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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 許麗卿(Lih-Ching Hsu) | |
dc.contributor.author | Hao-Cheng Weng | en |
dc.contributor.author | 翁顥誠 | zh_TW |
dc.date.accessioned | 2021-06-17T07:21:30Z | - |
dc.date.available | 2024-08-27 | |
dc.date.copyright | 2019-08-27 | |
dc.date.issued | 2019 | |
dc.date.submitted | 2019-07-04 | |
dc.identifier.citation | 1. Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A. and Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018, 68, 394-424.
2. Kaminska, M., Ciszewski, T., Lopacka-Szatan, K., Miotla, P. and Staroslawska, E. Breast cancer risk factors. Prz Menopauzalny 2015, 14, 196-202. 3. American Cancer Society. Breast Cancer. https://www.cancer.org/cancer/breast-cancer.html. Accessed on 6 March, 2019. 4. Coley, H. M. Mechanisms and strategies to overcome chemotherapy resistance in metastatic breast cancer. Cancer Treat Rev 2008, 34, 378-390. 5. Dasari, S. and Tchounwou, P. B. Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharmacol 2014, 740, 364-378. 6. Byrski, T., Huzarski, T., Dent, R., Gronwald, J., Zuziak, D., Cybulski, C., et al. Response to neoadjuvant therapy with cisplatin in BRCA1-positive breast cancer patients. Breast Cancer Res Treat 2009, 115, 359-363. 7. Helm, C. W. and States, J. C. Enhancing the efficacy of cisplatin in ovarian cancer treatment – could arsenic have a role. J Ovarian Res 2009, 2, 2. 8. Dhar, S., Kolishetti, N., Lippard, S. J. and Farokhzad, O. C. Targeted delivery of a cisplatin prodrug for safer and more effective prostate cancer therapy in vivo. Proc Natl Acad Sci U S A 2011, 108, 1850-1855. 9. Cui, L., Her, S., Dunne, M., Borst, G. R., De Souza, R., Bristow, R. G., et al. Significant Radiation Enhancement Effects by Gold Nanoparticles in Combination with Cisplatin in Triple Negative Breast Cancer Cells and Tumor Xenografts. Radiat Res 2017, 187, 147-160. 10. Pegram, M. D. and Slamon, D. J. Combination therapy with trastuzumab (Herceptin) and cisplatin for chemoresistant metastatic breast cancer: evidence for receptor-enhanced chemosensitivity. Semin Oncol 1999, 26, 89-95. 11. Thapa, R. K., Choi, J. Y., Gupta, B., Ramasamy, T., Poudel, B. K., Ku, S. K., et al. Liquid crystalline nanoparticles encapsulating cisplatin and docetaxel combination for targeted therapy of breast cancer. Biomater Sci 2016, 4, 1340-1350. 12. Wang, Y. D., Li, S. J. and Liao, J. X. Inhibition of glucose transporter 1 (GLUT1) chemosensitized head and neck cancer cells to cisplatin. Technol Cancer Res Treat 2013, 12, 525-535. 13. Li, P., Yang, X., Cheng, Y., Zhang, X., Yang, C., Deng, X., et al. MicroRNA-218 increases the sensitivity of bladder cancer to cisplatin by targeting Glut1. Cell Physiol Biochem 2017, 41, 921-932. 14. Vander Heiden, M. G., Cantley, L. C. and Thompson, C. B. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009, 324, 1029-1033. 15. Carvalho, K. C., Cunha, I. W., Rocha, R. M., Ayala, F. R., Cajaíba, M. M., Begnami, M. D., et al. GLUT1 expression in malignant tumors and its use as an immunodiagnostic marker. Clinics 2011, 66, 965-972. 