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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/17204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 | Wei-Ting Lai | en |
| dc.contributor.author | 賴韋婷 | zh_TW |
| dc.date.accessioned | 2021-06-08T00:00:53Z | - |
| dc.date.copyright | 2013-09-24 | |
| dc.date.issued | 2013 | |
| dc.date.submitted | 2013-08-15 | |
| dc.identifier.citation | 1 Hennessy, B. T., Coleman, R. L. & Markman, M. Ovarian cancer. Lancet 374, 1371-1382 (2009).
2 Siegel, R., Naishadham, D. & Jemal, A. Cancer statistics, 2013. CA Cancer J Clin 63, 11-30 (2013). 3 Burges, A. & Schmalfeldt, B. Ovarian cancer: diagnosis and treatment. Deutsches Arzteblatt international 108, 635-641 (2011). 4 Zhang, L. et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. The New England journal of medicine 348, 203-213 (2003). 5 Kaku, T. et al. Histological classification of ovarian cancer. Medical electron microscopy : official journal of the Clinical Electron Microscopy Society of Japan 36, 9-17 (2003). 6 McCluggage, W. G. My approach to and thoughts on the typing of ovarian carcinomas. Journal of clinical pathology 61, 152-163 (2008). 7 Han, E. S., Lin, P. & Wakabayashi, M. Current status on biologic therapies in the treatment of epithelial ovarian cancer. Current treatment options in oncology 10, 54-66 (2009). 8 Markman, M. Pharmaceutical management of ovarian cancer : current status. Drugs 68, 771-789 (2008). 9 Armstrong, D. K. Relapsed ovarian cancer: challenges and management strategies for a chronic disease. The oncologist 7 Suppl 5, 20-28 (2002). 10 Smolle, E. et al. Targeting signaling pathways in epithelial ovarian cancer. International journal of molecular sciences 14, 9536-9555 (2013). 11 Peyssonnaux, C. & Eychene, A. The Raf/MEK/ERK pathway: new concepts of activation. Biology of the cell / under the auspices of the European Cell Biology Organization 93, 53-62 (2001). 12 Allen, L. F., Sebolt-Leopold, J. & Meyer, M. B. CI-1040 (PD184352), a targeted signal transduction inhibitor of MEK (MAPKK). Seminars in oncology 30, 105-116 (2003). 13 Zeineldin, R., Muller, C. Y., Stack, M. S. & Hudson, L. G. Targeting the EGF receptor for ovarian cancer therapy. Journal of oncology 2010, 414676 (2010). 14 Jorissen, R. N. et al. Epidermal growth factor receptor: mechanisms of activation and signalling. Experimental cell research 284, 31-53 (2003). 15 Lu, Z., Jiang, G., Blume-Jensen, P. & Hunter, T. Epidermal growth factor-induced tumor cell invasion and metastasis initiated by dephosphorylation and downregulation of focal adhesion kinase. Molecular and cellular biology 21, 4016-4031 (2001). 16 Perrimon, N. Signalling pathways initiated by receptor protein tyrosine kinases in Drosophila. Current opinion in cell biology 6, 260-266 (1994). 17 Altomare, D. A. et al. AKT and mTOR phosphorylation is frequently detected in ovarian cancer and can be targeted to disrupt ovarian tumor cell growth. Oncogene 23, 5853-5857 (2004). 18 Grossi, V. & Simone, C. Special Agents Hunting Down Women Silent Killer: The Emerging Role of the p38alpha Kinase. Journal of oncology 2012, 382159 (2012). 19 Stark, G. R. & Taylor, W. R. Control of the G2/M transition. Molecular biotechnology 32, 227-248 (2006). 20 Niida, H. et al. Depletion of Chk1 leads to premature activation of Cdc2-cyclin B and mitotic catastrophe. The Journal of biological chemistry 280, 39246-39252 (2005). 21 Baker, D. J., Dawlaty, M. M., Galardy, P. & van Deursen, J. M. Mitotic regulation of the anaphase-promoting complex. Cellular and molecular life sciences : CMLS 64, 589-600 (2007). 