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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 顧記華 | zh_TW |
| dc.contributor.advisor | Jih-Hwa Guh | en |
| dc.contributor.author | 盛怡樺 | zh_TW |
| dc.contributor.author | Yi-Hua Sheng | en |
| dc.date.accessioned | 2021-07-11T15:39:14Z | - |
| dc.date.available | 2024-02-28 | - |
| dc.date.copyright | 2018-10-11 | - |
| dc.date.issued | 2018 | - |
| dc.date.submitted | 2002-01-01 | - |
| dc.identifier.citation | 1.American cancer society. Cancer facts & figures. 2018.
2.Ministry of health and welfare. Cancer registry annual report. 2015. 3.Al-Batran, S.E., Hozaeel, W., Tauchert, F.K., Hofheinz, R.D., Hinke, A., et al. The impact of docetaxel-related toxicities on health-related quality of life in patients with metastatic cancer (qolitax). Ann Oncol. 2015. 26(6): p. 1244-8. 4.Karavelioglu, E., Gonul, Y., Aksit, H., Boyaci, M.G., Karademir, M., et al. Cabazitaxel causes a dose-dependent central nervous system toxicity in rats. J Neurol Sci. 2016. 360: p. 66-71. 5.Tonyali, S., Haberal, H.B., and Sogutdelen, E. Toxicity, adverse events, and quality of life associated with the treatment of metastatic castration-resistant prostate cancer. Curr Urol. 2017. 10(4): p. 169-173. 6.American joint committee on cancer. Prostate cancer staging 7th edition. 2009. 7.Litwin, M.S. and Tan, H.J. The diagnosis and treatment of prostate cancer: A review. Jama. 2017. 317(24): p. 2532-2542. 8.Nussbaum, N., George, D.J., Abernethy, A.P., Dolan, C.M., Oestreicher, N., et al. Patient experience in the treatment of metastatic castration-resistant prostate cancer: State of the science. Prostate Cancer Prostatic Dis. 2016. 19(2): p. 111-21. 9.Armstrong, C.M. and Gao, A.C. Drug resistance in castration resistant prostate cancer: Resistance mechanisms and emerging treatment strategies. Am J Clin Exp Urol. 2015. 3(2): p. 64-76. 10.Seruga, B., Ocana, A., and Tannock, I.F. Drug resistance in metastatic castration-resistant prostate cancer. Nat Rev Clin Oncol. 2011. 8(1): p. 12-23. 11.Johnson, I.S., Wright, H.F., Svoboda, G.H., and Vlantis, J. Antitumor principles derived from Vinca rosea linn. I. Vincaleukoblastine and leurosine. Cancer Res. 1960. 20: p. 1016-22. 12.Noble, R.L., Beer, C.T., and Cutts, J.H. Role of chance observations in chemotherapy: Vinca rosea. Ann N Y Acad Sci. 1958. 76(3): p. 882-94. 13.Daliani, D.D., Assikis, V., Tu, S.M., Papandreou, C.N., Pagliaro, L.C., et al. Phase Ⅱ trial of cyclophosphamide, vincristine, and dexamethasone in the treatment of androgen-independent prostate carcinoma. Cancer. 2003. 97(3): p. 561-7. 14.Lin, Y.H., Chen, K.K., and Chiu, J.H. Use of chinese medicine among prostate cancer patients in Taiwan: A retrospective longitudinal cohort study. Int J Urol. 2011. 18(5): p. 383-6. 15.Liu, J.M., Lin, P.H., Hsu, R.J., Chang, Y.H., Cheng, K.C., et al. Complementary traditional chinese medicine therapy improves survival in patients with metastatic prostate cancer. Medicine (Baltimore). 2016. 95(31): p. e4475. 16.Xu, Y., Cai, X., Zong, B., Feng, R., Ji, Y., et al. Qianlie Xiaozheng decoction induces autophagy in human prostate cancer cells via inhibition of the Akt/mTor pathway. Front Pharmacol. 2018. 9: p. 234. 17.Wu, Z., Zhu, Q., Yin, Y., Kang, D., Cao, R., et al. Traditional chinese medicine CFF-1 induced cell growth inhibition, autophagy, and apoptosis via inhibiting EGFR-related pathways in prostate cancer. Cancer Med. 2018. 