 77. Chen R, Lai UH, Zhu L, Singh A, Ahmed M, Forsyth NR. Reactive Oxygen Species Formation in the Brain at Different Oxygen Levels: The Role of Hypoxia Inducible Factors. Frontiers in Cell and Developmental Biology 2018;6(132) doi:10.3389/fcell.2018.00132 78. Na HK, Kim EH, Jung JH, Lee HH, Hyun JW, Surh YJ. (-)-Epigallocatechin gallate induces Nrf2-mediated antioxidant enzyme expression via activation of PI3K and ERK in human mammary epithelial cells. Archives of biochemistry and biophysics 2008;476(2):171-7 doi: 10.1016/j.abb.2008.04.003 79. Yuan JH, Li YQ, Yang XY. Inhibition of epigallocatechin gallate on orthotopic colon cancer by upregulating the Nrf2-UGT1A signal pathway in nude mice. Pharmacology 2007;80(4):269-78 doi: 10.1159/000106447 80. Lambert JD, Kennett MJ, Sang S, Reuhl KR, Ju J, Yang CS. Hepatotoxicity of high oral dose (-)-epigallocatechin-3-gallate in mice. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 2010;48(1):409-16 doi: 10.1016/j.fct.2009.10.030 81. Nakazato T, Ito K, Ikeda Y, Kizaki M. Green Tea Component, Catechin, Induces Apoptosis of Human Malignant B Cells via Production of Reactive Oxygen Species. Clinical Cancer Research 2005;11(16):6040 doi: 10.1158/1078-0432. CCR-04-2273 82. Hintze KJ, Katoh Y, Igarashi K, Theil EC. Bach1 repression of ferritin and thioredoxin reductase1 is heme-sensitive in cells and in vitro and coordinates expression with heme oxygenase1, beta-globin, and NADP(H) quinone (oxido) reductase1. The Journal of biological chemistry 2007;282(47):34365-71 doi: 10.1074/jbc.M700254200 83. Adachi T, Nakagawa H, Chung I, et al. Nrf2-dependent and –independent induction of ABC transporters ABCC1, ABCC2, and ABCG2 in HepG2 cells under oxidative stress. Journal of experimental therapeutics & oncology 2007;6(4):335-48 | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/21250 | - |
dc.description.abstract | 口腔癌列屬106年臺灣癌症十大死亡率中第五名,對國人健康造成危害。現今治療方法以手術切除為主,但手術可能造成大範圍的顏面缺損和口腔功能缺失,也會使病患產生心理壓力。為了尋求更好的治療方法,近年來也投入研究新興的治療方式,包含光動力療法(Photodynamic Therapy;PDT)、冷凍治療等,以避免手術切除的負面影響。
5-氨基酮戊酸 (5-Aminolevulinic Acid;ALA)為光動力治療的一種常用藥,ALA進到細胞內部後,經過一連串代謝路徑形成protopophyrin(PpIX),成為PDT當中的光感物質,受光激發後產生單態氧及自由基殺死癌細胞。在臨床上ALA-PDT已被用於治療口腔癌和癌前病變,治療效果不錯且治療後病灶部位不會有明顯的傷口,對腫瘤周邊正常組織影響較小。但是治療所需時間長、需要照射次數多、藥物價格較高,先前研究也指出不同腫瘤的大小、位置、深度等因素都可能影響到ALA-PDT的療效。此外,腫瘤快速增長或PDT後造成的腫瘤血管異常都有可能導致缺氧(hypoxia),使PDT過程中所需的氧含量不足,也會影響口腔癌治療效果。 缺氧狀態下,會活化缺氧誘導因子1α(Hypoxia-inducible factor-1α;HIF1α),與Hypoxia-Response Element (HRE) 結合引起訊息傳遞,活化下游基因使癌細胞產生血管新生、侵襲性、細胞凋亡、轉移、化療抗性及放療抗性等特性。許多研究指出HIF1α也會促使ATP-binding cassette sub-family G member 2 (ABCG2)、Heme oxygenase 1 (HO1)表現量增加,可能減少細胞內的PpIX累積,造成治療不利。 本研究主要探討HIF1α是如何影響到口腔癌細胞PDT效果,並以輔助抑制劑或天然藥物降低其影響,希望透過合併療法提升治療效率,縮短治療時間和成本。 研究結果顯示,除了缺氧環境以外,光動力治療本身亦會引發細胞內HIF1α活化。使用氯化鈷(CoCl2)模擬缺氧細胞內HIF1α大量表現時,光動力治療效果和PpIX累積量都會下降,p-ERK、p-AKT、ABCG2、Nrf2、HO1等蛋白表現量則有顯著提升,使用HIF1α抑制劑YC-1(5-[1-(phenyl-methyl)-1H-indazol-3-yl] -2-furanmethanol)抑制HIF1α之後得到上述蛋白表現量下降的結果。推測HIF1α可能是透過EGFR下游p-ERK、p-AKT訊息傳遞路徑調控Nrf2,促使ABCG2和HO1轉錄,降低細胞內PpIX累積,影響PDT治療效率。以不同抑制劑和天然藥物處理後,發現除了YC-1以外薑黃素(curcumin)和MAPK/ERK抑制劑(PD98059)提高PpIX累積量和PDT效果最好。且Curcumin也能抑制因HIF1α過度表現而增加的ABCG2、Nrf2、HO1表現。 由本研究結果得知,處於缺氧狀態或是HIF1α表現量高的細胞於PDT前先以低毒性的抑制劑或天然藥物處理,可以明顯增加PpIX的生成,進而降低ALA-PDT後細胞存活率,提升治療效果。 | zh_TW |