16. Liu, Y., Cao, Y., Zhang, W., Bergmeier, S., Qian, Y., Akbar, H., et al. A small-molecule inhibitor of glucose transporter 1 downregulates glycolysis, induces cell-cycle arrest, and inhibits cancer cell growth in vitro and in vivo. Mol Cancer Ther 2012, 11, 1672-1682. 17. Chen, Q., Meng, Y. Q., Xu, X. F. and Gu, J. Blockade of GLUT1 by WZB117 resensitizes breast cancer cells to adriamycin. Anticancer Drugs 2017, 28, 880-887. 18. Zhao, F., Ming, J., Zhou, Y. and Fan, L. Inhibition of Glut1 by WZB117 sensitizes radioresistant breast cancer cells to irradiation. Cancer Chemother Pharmacol 2016, 77, 963-972. 19. Siegel, R. L., Miller, K. D. and Jemal, A. Cancer statistics, 2019. CA Cancer J Clin 2019, 69, 7-34. 20. Ministry of Health and Walfare. 2017 Statistics of Causes of Death. https://www.mohw.gov.tw/cp-3961-42866-2.html. Accessed on 7 March, 2019. 21. Allied Academies. Staging Of Breast Cancer. http://breastpathology.alliedacademies.com/2018/events-list/breast-cancer-staging. Accessed on May 23, 2018. 22. National Cancer Institute. Cancer Stat Facts: Female Breast Cancer. https://seer.cancer.gov/statfacts/html/breast.html. Accessed on March 17, 2019. 23. Dai, X., Cheng, H., Bai, Z. and Li, J. Breast cancer cell line classification and its relevance with breast tumor subtyping. J Cancer 2017, 8, 3131-3141. 24. Neve, R. M., Chin, K., Fridlyand, J., Yeh, J., Baehner, F. L., Fevr, T., et al. A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell 2006, 10, 515-527. 25. Leroy, B., Girard, L., Hollestelle, A., Minna, J. D., Gazdar, A. F. and Soussi, T. Analysis of TP 53 mutation status in human cancer cell lines: a reassessment. Human mutation 2014, 35, 756-765. 26. Oh, S., Kim, H., Nam, K. and Shin, I. Glut1 promotes cell proliferation, migration and invasion by regulating epidermal growth factor receptor and integrin signaling in triple-negative breast cancer cells. BMB Rep 2017, 50, 132-137. 27. Kato, Y., Ozawa, S., Miyamoto, C., Maehata, Y., Suzuki, A., Maeda, T., et al. Acidic extracellular microenvironment and cancer. Cancer Cell Int 2013, 13, 89. 28. Gill, K. S., Fernandes, P., O'Donovan, T. R., McKenna, S. L., Doddakula, K. K., Power, D. G., et al. Glycolysis inhibition as a cancer treatment and its role in an anti-tumour immune response. Biochim Biophys Acta. 2016, 1866, 87-105. 29. Adekola, K., Rosen, S. T. and Shanmugam, M. Glucose transporters in cancer metabolism. Curr Opin Oncol 2012, 24, 650-654. 30. Navale, A. M. and Paranjape, A. N. Glucose transporters: physiological and pathological roles. Biophys Rev 2016, 8, 5-9. 31. Kauffman, G. B., Pentimalli, R., Doldi, S. and Hall, M. D. Michele Peyrone (1813‐1883), discoverer of cisplatin. Platin Met Rev 2010, 54, 250-256. 32. Rosenberg, B. Some biological effects of platinum compounds. Platin Met Rev 1971, 15, 42-51. 33. Alderden, R. A., Hall, M. D. and Hambley, T. W. The discovery and development of cisplatin. J Chem Educ 2006, 83, 728. 34. Kelland, L. The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer 2007, 7, 573-584. 35. Florea, A. M. and Büsselberg, D. Cisplatin as an anti-tumor drug: cellular mechanisms of activity, drug resistance and induced side effects. Cancers 2011, 3, 1351-1371. 