7(4): p. 1546-1559. 18.Wang, Z., Ravula, R., Shi, L., Song, Y., Yeung, S., et al. Overcoming chemoresistance in prostate cancer with chinese medicine Tripterygium wilfordii via multiple mechanisms. Oncotarget. 2016. 7(38): p. 61246-61261. 19.Bendris, N., Lemmers, B., and Blanchard, J.M. Cell cycle, cytoskeleton dynamics and beyond: The many functions of cyclins and CDK inhibitors. Cell Cycle. 2015. 14(12): p. 1786-98. 20.Lim, S. and Kaldis, P. CDKs, cyclins and CKIs: Roles beyond cell cycle regulation. Development. 2013. 140(15): p. 3079-93. 21.Carnero, A. Targeting the cell cycle for cancer therapy. Br J Cancer. 2002. 87(2): p. 129-33. 22.Diaz-Moralli, S., Tarrado-Castellarnau, M., Miranda, A., and Cascante, M. Targeting cell cycle regulation in cancer therapy. Pharmacol Ther. 2013. 138(2): p. 255-71. 23.Kerr, J.F., Wyllie, A.H., and Currie, A.R. Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972. 26(4): p. 239-57. 24.Elmore, S. Apoptosis: A review of programmed cell death. Toxicol Pathol. 2007. 35(4): p. 495-516. 25.Kischkel, F.C., Hellbardt, S., Behrmann, I., Germer, M., Pawlita, M., et al. Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. Embo j. 1995. 14(22): p. 5579-88. 26.Hill, M.M., Adrain, C., Duriez, P.J., Creagh, E.M., and Martin, S.J. Analysis of the composition, assembly kinetics and activity of native APAF-1 apoptosomes. Embo j. 2004. 23(10): p. 2134-45. 27.Wong, R.S. Apoptosis in cancer: From pathogenesis to treatment. J Exp Clin Cancer Res. 2011. 30: p. 87. 28.Hassan, M., Watari, H., AbuAlmaaty, A., Ohba, Y., and Sakuragi, N. Apoptosis and molecular targeting therapy in cancer. Biomed Res Int. 2014. 2014: p. 150845. 29.Czabotar, P.E., Lessene, G., Strasser, A., and Adams, J.M. Control of apoptosis by the Bcl-2 protein family: Implications for physiology and therapy. Nat Rev Mol Cell Biol. 2014. 15(1): p. 49-63. 30.Youle, R.J. and Strasser, A. The Bcl-2 protein family: Opposing activities that mediate cell death. Nat Rev Mol Cell Biol. 2008. 9(1): p. 47-59. 31.Siddiqui, W.A., Ahad, A., and Ahsan, H. The mystery of Bcl-2 family: Bcl-2 proteins and apoptosis: An update. Arch Toxicol. 2015. 89(3): p. 289-317. 32.Huang, Z. Bcl-2 family proteins as targets for anticancer drug design. Oncogene. 2000. 19(56): p. 6627-31. 33.Delbridge, A.R. and Strasser, A. The Bcl-2 protein family, BH3-mimetics and cancer therapy. Cell Death Differ. 2015. 22(7): p. 1071-80. 34.Pellegrini, F. and Budman, D.R. Review: Tubulin function, action of antitubulin drugs, and new drug development. Cancer Invest. 2005. 23(3): p. 264-73. 35.Jordan, M.A. and Wilson, L. Microtubules as a target for anticancer drugs. Nat Rev Cancer. 2004. 4(4): p. 253-65. 36.Stanton, R.A., Gernert, K.M., Nettles, J.H., and Aneja, R. Drugs that target dynamic microtubules: A new molecular perspective. Med Res Rev. 2011. 31(3): p. 443-81. 37.Ye, L., Jia, Y., Ji, K.E., Sanders, A.J., Xue, K., et al. Traditional chinese medicine in the prevention and treatment of cancer and cancer metastasis. Oncol Lett. 2015. 10(3): p. 1240-1250. 38.Chou, T.C. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res. 2010. 70(2): p. 440-6. 39.Lengsfeld, A.M., Schultze, B., and Maurer, W. Time-lapse studies on the effect of vincristine on HeLa cells. Eur J Cancer. 1981. 17(3): p. 307-19. 40.Tu, Y., Cheng, S., Zhang, S., Sun, H., and Xu, Z. Vincristine induces cell cycle arrest and apoptosis in SH-SY5Y human neuroblastoma cells. Int J Mol Med. 2013. 