dc.description.abstract | Oral cancer was ranked fifth among the top 10 cancer deaths in Taiwan in 106 years, threats to people's lives. Surgical resection is the mainly treatment nowadays, but it may cause a wide range of facial defects and loss of oral function, which will also cause psychological stress to patients. To avoid the negative effects of traditional treatment and find a better way, researchers get into emerging treatment in recent years, including photodynamic therapy (PDT), cryotherapy, etc.
5-Aminolevulinic acid (ALA) is a commonly used drug for PDT. Through a series of metabolic pathways, it forms a protoporphyrin (PpIX)--the photosensitizer in ALA-PDT. PpIX is excited by light, produces singlet oxygen and free radicals to kill cancer cells. Clinically, ALA-PDT has been used to treat oral cancer and oral potential malignant disorder without obvious wound after treatment. The treatment effect is good and causes little effect on the normal tissue. However, PDT treatment takes times for repeating irradiation, and the price of ALA is high. Previous studies have also pointed out that different tumor size, location, depth and other factors may affect the efficacy of ALA-PDT. In addition, rapid tumor growth and PDT-mediated tumor vascular abnormalities may lead to hypoxia--which may cause insufficient oxygen content in the PDT process, and affect the therapeutic effect. Under hypoxic condition, a transcription factor called “hypoxia-inducible factor 1α (HIF1α)” is activated to protect cell. HIF1α binds to Hypoxia-Response Element (HRE) to cause signal transduction, and activates downstream genes causeing angiogenesis, invasiveness, apoptosis, metastasis, chemotherapy and radiotherapy resistance in cancer cells. Many studies have pointed out that HIF1α also promotes the increase of ATP-binding cassette sub-family G member 2 (ABCG2) and Heme oxygenase 1 (HO1) expression, which may reduce the accumulation of PpIX in cells, resulting in low PDT effectiveness. This study focused on how HIF1α affects PDT in oral cancer cells, and used inhibitors or natural drugs to reduces the effects. Aim to improve treatment efficiency and shorten treatment time and cost with combination therapy. Results of the study show that in addition to the hypoxic environment, photodynamic therapy itself also triggered the activation of HIF1α in cells. Cobalt chloride (CoCl2) was used to simulate HIF1α expression in hypoxic cells. We observed that PDT effect and the cumulative amount of PpIX decreased, and the expression levels of p-ERK, p-AKT, ABCG2, Nrf2, and HO1 were increased when we add CoCl2. There was a significant decrease in the expression of the above-mentioned proteins after inhibiting HIF1α by inhibitor YC-1. It is speculated that HIF1α may regulate Nrf2 through p-ERK and p-AKT signal transduction pathway, promote ABCG2 and HO1 transcription. These