22 Wasch, R. & Engelbert, D. Anaphase-promoting complex-dependent proteolysis of cell cycle regulators and genomic instability of cancer cells. Oncogene 24, 1-10 (2005). 23 Castedo, M. et al. Cell death by mitotic catastrophe: a molecular definition. Oncogene 23, 2825-2837 (2004). 24 Johnstone, R. W., Ruefli, A. A. & Lowe, S. W. Apoptosis: a link between cancer genetics and chemotherapy. Cell 108, 153-164 (2002). 25 Mansilla, S., Bataller, M. & Portugal, J. Mitotic catastrophe as a consequence of chemotherapy. Anti-cancer agents in medicinal chemistry 6, 589-602 (2006). 26 Mansilla, S., Priebe, W. & Portugal, J. Mitotic catastrophe results in cell death by caspase-dependent and caspase-independent mechanisms. Cell cycle (Georgetown, Tex.) 5, 53-60 (2006). 27 Vakifahmetoglu, H. et al. DNA damage induces two distinct modes of cell death in ovarian carcinomas. Cell death and differentiation 15, 555-566 (2008). 28 Roninson, I. B., Broude, E. V. & Chang, B. D. If not apoptosis, then what? Treatment-induced senescence and mitotic catastrophe in tumor cells. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy 4, 303-313 (2001). 29 Malumbres, M. & Barbacid, M. Mammalian cyclin-dependent kinases. Trends in biochemical sciences 30, 630-641 (2005). 30 Lam, M. H., Liu, Q., Elledge, S. J. & Rosen, J. M. Chk1 is haploinsufficient for multiple functions critical to tumor suppression. Cancer cell 6, 45-59, (2004). 31 Nitta, M. et al. Spindle checkpoint function is required for mitotic catastrophe induced by DNA-damaging agents. Oncogene 23, 6548-6558 (2004). 32 Swanson, P. E., Carroll, S. B., Zhang, X. F. & Mackey, M. A. Spontaneous premature chromosome condensation, micronucleus formation, and non-apoptotic cell death in heated HeLa S3 cells. Ultrastructural observations. The American journal of pathology 146, 963-971 (1995). 33 Dobbin, Z. C. & Landen, C. N. The Importance of the PI3K/AKT/MTOR Pathway in the Progression of Ovarian Cancer. International journal of molecular sciences 14, 8213-8227 (2013). 34 Cantley, L. C. The phosphoinositide 3-kinase pathway. Science (New York, N.Y.) 296, 1655-1657 (2002). 35 Markman, B., Dienstmann, R. & Tabernero, J. Targeting the PI3K/Akt/mTOR pathway--beyond rapalogs. Oncotarget 1, 530-543 (2010). 36 Engelman, J. A., Luo, J. & Cantley, L. C. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nature reviews. Genetics 7, 606-619 (2006). 37 Sarbassov, D. D., Guertin, D. A., Ali, S. M. & Sabatini, D. M. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science (New York, N.Y.) 307, 1098-1101 (2005). 38 Brunet, A. et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96, 857-868 (1999). 39 Brown, E. J. et al. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 369, 756-758 (1994). 40 Montero, J. C., Chen, X., Ocana, A. & Pandiella, A. Predominance of mTORC1 over mTORC2 in the regulation of proliferation of ovarian cancer cells: therapeutic implications. Molecular cancer therapeutics 11, 1342-1352, (2012). 41 Katsetos, C. D. & Draber, P. Tubulins as therapeutic targets in cancer: from bench to bedside. Current pharmaceutical design 18, 2778-2792 (2012). 42 Downing, K. H. & Nogales, E. New insights into microtubule structure and function from the atomic model of tubulin. European biophysics journal : EBJ 27, 431-436 (1998). 43 Nogales, E. Structural insights into microtubule function. Annual review of biochemistry 69, 277-302 (2000). 44 Akhmanova, A. & Steinmetz, M. O. Tracking the ends: a dynamic protein network controls the fate of microtubule tips. Nature reviews. Molecular cell biology 9, 309-322 (2008). 