36. Ljungman, M. Activation of DNA damage signaling. Mutat Res 2005, 577, 203-216. 37. Bohgaki, T., Bohgaki, M. and Hakem, R. DNA double-strand break signaling and human disorders. Genome Integr 2010, 1, 15. 38. Marechal, A. and Zou, L. DNA damage sensing by the ATM and ATR kinases. Cold Spring Harb Perspect Biol 2013, 5 39. Ouyang, L., Shi, Z., Zhao, S., Wang, F. T., Zhou, T. T., Liu, B., et al. Programmed cell death pathways in cancer: a review of apoptosis, autophagy and programmed necrosis. Cell Prolif 2012, 45, 487-498. 40. Norbury, C. J. and Hickson, I. D. Cellular responses to DNA damage. Annu Rev Pharmacol Toxicol 2001, 41, 367-401. 41. Kerr, J. F., Wyllie, A. H. and Currie, A. R. Apoptosis: a basic biological phenomenon with wideranging implications in tissue kinetics. Br J Cancer 1972, 26, 239. 42. Elmore, S. Apoptosis: a review of programmed cell death. Toxicol Pathol 2007, 35, 495-516. 43. Hemann, M. T. and Lowe, S. W. The p53-Bcl-2 connection. Cell Death Differ 2006, 13, 1256-1259. 44. Dikic, I. and Elazar, Z. Mechanism and medical implications of mammalian autophagy. Nat Rev Mol Cell Biol 2018, 19, 349-364. 45. Yu, L., Chen, Y. and Tooze, S. A. Autophagy pathway: cellular and molecular mechanisms. Autophagy 2018, 14, 207-215. 46. Dhuriya, Y. K. and Sharma, D. Necroptosis: a regulated inflammatory mode of cell death. J Neuroinflammation 2018, 15, 199. 47. Burton, G. J. and Jauniaux, E. Oxidative stress. Best Pract Res Clin Obstet Gynaecol 2011, 25, 287-299. 48. Porta, C., Paglino, C. and Mosca, A. Targeting PI3K/Akt/mTOR signaling in cancer. Front Oncol 2014, 4, 64. 49. Douros, J. and Suffness, M. New antitumor substances of natural origin. Cancer Treat Rev 1981, 8, 63-87. 50. Zaytseva, Y. Y., Valentino, J. D., Gulhati, P. and Evers, B. M. mTOR inhibitors in cancer therapy. Cancer Lett 2012, 319, 1-7. 51. Buti, S., Leonetti, A., Dallatomasina, A. and Bersanelli, M. Everolimus in the management of metastatic renal cell carcinoma: an evidence-based review of its place in therapy. Core Evid 2016, 11, 23-36. 52. Gajate, P., Martínez-Sáez, O., Alonso-Gordoa, T. and Grande, E. Emerging use of everolimus in the treatment of neuroendocrine tumors. Cancer Manag Res 2017, 9, 215. 53. Ciruelos Gil, E. M. Targeting the PI3K/AKT/mTOR pathway in estrogen receptor-positive breast cancer. Cancer Treat Rev 2014, 40, 862-871. 54. O'Shaughnessy, J., Beck, J. T. and Royce, M. Everolimus-based combination therapies for HR+, HER2–metastatic breast cancer. Cancer Treat Rev 2018 55. Porta, C., Osanto, S., Ravaud, A., Climent, M. A., Vaishampayan, U., White, D. A., et al. Management of adverse events associated with the use of everolimus in patients with advanced renal cell carcinoma. Eur J Cancer 2011, 47, 1287-1298. 56. FDA. FDA approves first PI3K inhibitor for breast cancer. https://www.fda.gov/news-events/press-announcements/fda-approves-first-pi3k-inhibitor-breast-cancer. Accessed on 29 May, 2019. 57. Song, M., Bode, A. M., Dong, Z. and Lee, M. H. AKT as a therapeutic target for cancer. Cancer Res 2019, 79, 1019-1031. 