changes reduce intracellular PpIX accumulation, and affect the efficiency of PDT treatment. After combination treatment with different inhibitors and natural drugs, curcumin and PD98059 were found to increase PpIX accumulation and PDT best except YC-1. Also, curcumin reduced the expression of ABCG2, Nrf2, and HO1. From the results of this study, cells in hypoxia or high HIF1α expression were treated with low toxicity inhibitors before PDT, which significantly increased the production of PpIX, thereby reducing the cell survival rate after ALA-PDT and improving treatment effect. | en |
dc.description.provenance | Made available in DSpace on 2021-06-08T03:29:31Z (GMT). No. of bitstreams: 1 ntu-108-R06450007-1.pdf: 2993625 bytes, checksum: d61753907904df3750903d0843f70a37 (MD5) Previous issue date: 2019 | en |
dc.description.tableofcontents | 口試委員會審定書..................................i
中文摘要 .........................................ii ABSTRACT.........................................iv 目錄.............................................vii 第一章 緒論(Introduction) p1 1.1 口腔癌(Oral cancer) p1 1.1.1 定義 p1 1.1.2 流行病學 p1 1.1.3 治療和預後 p2 1.2 光動力治療(Photodynamic Therapy) p4 1.2.1 緣起 p4 1.2.2 基本原理 p5 1.2.3 5-氨基酮戊酸光動力治療(5-Aminolevulinic Acid Photodynamic Therapy) p6 1.2.4 優勢與限制 p7 1.3 Heme oxygenase 1 (HO1) p8 1.4 ATP-binding cassette sub-family G member 2 (ABCG2) p9 1.4.1 基本介紹 p9 1.4.2 ABCG2與PDT p10 1.4.3 ABCG2與HIF1α p10 1.5 Nuclear Factor, Erythroid 2-related factor 2 (Nrf2) p11 1.6 缺氧(Hypoxia) p12 1.6.1 缺氧與腫瘤微環境 p12 1.6.2 缺氧誘導因子1α(Hypoxia-inducible factor-1α) p12 1.6.3 缺氧對治療的影響 p13 1.7 YC-1 p14 1.8 PD98059 p14 1.9 兒茶素(EGCG) p15 1.10 薑黃素(Curcumin) p16 1.11 研究目標 p17 第二章 材料與方法(Materials and Methods) p18 2.1 細胞株來源與培養 p18 2.2 光動力治療 p18 2.2.1 細胞處理 p18 2.2.2 光動力治療機器 p19 2.4 化學誘導HIF1α生成 p20 2.5 西方墨點法(Western blotting) p21 2.5.1 蛋白質萃取 p21 2.5.2 蛋白質定量(Bicinchoninic Acid (BCA) Protein Assay) p21 2.5.3 膠體電泳(SDS-PAGE)與轉漬(Transfer) p22 2.5.4 抗體辨識及呈色 p23 2.6 PpIX螢光測定 p25 2.7 抑制劑處理 p25 2.8 ROS螢光測定 p26 2.9 1O2螢光測定 p26 第三章 實驗結果(Results) p27 3.1 光動力治療會誘發HIF1α表現 p27 3.2 HIF1α蛋白表現量提高時細胞PpIX累積量下降,ALA-PDT效果較差 p28 3.3 HIF1α蛋白表現量提高時,相關的分子機轉 p29 3.4 YC-1抑制HIF1α與相關蛋白的表現 p29 3.5 經抑制劑處理之細胞PpIX累積量上升,ALA-PDT後細胞存活率變低 p30 3.6 Curcumin抑制HIF1α下游相關蛋白的表現 p31 第四章 討論(Discussions) p32 第五章 圖與表(Figures and Tables) p34 參考資料 p51 | |
dc.language.iso | zh-TW | |
dc.title | 探討氯化鈷藥物處理對光動力治療口腔癌細胞之影響 | zh_TW |
dc.title | The Effect of Cobaltous Chloride Treatment on Oral Cancer Cell Treated with Photodynamic Therapy | en |
dc.type | Thesis | |
dc.date.schoolyear | 107-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 江俊斌,郭彥彬,黎萬君 | |
dc.subject.keyword | 口腔癌,光動力治療,氯化鈷,HIF1α,ABCG2,PpIX,薑黃素, | zh_TW |
dc.subject.keyword | Oral Cancer,ALA-PDT,Cobaltous Chloride,HIF1α,ABCG2,PpIX,Curcumin, | en |
dc.relation.page | 65 | |
dc.identifier.doi | 10.6342/NTU201903551 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2019-08-16 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 口腔生物科學研究所 | zh_TW |
顯示於系所單位: | 口腔生物科學研究所 |
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