45 Muller-Reichert, T., Chretien, D., Severin, F. & Hyman, A. A. Structural changes at microtubule ends accompanying GTP hydrolysis: information from a slowly hydrolyzable analogue of GTP, guanylyl (alpha,beta)methylenediphosphonate. Proceedings of the National Academy of Sciences of the United States of America 95, 3661-3666 (1998). 46 Panda, D., Miller, H. P. & Wilson, L. Determination of the size and chemical nature of the stabilizing 'cap' at microtubule ends using modulators of polymerization dynamics. Biochemistry 41, 1609-1617 (2002). 47 Galjart, N. & Perez, F. A plus-end raft to control microtubule dynamics and function. Current opinion in cell biology 15, 48-53 (2003). 48 Pellegrini, F. & Budman, D. R. Review: tubulin function, action of antitubulin drugs, and new drug development. Cancer investigation 23, 264-273 (2005). 49 Carre, M. et al. Tubulin is an inherent component of mitochondrial membranes that interacts with the voltage-dependent anion channel. The Journal of biological chemistry 277, 33664-33669 (2002). 50 Perez, E. A. Microtubule inhibitors: Differentiating tubulin-inhibiting agents based on mechanisms of action, clinical activity, and resistance. Molecular cancer therapeutics 8, 2086-2095 (2009). 51 Kavallaris, M. Microtubules and resistance to tubulin-binding agents. Nature reviews. Cancer 10, 194-204 (2010). 52 Rieder, C. L. & Maiato, H. Stuck in division or passing through: what happens when cells cannot satisfy the spindle assembly checkpoint. Developmental cell 7, 637-651 (2004). 53 Brito, D. A. & Rieder, C. L. The ability to survive mitosis in the presence of microtubule poisons differs significantly between human nontransformed (RPE-1) and cancer (U2OS, HeLa) cells. Cell motility and the cytoskeleton 66, 437-447 (2009). 54 Gross, A., McDonnell, J. M. & Korsmeyer, S. J. BCL-2 family members and the mitochondria in apoptosis. Genes & development 13, 1899-1911 (1999). 55 Newmeyer, D. D. & Ferguson-Miller, S. Mitochondria: releasing power for life and unleashing the machineries of death. Cell 112, 481-490 (2003). 56 Kuwana, T. & Newmeyer, D. D. Bcl-2-family proteins and the role of mitochondria in apoptosis. Current opinion in cell biology 15, 691-699 (2003). 57 Cory, S. & Adams, J. M. The Bcl2 family: regulators of the cellular life-or-death switch. Nature reviews. Cancer 2, 647-656 (2002). 58 Talpir, R., Benayahu, Y., Kashman, Y., Pannell, L. & Schleyer, M. Hemiasterlin and geodiamolide TA; two new cytotoxic peptides from the marine sponge Hemiasterella minor (Kirkpatrick). Tetrahedron letters 35, 4453-4456 (1994). 59 Coleman, J. E., Dilip de Silva, E., Kong, F., Andersen, R. J. & Allen, T. M. Cytotoxic peptides from the marine sponge Cymbastela sp. Tetrahedron 51, 10653-10662 (1995). 60 Nieman, J. A. et al. Synthesis and antimitotic/cytotoxic activity of hemiasterlin analogues. Journal of natural products 66, 183-199 (2003). 61 Hsu, L. C. et al. Development of hemiasterlin derivatives as potential anticancer agents that inhibit tubulin polymerization and synergize with a stilbene tubulin inhibitor. Investigational new drugs 30, 1379-1388 (2012). 62 Anderson, H. J., Coleman, J. E., Andersen, R. J. & Roberge, M. Cytotoxic peptides hemiasterlin, hemiasterlin A and hemiasterlin B induce mitotic arrest and abnormal spindle formation. Cancer chemotherapy and pharmacology 39, 223-226 (1997). 