58. Zhang, W. and Liu, H. T. MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res 2002, 12, 9-18. 59. Morrison, D. K. MAP kinase pathways. Cold Spring Harb Perspect Biol 2012, 4 60. Liu, F., Yang, X., Geng, M. and Huang, M. Targeting ERK, an Achilles' Heel of the MAPK pathway, in cancer therapy. Acta Pharm Sin B 2018, 8, 552-562. 61. Hung, C. H. Targeting GLUT1 for the development of novel anticancer agents. Master’s thesis of Graduate institute of pharmaceuticals. National Taiwan University 2018, 1-67. 62. Choi, Y. M., Kim, H. K., Shim, W., Anwar, M. A., Kwon, J. W., Kwon, H. K., et al. Mechanism of cisplatin-induced cytotoxicity is correlated to impaired metabolism due to mitochondrial ROS generation. PLoS One 2015, 10, e0135083. 63. Ren, Y. and Shen, H. M. Critical role of AMPK in redox regulation under glucose starvation. Redox Biol 2019, 101154. 64. Marchi, S., Giorgi, C., Suski, J. M., Agnoletto, C., Bononi, A., Bonora, M., et al. Mitochondria-ros crosstalk in the control of cell death and aging. J Signal Transduct 2012, 2012, 329635. 65. Krzeslak, A., Wojcik-Krowiranda, K., Forma, E., Jozwiak, P., Romanowicz, H., Bienkiewicz, A., et al. Expression of GLUT1 and GLUT3 glucose transporters in endometrial and breast cancers. Pathol Oncol Res 2012, 18, 721-728. 66. Velma, V., Dasari, S. R. and Tchounwou, P. B. Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights 2016, 11, 113-121. 67. Henkels, K. M. and Turchi, J. J. Cisplatin-induced apoptosis proceeds by caspase-3-dependent and -independent pathways in cisplatin-resistant and -sensitive human ovarian cancer cell lines. Cancer Res 1999, 59, 3077-3083. 68. Cregan, I. L., Dharmarajan, A. M. and Fox, S. A. Mechanisms of cisplatin-induced cell death in malignant mesothelioma cells: role of inhibitor of apoptosis proteins (IAPs) and caspases. Int J Oncol 2013, 42, 444-452. 69. Matsumoto, M., Nakajima, W., Seike, M., Gemma, A. and Tanaka, N. Cisplatin-induced apoptosis in non-small-cell lung cancer cells is dependent on Bax- and Bak-induction pathway and synergistically activated by BH3-mimetic ABT-263 in p53 wild-type and mutant cells. Biochem Bioph Res Co 2016, 473, 490-496. 70. Matsumoto, T., Jimi, S., Migita, K., Takamatsu, Y. and Hara, S. Inhibition of glucose transporter 1 induces apoptosis and sensitizes multiple myeloma cells to conventional chemotherapeutic agents. Leuk Res 2016, 41, 103-110. 71. Yan, X., Qi, M., Li, P., Zhan, Y. and Shao, H. Apigenin in cancer therapy: anti-cancer effects and mechanisms of action. Cell Biosci 2017, 7, 50. 72. Teijido, O. and Dejean, L. Upregulation of Bcl2 inhibits apoptosis-driven BAX insertion but favors BAX relocalization in mitochondria. FEBS Lett 2010, 584, 3305-3310. 73. Marullo, R., Werner, E., Degtyareva, N., Moore, B., Altavilla, G., Ramalingam, S. S., et al. Cisplatin induces a mitochondrial-ROS response that contributes to cytotoxicity depending on mitochondrial redox status and bioenergetic functions. Plos One 2013, 8 74. Choi, Y. M., Kim, H. K., Shim, W., Anwar, M. A., Kwon, J. W., Kwon, H. K., et al. Mechanism of cisplatin-induced cytotoxicity is correlated to impaired metabolism due to mitochondrial ROS generation. Plos One 2015, 10 75. Andrisse, S., Koehler, R. M., Chen, J. E., Patel, G. D., Vallurupalli, V. R., Ratliff, B. A., et al. Role of GLUT1 in regulation of reactive oxygen species. Redox Biology 2014, 2, 764-771. 