31(1): p. 113-9. 41.Kothari, A., Hittelman, W.N., and Chambers, T.C. Cell cycle-dependent mechanisms underlie vincristine-induced death of primary acute lymphoblastic leukemia cells. Cancer Res. 2016. 76(12): p. 3553-61. 42.Tapia, C., Kutzner, H., Mentzel, T., Savic, S., Baumhoer, D., et al. Two mitosis-specific antibodies, MPM-2 and phospho-histone H3 (Ser28), allow rapid and precise determination of mitotic activity. Am J Surg Pathol. 2006. 30(1): p. 83-9. 43.De Boer, L., Oakes, V., Beamish, H., Giles, N., Stevens, F., et al. Cyclin a/CDK2 coordinates centrosomal and nuclear mitotic events. Oncogene. 2008. 27(31): p. 4261-8. 44.Soni, D.V., Sramkoski, R.M., Lam, M., Stefan, T., and Jacobberger, J.W. Cyclin B1 is rate limiting but not essential for mitotic entry and progression in mammalian somatic cells. Cell Cycle. 2008. 7(9): p. 1285-300. 45.Groninger, E., Meeuwsen-De Boer, G.J., De Graaf, S.S., Kamps, W.A., and De Bont, E.S. Vincristine induced apoptosis in acute lymphoblastic leukaemia cells: A mitochondrial controlled pathway regulated by reactive oxygen species? Int J Oncol. 2002. 21(6): p. 1339-45. 46.Conway, R.M., Madigan, M.C., Billson, F.A., and Penfold, P.L. Vincristine-and cisplatin-induced apoptosis in human retinoblastoma. Potentiation by sodium butyrate. Eur J Cancer. 1998. 34(11): p. 1741-8. 47.Thomas, L.W., Lam, C., and Edwards, S.W. Mcl-1; the molecular regulation of protein function. FEBS Lett. 2010. 584(14): p. 2981-9. 48.Perciavalle, R.M., Stewart, D.P., Koss, B., Lynch, J., Milasta, S., et al. Anti-apoptotic Mcl-1 localizes to the mitochondrial matrix and couples mitochondrial fusion to respiration. Nat Cell Biol. 2012. 14(6): p. 575-83. 49.Domina, A.M., Smith, J.H., and Craig, R.W. Myeloid cell leukemia 1 is phosphorylated through two distinct pathways, one associated with extracellular signal-regulated kinase activation and the other with G2/M accumulation or protein phosphatase 1/2A inhibition. J Biol Chem. 2000. 275(28): p. 21688-94. 50.Maurer, U., Charvet, C., Wagman, A.S., Dejardin, E., and Green, D.R. Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of Mcl-1. Molecular Cell. 2006. 21(6): p. 749-760. 51.Chu, R., Alford, S.E., Hart, K., Kothari, A., Mackintosh, S.G., et al. Mitotic arrest-induced phosphorylation of Mcl-1 revisited using two-dimensional gel electrophoresis and phosphoproteomics: Nine phosphorylation sites identified. Oncotarget. 2016. 7(48): p. 78958-78970. 52.Lobert, S., Vulevic, B., and Correia, J.J. Interaction of vinca alkaloids with tubulin: A comparison of vinblastine, vincristine, and vinorelbine. Biochemistry. 1996. 35(21): p. 6806-14. 53.Longuet, M., Serduc, R., and Riva, C. Implication of Bax in apoptosis depends on microtubule network mobility. Int J Oncol. 2004. 25(2): p. 309-17. 54.Esteve, M.A., Carre, M., and Braguer, D. Microtubules in apoptosis induction: Are they necessary? Curr Cancer Drug Targets. 2007. 7(8): p. 713-29. 55.Deng, Y., Balunas, M.J., Kim, J.A., Lantvit, D.D., Chin, Y.W., et al. Bioactive 5,6-dihydro-alpha-pyrone derivatives from Hyptis brevipes. J Nat Prod. 2009. 72(6): p. 1165-9. 56.Suarez-Ortiz, G.A., Cerda-Garcia-Rojas, C.M., Hernandez-Rojas, A., and Pereda-Miranda, R. Absolute configuration and conformational analysis of brevipolides, bioactive 5,6-dihydro-alpha-pyrones from Hyptis brevipes. J Nat Prod. 2013. 76(1): p. 72-8. 