63 Bai, R., Durso, N. A., Sackett, D. L. & Hamel, E. Interactions of the sponge-derived antimitotic tripeptide hemiasterlin with tubulin: comparison with dolastatin 10 and cryptophycin 1. Biochemistry 38, 14302-14310 (1999). 64 Kindler, H. L. et al. Phase II trials of dolastatin-10 in advanced pancreaticobiliary cancers. Investigational new drugs 23, 489-493 (2005). 65 Ravi, M., Zask, A. & Rush, T. S., 3rd. Structure-based identification of the binding site for the hemiasterlin analogue HTI-286 on tubulin. Biochemistry 44, 15871-15879 (2005). 66 Krishnamurthy, G. et al. Biophysical characterization of the interactions of HTI-286 with tubulin heterodimer and microtubules. Biochemistry 42, 13484-13495 (2003). 67 Hadaschik, B. A. et al. Targeting prostate cancer with HTI-286, a synthetic analog of the marine sponge product hemiasterlin. International journal of cancer. Journal international du cancer 122, 2368-2376 (2008). 68 Lindsley, C. W., Barnett, S. F., Yaroschak, M., Bilodeau, M. T. & Layton, M. E. Recent progress in the development of ATP-competitive and allosteric Akt kinase inhibitors. Current topics in medicinal chemistry 7, 1349-1363 (2007). 69 Hirai, H. et al. MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo. Molecular cancer therapeutics 9, 1956-1967 (2010). 70 Cheng, Y. et al. MK-2206, a novel allosteric inhibitor of Akt, synergizes with gefitinib against malignant glioma via modulating both autophagy and apoptosis. Molecular cancer therapeutics 11, 154-164 (2012). 71 Portugal, J., Mansilla, S. & Bataller, M. Mechanisms of drug-induced mitotic catastrophe in cancer cells. Current pharmaceutical design 16, 69-78 (2010). 72 McGrogan, B. T., Gilmartin, B., Carney, D. N. & McCann, A. Taxanes, microtubules and chemoresistant breast cancer. Biochimica et biophysica acta 1785, 96-132 (2008). 73 Vakifahmetoglu, H., Olsson, M. & Zhivotovsky, B. Death through a tragedy: mitotic catastrophe. Cell death and differentiation 15, 1153-1162 (2008). 74 Zhao, L., Wientjes, M. G. & Au, J. L. Evaluation of combination chemotherapy: integration of nonlinear regression, curve shift, isobologram, and combination index analyses. Clinical cancer research : an official journal of the American Association for Cancer Research 10, 7994-8004 (2004). 75 Durrant, D. et al. cis-3, 4', 5-Trimethoxy-3'-aminostilbene disrupts tumor vascular perfusion without damaging normal organ perfusion. Cancer chemotherapy and pharmacology 63, 191-200 (2009). 76 McIntosh, J. R., Grishchuk, E. L. & West, R. R. Chromosome-microtubule interactions during mitosis. Annual review of cell and developmental biology 18, 193-219 (2002). 77 Zhou, J. & Giannakakou, P. Targeting microtubules for cancer chemotherapy. Current medicinal chemistry. Anti-cancer agents 5, 65-71 (2005). 78 Galan-Malo, P. et al. Cell fate after mitotic arrest in different tumor cells is determined by the balance between slippage and apoptotic threshold. Toxicology and applied pharmacology 258, 384-393 (2012). 79 Torres, K. & Horwitz, S. B. Mechanisms of Taxol-induced cell death are concentration dependent. Cancer research 58, 3620-3626 (1998). 80 Weaver, B. A. & Cleveland, D. W. Decoding the links between mitosis, cancer, and chemotherapy: The mitotic checkpoint, adaptation, and cell death. Cancer cell 8, 7-12 (2005). 81 Agarwal, M. L., Agarwal, A., Taylor, W. R. & Stark, G. R. p53 controls both the G2/M and the G1 cell cycle checkpoints and mediates reversible growth arrest in human fibroblasts. Proceedings of the National Academy of Sciences of the United States of America 92, 8493-8497 (1995). 