76. Florea, A. M. and Büsselberg, D. Cisplatin as an anti-tumor drug: cellular mechanisms of activity, drug resistance and induced side effects. Cancers 2011, 3, 1351-1371. 77. Vaseva, A. V., Marchenko, N. D., Ji, K., Tsirka, S. E., Holzmann, S. and Moll, U. M. p53 opens the mitochondrial permeability transition pore to trigger necrosis. Cell 2012, 149, 1536-1548. 78. Sears, C. R., Cooney, S. A., Chin-Sinex, H., Mendonca, M. S. and Turchi, J. J. DNA damage response (DDR) pathway engagement in cisplatin radiosensitization of non-small cell lung cancer. DNA Repair (Amst) 2016, 40, 35-46. 79. Turgeon, M. O., Perry, N. J. S. and Poulogiannis, G. DNA damage, repair, and cancer metabolism. Front Oncol 2018, 8, 15. 80. Yoshiyama, K. O., Sakaguchi, K. and Kimura, S. DNA damage response in plants: conserved and variable response compared to animals. Biology (Basel) 2013, 2, 1338-1356. 81. Abbas, T. and Dutta, A. p21 in cancer: intricate networks and multiple activities. Nat Rev Cancer 2009, 9, 400-414. 82. Winograd-Katz, S. E. and Levitzki, A. Cisplatin induces PKB/Akt activation and p38(MAPK) phosphorylation of the EGF receptor. Oncogene 2006, 25, 7381-7390. 83. Wang, M., Liu, Z. M., Li, X. C., Yao, Y. T. and Yin, Z. X. Activation of ERK1/2 and Akt is associated with cisplatin resistance in human lung cancer cells. J Chemotherapy 2013, 25, 162-169. 84. Gao, M., Liang, J., Lu, Y., Guo, H., German, P., Bai, S., et al. Site-specific activation of AKT protects cells from death induced by glucose deprivation. Oncogene 2014, 33, 745-755. 85. Memmott, R. M. and Dennis, P. A. Akt-dependent and -independent mechanisms of mTOR regulation in cancer. Cell Signal 2009, 21, 656-664. 86. Guegan, J. P., Ezan, F., Theret, N., Langouet, S. and Baffet, G. MAPK signaling in cisplatin-induced death: predominant role of ERK1 over ERK2 in human hepatocellular carcinoma cells. Carcinogenesis 2013, 34, 38-47. 87. Germain, C. S., Niknejad, N., Ma, L., Garbuio, K., Hai, T. and Dimitroulakos, J. Cisplatin induces cytotoxicity through the mitogen-activated protein kinase pathways ana activating transcription factor 3. Neoplasia 2010, 12, 527-538. 88. Hernandez Losa, J., Parada Cobo, C., Guinea Viniegra, J., Sanchez-Arevalo Lobo, V. J., Ramon y Cajal, S. and Sanchez-Prieto, R. Role of the p38 MAPK pathway in cisplatin-based therapy. Oncogene 2003, 22, 3998-4006. 89. Mansouri, A., Ridgway, L. D., Korapati, A. L., Zhang, Q., Tian, L., Wang, Y., et al. Sustained activation of JNK/p38 MAPK pathways in response to cisplatin leads to Fas ligand induction and cell death in ovarian carcinoma cells. J Biol Chem 2003, 278, 19245-19256. 90. Kim, M. S., Kwon, J. Y., Kang, N. J., Lee, K. W. and Lee, H. J. Phloretin induces apoptosis in H-Ras MCF10A human breast tumor cells through the activation of p53 via JNK and p38 mitogen-activated protein kinase signaling. Ann Ny Acad Sci 2009, 1171, 479-483. 91. Min, J., Li, X., Huang, K. N., Tang, H., Ding, X. Y., Qi, C., et al. Phloretin induces apoptosis of non-small cell lung carcinoma A549 cells via JNK1/2 and p38 MAPK pathways. Oncol Rep 2015, 34, 2871-2879. 92. Koch, A., Lang, S. A., Wild, P. J., Gantner, S., Mahli, A., Spanier, G., et al. Glucose transporter isoform 1 expression enhances metastasis of malignant melanoma cells. Oncotarget 2015, 6, 32748-32760. 93. Cai, B., Chang, S. H., Becker, E. B., Bonni, A. and Xia, Z. p38 MAP kinase mediates apoptosis through phosphorylation of BimEL at Ser-65. J Biol Chem 2006, 281, 25215-25222. 94. Dhanasekaran, D. N. and Reddy, E. P. JNK-signaling: a multiplexing hub in programmed cell death. Genes Cancer 2017, 8, 682-694. 95. Wan, P. T., Garnett, M. J., Roe, S. M., Lee, S., Niculescu-Duvaz, D., Good, V. M., et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 2004, 116, 855-867. 96. Solit, D. B., Garraway, L. A., Pratilas, C. A., Sawai, A., Getz, G., Basso, A., et al. BRAF mutation predicts sensitivity to MEK inhibition. Nature 2006, 439, 358-362. 97. Schleich, K. and Lavrik, I. N. Mathematical modeling of apoptosis. Cell Commun Signal 2013, 11, 44. 98. Yu, J. S. and Cui, W. Proliferation, survival and metabolism: the role of PI3K/AKT/mTOR signalling in pluripotency and cell fate determination. Development 2016, 143, 3050-3060. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/73187 | - |
dc.description.abstract | 乳癌在全世界無論是癌症發生率或致死率都居高不下。順鉑為乳癌化療之常見用藥。然而,因順鉑產生之眾多嚴重副作用,併用療法可能為可同時減少副作用並增強抗癌活性之策略。日前研究中發現由於 Warburg effect ,第一型葡萄糖轉運蛋白可能為癌症治療之新標靶。此研究目的為探討順鉑與由高通量篩選出具潛力之葡萄糖轉運蛋白抑制劑, #43合併使用於 MCF-7 乳癌細胞株之協同作用及其機轉。研究過程中發現順鉑與 #43併用會藉由細胞凋亡路徑增加細胞毒性,且順鉑與 #43 會分別造成細胞週期停滯於 S 、 G2/M 及 G0/G1。此外,藥物合併使用也觀察到細胞中活性含氧物之提升及粒線體膜電位之損失。因順鉑對於 DNA 的破壞性,實驗結果顯示合併處理藥物使 Chk1、Chk2 磷酸化及 -H2AX 上升且增加 p53 表現及活化,顯示出 #43 可增強順鉑之 DNA 破壞性。MAPK 訊息傳導調控細胞增殖、細胞分化及細胞凋亡。特別的是 #43 單獨使用使促進對於細胞存活重要之 MEK1/2 及 ERK1/2 磷酸化上升。但當與順鉑合併使用時此效果會被消去且磷酸化之 MEK1/2 及 ERK1/2 甚至與控制組相比更加減少。另一方面,p38 磷酸化於順鉑及 #43 合併使用時增加。Akt/mTOR 訊息傳遞路徑與細胞生長、細胞增殖及細胞代謝皆有相關性。此路徑之下游蛋白 p70S6K 及 4EBP1 之磷酸化於合併使用順鉑與 #43 之情形下被抑制,顯示其細胞生長抑制作用之效果。總結來說, MAPK 訊息傳遞路徑、Akt/mTOR 訊息傳遞路徑、氧化壓力及細胞凋亡皆可能於順鉑及 #43 在 MCF-7 細胞株之協同作用扮演重要的角色。 | zh_TW |
dc.description.abstract | Breast cancer remains within the top position when it comes to the cancer incidence and mortality rate worldwide. Cisplatin is a commonly used chemotherapeutic drug for breast cancer. However, owing to the serious side effects of cisplatin, drug combination may be an effective strategy to reduce side effects and increase the anticancer activities simultaneously. In recent studies, it was found that GLUT1 may be a target for cancer treatment because of the Warburg effect. The purpose of this study was to determine whether the combination of a potential GLUT1 inhibitor #43 (obtained from a high throughput screening) and cisplatin exerted a synergistic anticancer effect in MCF 7 breast cancer cells and to investigate the underlying mechanisms. In the present study, we found that #43 could enhance the cytotoxicity of cisplatin via induction of apoptosis, and that cisplatin and #43 cause S, G2/M and G0/G1 