82 Senovilla, L. et al. p53 represses the polyploidization of primary mammary epithelial cells by activating apoptosis. Cell cycle (Georgetown, Tex.) 8, 1380-1385 (2009). 83 de Bruin, E. C. & Medema, J. P. Apoptosis and non-apoptotic deaths in cancer development and treatment response. Cancer treatment reviews 34, 737-749 (2008). 84 Davis, R. J. MAPKs: new JNK expands the group. Trends in biochemical sciences 19, 470-473 (1994). 85 Choi, K. C., Auersperg, N. & Leung, P. C. Mitogen-activated protein kinases in normal and (pre)neoplastic ovarian surface epithelium. Reproductive biology and endocrinology : RB&E 1, 71 (2003). 86 Phong, M. S. et al. p38 mitogen-activated protein kinase promotes cell survival in response to DNA damage but is not required for the G(2) DNA damage checkpoint in human cancer cells. Molecular and cellular biology 30, 3816-3826 (2010). 87 Winograd-Katz, S. E. & Levitzki, A. Cisplatin induces PKB/Akt activation and p38(MAPK) phosphorylation of the EGF receptor. Oncogene 25, 7381-7390, (2006). 88 Bellacosa, A., Kumar, C. C., Di Cristofano, A. & Testa, J. R. Activation of AKT kinases in cancer: implications for therapeutic targeting. Advances in cancer research 94, 29-86 (2005). 89 Clark, A. S., West, K., Streicher, S. & Dennis, P. A. Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells. Molecular cancer therapeutics 1, 707-717 (2002). 90 Wrighton, K. H. Autophagy: Kinase ups and downs. Nature reviews. Molecular cell biology 11, 464 (2010). 91 Carracedo, A. et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. The Journal of clinical investigation 118, 3065-3074 (2008). 92 Menges, C. W. & McCance, D. J. Constitutive activation of the Raf-MAPK pathway causes negative feedback inhibition of Ras-PI3K-AKT and cellular arrest through the EphA2 receptor. Oncogene 27, 2934-2940 (2008). 93 Onishi, K., Higuchi, M., Asakura, T., Masuyama, N. & Gotoh, Y. The PI3K-Akt pathway promotes microtubule stabilization in migrating fibroblasts. Genes to cells : devoted to molecular & cellular mechanisms 12, 535-546 (2007). | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/17204 | - |
| dc.description.abstract | 合併用藥在癌症治療上扮演重要的角色，常結合分子標靶藥物與毒殺細胞藥物的共同使用藉由降低劑量以達到降低毒性及副作用的目的，提高藥物抗癌作用。訊息傳導路徑PI3K/Akt/mTOR的異常會導致細胞不正常的生長及癌化的發生；在癌症細胞中此路徑的過度活化亦容易導致腫瘤細胞對化學治療產生抗藥性。
本論文測試一系列海綿胜肽成分hemiasterlin的全合成衍生物，包括BF65、BA32、LC15、LC17、LC20、LC22、BA35與BA36。實驗結果發現大部份化合物當具有(R)(S)(S)組態對於卵巢癌細胞(SKOV3)及前列腺癌細胞(PC-3)都有生長抑制的作用，並使細胞週期停滯於有絲分裂期(mitosis phase);其中，以BF65具有最強的抑制細胞生長作用。實驗發現BF65可擾亂細胞骨架微管的形成，並造成抗細胞凋亡蛋白Bcl-2的磷酸化，Mcl-1表現下降、PARP斷裂，而產生細胞凋亡，並可藉由抑制Akt、ERK、p38來抑制細胞保護作用，抑制細胞生長與增生，並且在長時間處理後造成細胞DNA的損傷。 MK-2206為Akt (又稱蛋白質激酶B，PKB)的抑制劑，可抑制Akt的磷酸化，並抑制蛋白質生合成及癌細胞生長。本論文將BF65與MK-2206合併使用，發現MK-2206可以提升BF65抑制微管聚合的作用及提高SKOV-3卵巢癌細胞的死亡率，且此併用組合可同時造成細胞週期G0/G1及G2/M的停滯。進一步探究其分子作用機轉發現，此組合可抑制Akt及其下游受質mRNA轉錄抑制因子p70S6K與4EBP1的磷酸化，進而阻礙蛋白質的生合成。此外，MK-2206可以提高因BF65所造成的Bcl-2磷酸化，而BF65則可降低MK-2206誘導Bcl-2蛋白的效應。另外，兩者併用對於Mcl-1下降、PARP斷裂、DNA損傷標記 r-H2AX的產生都有明顯的協同作用。而兩者併用可更進一步的破壞微管蛋白，而BF65對於p38、ERK的抑制能力可以解決MK-2206由於抑制Akt而造成MAPK路徑活化回饋。這些機制可能是BF65與MK-2206合併使用能產生協同作用，提高細胞死亡率的原因。 | zh_TW |
| dc.description.abstract | The concept of combination treatment plays an important role in cancer therapy. Molecular targeted agents are frequently combined with traditional cytotoxic drugs at lower doses than those required for single treatment to reduce the toxicity and side effects, and to enhance the anticancer effect. Abnormal activation of the PI3K/Akt/mTOR signaling pathway may lead to aberrant cell growth and contribute to tumorigenesis. In addition, overactivation of this signaling pathway is also associated with resistance to chemotherapy.
In this study, we screened a series of synthetic hemiasterlin derivatives including BF65, BA32, LC15, LC17, LC20, LC22, BF35 and BA36, and discovered that compounds in the (R)(S)(S) configuration could inhibit the growth of an ovarian cancer cell line SKOV3 and a prostate cancer cell line PC-3, and arrest cells in mitosis. BF65 is the most potent hemiasterlin derivative among all the compounds tested. BF65 disrupted microtubule assembly, induced phosphorylation and inactivation of the pro-survival protein Bcl-2, decreased the level of another pro-survival protein Mcl-1 and caused PARP cleavage, leading to apoptosis. BF65 also inhibited ERK, p38 and Akt, which can stimulate cell proliferation upon activation, and induced DNA damage in SKOV3 cells after long-term treatment. MK-2206 is an allosteric inhibitor of Akt (also called serine/threonine kinase B, PKB) and can inhibit Akt phosphorylation/activation, protein synthesis and cancer cell growth. We show here that combination treatment of BF65 and MK-2206 synergistically reduced SKOV3 viability. MK-2206 enhanced microtubule depolymerization effect of BF65 and the combination treatment resulted in G0/G1 and G2/M cell cycle arrest at the same time. Study of the underlying molecular mechanisms revealed that BF65/MK-2206 inhibited phosphorylation of Akt and its downstream effectors p-P70S6K and p-4EBP1, thereby downregulated protein synthesis. Furthermore, MK-2206 potentiated Bcl-2 phosphorylation induced by BF65, and BF65 caused phosphorylation and inactivation of Bcl-2 induced by MK-2206. The combination also caused a significant reduction in Mcl-1 protein, more serious PARP cleavage, and induction of the DNA damage marker r-H2AX. BF65/MK-2206 combination also caused more significant microtubule disruption and the inhibitory effect of BF65 on p38 and ERK blocked the activation of MAPK pathway resulting from a feedback of Akt inhibition by MK-2206. These molecular changes may explain why BF65 can synergize with MK-2206 to inhibit ovarian cancer cell growth and to enhance cytotoxicity. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-08T00:00:53Z (GMT). No. of bitstreams: 1 ntu-102-R00423010-1.pdf: 6490311 bytes, checksum: c5078314aace09905b6750ffa1aeacc7 (MD5) Previous issue date: 2013 | en |
| dc.description.tableofcontents | 目 錄
口試委員會審定書…………………………………………….…..……… i 誌謝……………………………………………………..……………...…. ii 中文摘要……………………………………………..……………………iii 英文摘要……………………………………………..…….…………….. iv 目錄…………………………………………………..…………...…….…vi 圖目錄………………………………………………..…………..………viii 表目錄…………………………………………….…………….……….…x 縮寫表…………………………………………….…………………….…xi 第一章 背景介紹……………………………………………….………..1 1.1 卵巢癌 (Ovarian cancer)…………………………………………1 1.2 G2/M transition ……………………………………......…………2 1.3 有絲分裂風暴 (Mitotic catastrophe) ……………………………3 1.4 PI3K/ Akt/ mTOR路徑在癌症及抗藥性所扮演的角色.….……4 1.5 抗微管藥物 (Anti-microtubule agents) …………………………5 1.6 Bc1-2家族蛋白……………………………………………….….7 1.7 Hemiasterlins...………………………………………………...…7 1.8 MK-2206 (an allosteric Akt inhibitor)…...………….……………8 第二章 實驗主題與目的…………………………………….…………17 2.1實驗目的…………………………………………………………17 2.2 實驗架構…………………………………………………..…… 18 第三章 實驗材料與方法…………………………………………….…19 3.1 實驗材料………………………. .………………………………19 3.2 細胞培養………………………. ………………………..…...…21 3.3 細胞計數……. ……………………..………. ………….………21 3.4 抑制細胞生長測定法 (SRB assay) ……. ………………..……21 3.5 毒殺細胞測定法 (MTT assay) ……………………………. .....23 3.6 細胞週期分析………………………………………………...…23 3.7 西方墨點法………….………………………………………. ....24 3.8 免疫螢光染色………………………..………………………… 25 3.9 Combination index (CI)分析……………………....……………26 第四章 實驗結果………………………………………..…………….. 28 第五章 討論……………………..…………………………………….. 39 第六章 結論……………………...……………….…………………….44 參考文獻…………………………………………………………….……45 附錄……………………………………………………………………….55 | |
| dc.language.iso | zh-TW | |
| dc.title | Hemiasterlin衍生物BF65與Akt抑制劑MK-2206協同抑制卵巢癌細胞生長 | zh_TW |
| dc.title | The Hemiasterlin Derivative BF65 Synergizes with an Akt Inhibitor MK-2206 to Inhibit Ovarian Cancer Cell Growth | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 101-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 顧記華,孔繁璐 | |
| dc.subject.keyword | 卵巢癌,hemiasterlins,Akt抑制劑,協同作用,抗微管藥物, | zh_TW |
| dc.subject.keyword | ovarian cancer,hemiasterlins,Akt inhibitor,synergistic effect,anti-microtubule agents, | en |
| dc.relation.page | 76 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2013-08-16 | |
| 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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