arrest, respectively. Moreover, an increase in intracellular ROS and the loss of mitochondrial membrane potential were also observed. Cisplatin is a DNA damaging agent. We found that phosphorylation of DNA damage checkpoint kinases Chk1 and Chk2, and DNA damage marker, -H2AX were increased and p53 was also induced and activated by the combination treatment, suggesting that #43 may enhance the DNA damaging effect of cisplatin. The MAPK pathway regulates cell proliferation, differentiation and apoptosis. Interestingly, #43 alone induced phosphorylation of MEK1/2 and ERK1/2, which may be involved in cell survival. When combined with cisplatin, the effects were reversed and both p-MEK1/2 and p-ERK1/2 were even downregulated compared to the untreated controls. On the other hand, p38 phosphorylation was increased by the combination of cisplatin and #43. The Akt/mTOR signaling pathway is involved in cell growth, proliferation and metabolism. Phosphorylation of p70S6K and 4EBP1, downstream effectors of this pathway, was inhibited by the combination treatment, indicating a growth inhibitory effect. In conclusion, our data indicate that the MAPK pathway, Akt/mTOR pathway, oxidative stress and apoptosis may be involved in the synergism of cisplatin and #43 in MCF-7 breast cancer cells. | en |
dc.description.provenance | Made available in DSpace on 2021-06-17T07:21:30Z (GMT). No. of bitstreams: 1 ntu-108-R06423013-1.pdf: 4446660 bytes, checksum: ff34da51d1e202b0c6b97010a73b85dc (MD5) Previous issue date: 2019 | en |
dc.description.tableofcontents | 國立臺灣大學(碩)博士學位論文口試委員會審定書 i
誌謝 ii List of abbreviations iii 中文摘要 vi Abstract vii Contents ix Aim of the study 1 Chapter 1: Introduction 3 1.1. Breast cancer 3 1.2. Human breast cancer cell lines 7 1.3. The Warburg effect and glucose transporters 7 1.4. Cisplatin 8 1.5. DNA damage signaling and DNA double strand breaks repair 9 1.6. Programmed cell death 10 1.7. Oxidative stress 12 1.8. The PI3K/Akt/mTOR pathway 13 1.9. The MAPK pathway 14 Chapter 2: Materials and Methods 16 2.1. Materials 16 2.2. Methods 17 2.2.1. Cell culture 17 2.2.2. Cell viability assay and combination index analysis 17 2.2.3. Colony formation assay 17 2.2.4. 2-NBDG uptake assay 18 2.2.5 Small interfering RNA (siRNA) transfection and cell viability assay 18 2.2.6. Propidium Iodide (PI) staining (cell cycle analysis) 19 2.2.7. Annexin V-FITC/PI double staining 19 2.2.8. DCFH-DA assay (measurement of reactive oxygen species) 19 2.2.9. JC-1 assay 20 2.2.10. Western blotting 20 2.2.11. Immunofluorescence staining 22 2.2.12. Data analysis 22 Chapter 3: Results 23 3.1. Effects of cisplatin and #43 on cell viability and clonogenic growth 23 3.2. Effect of #43 on glucose uptake 23 3.3. Effects of cisplatin and #43 on cell cycle progression 24 3.4. Enhancement of apoptosis by #43 in combination with cisplatin 25 3.5. Elevation of cellular ROS production induced by cisplatin and #43 25 3.6. Induction of mitochondrial membrane potential loss by cisplatin combined with #43 26 3.7. Enhancement of DNA damage response by #43 in combination with cisplatin 27 3.8. Effects of cisplatin and #43 on the Akt/mTOR signaling pathway 28 3.9. Effects of cisplatin and #43 on the MAPK signaling pathway 29 3.10. Effects of Akt and the ERK signaling pathway on #43-induced cytotoxicity 30 Chapter 4: Discussion 31 4.1. Effects of cisplatin and #43 on cell cycle progression 31 4.2. Effects of cisplatin and #43 on apoptosis 32 4.3. Effects of cisplatin and #43 on ROS and mitochondrial membrane potential 33 4.4. The DNA damage response induced by cisplatin and #43 and their effects on the DNA repair system 34 4.5. Effects of cisplatin and #43 on the Akt/mTOR signaling pathway 35 4.6. Effects of cisplatin and #43 on the MAPK pathway 36 4.7. The role of Akt and the ERK signaling pathway in #43-induced cytotoxicity 37 Chapter 5: Conclusion 38 Figures Figure 1. Effects of cisplatin and #43 on the growth inhibition and clonogenicity of MCF-7 cells. 40 Figure 2. Glucose uptake was inhibited by #43 in MCF-7 cells. 42 Figure 3. Effects of cisplatin and #43 on cell cycle progression in MCF-7 cells. 44 Figure 4. The combination of cisplatin and #43 significantly induced apoptosis in MCF-7 cells. 46 Figure 5. Effects of cisplatin and #43 on proteins involved in apoptosis in MCF-7 cells. 48 Figure 6. Cisplatin and #43 combination induced ROS generation in MCF-7 cells. 50 Figure 7. The combination of cisplatin and #43 induced mitochondrial membrane potential loss in MCF-7 cells. 52 Figure 8. Effects of cisplatin and #43 on proteins involved in DNA damage response and DNA repair in MCF-7 cells. 54 Figure 9. The combination of cisplatin and #43 increased r-H2AX positive MCF-7 cells. 56 Figure 10. Effects of cisplatin and #43 on proteins involved in the Akt/mTOR signaling pathway in MCF-7 cells. 58 Figure 11. Effects of cisplatin and #43 on proteins involved in the MAPK signaling pathway in MCF-7 cells. 60 Figure 12. MK-2206 and U0126 potentiated #43-induced cytotoxicity in MCF-7 cells. 61 Tables Table 1. Staging system and estimated 5-year survival rate for breast cancer. 4 Table 2. The status of commonly used breast cancer cell lines. 7 Appendixes 62 Appendix 1. The Warburg effect. 62 Appendix 2. The DNA damage response. 63 Appendix 3. The extrinsic and intrinsic apoptosis pathways. 64 Appendix 4. The PI3K/Akt/mTOR signaling pathway. 65 Appendix 5. The MAPK signaling pathway. 66 References 67 | |
dc.language.iso | en | |
dc.title | 具潛力之第一型葡萄糖轉運蛋白抑制劑與順鉑合併使用於乳癌細胞協同機轉之研究 | zh_TW |
dc.title | Study on the synergistic mechanism of a potential GLUT1 inhibitor and cisplatin against breast cancer cells | en |
dc.type | Thesis | |
dc.date.schoolyear | 107-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 顧記華(Jih-Hwa Guh),孔繁璐(Fan-Lu Kung) | |
dc.subject.keyword | 順鉑,第一型葡萄糖轉運蛋白抑制劑,乳癌,MAPK 訊息傳遞路徑,PI3K/Akt/mTOR 訊息傳遞路徑,DNA 損傷,氧化壓力, | zh_TW |
dc.subject.keyword | Cisplatin,GLUT1 inhibitor,breast cancer,MAPK pathway,PI3K/Akt/mTOR pathway,DNA damage,oxidative stress, | en |
dc.relation.page | 74 | |
dc.identifier.doi | 10.6342/NTU201901193 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2019-07-04 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 藥學研究所 | zh_TW |
顯示於系所單位: | 藥學系 |
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