57.Lin, J.W., Kurniawan, Y.D., Chang, W.J., Leu, W.J., Chan, S.H., et al. Asymmetric synthesis of (-)-brevipolide H through cyclopropanation of the alpha,beta-unsaturated ketone. Org Lett. 2014. 16(20): p. 5328-31. 58.Manning, B.D. and Toker, A. Akt/PKB signaling: Navigating the network. Cell. 2017. 169(3): p. 381-405. 59.Polivka, J. and Janku, F. Molecular targets for cancer therapy in the PI3K/Akt/mTOR pathway. Pharmacology & Therapeutics. 2014. 142(2): p. 164-175. 60.Vara, J.Á.F., Casado, E., de Castro, J., Cejas, P., Belda-Iniesta, C., et al. PI3K/Akt signalling pathway and cancer. Cancer Treatment Reviews. 2004. 30(2): p. 193-204. 61.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(17): p. 3050-60. 62.Saxton, R.A. and Sabatini, D.M. mTOR signaling in growth, metabolism, and disease. Cell. 2017. 168(6): p. 960-976. 63.Schieber, M. and Chandel, N.S. ROS function in redox signaling and oxidative stress. Curr Biol. 2014. 24(10): p. R453-62. 64.Reczek, C.R. and Chandel, N.S. ROS-dependent signal transduction. Curr Opin Cell Biol. 2015. 33: p. 8-13. 65.Finkel, T. Signal transduction by reactive oxygen species. J Cell Biol. 2011. 194(1): p. 7-15. 66.Holmstrom, K.M. and Finkel, T. Cellular mechanisms and physiological consequences of redox-dependent signalling. Nat Rev Mol Cell Biol. 2014. 15(6): p. 411-21. 67.Mokhtari, V., Afsharian, P., Shahhoseini, M., Kalantar, S.M., and Moini, A. A review on various uses of N-acetyl cysteine. Cell J. 2017. 19(1): p. 11-17. 68.Berridge, M.J., Lipp, P., and Bootman, M.D. The versatility and universality of calcium signalling. Nat Rev Mol Cell Biol. 2000. 1(1): p. 11-21. 69.Clapham, D.E. Calcium signaling. Cell. 2007. 131(6): p. 1047-58. 70.Zheng, F., Hang, T., Wu, C., Di, B., Liu, W., et al. Determination of BAPTA-AM, the acetoxymethyl tetraester of BAPTA, in rat plasma by liquid chromatography tandem mass spectrometry. J Mass Spectrom. 2006. 41(12): p. 1615-22. 71.Yan, Y., Wei, C.L., Zhang, W.R., Cheng, H.P., and Liu, J. Cross-talk between calcium and reactive oxygen species signaling. Acta Pharmacol Sin. 2006. 27(7): p. 821-6. 72.Gorlach, A., Bertram, K., Hudecova, S., and Krizanova, O. Calcium and ROS: A mutual interplay. Redox Biol. 2015. 6: p. 260-71. 73.Brookes, P.S., Yoon, Y., Robotham, J.L., Anders, M.W., and Sheu, S.S. Calcium, ATP, and ROS: A mitochondrial love-hate triangle. Am J Physiol Cell Physiol. 2004. 287(4): p. C817-33. 74.Hudasek, K., Brown, S.T., and Fearon, I.M. H2O2 regulates recombinant Ca2+ channel alpha1C subunits but does not mediate their sensitivity to acute hypoxia. Biochem Biophys Res Commun. 2004. 318(1): p. 135-41. 75.Meissner, G. Regulation of ryanodine receptor ion channels through posttranslational modifications. Curr Top Membr. 2010. 66: p. 91-113. 76.Zima, A.V. and Blatter, L.A. Redox regulation of cardiac calcium channels and transporters. Cardiovasc Res. 2006. 71(2): p. 310-21. 77.Baldin, V., Lukas, J., Marcote, M.J., Pagano, M., and Draetta, G. Cyclin D1 is a nuclear protein required for cell cycle progression in G1. Genes Dev. 1993. 7(5): p. 812-21. 78.Hinz, M., Krappmann, D., Eichten, A., Heder, A., Scheidereit, C., et al. NF-kappaB function in growth control: Regulation of cyclin D1 expression and G0/G1-to-S-phase transition. Mol Cell Biol. 1999. 19(4): p. 2690-8. 79.Lu, H.F., Chen, Y.S., Yang, J.S., Chen, J.C., Lu, K.W., et al. Gypenosides induced G0/G1 arrest via inhibition of cyclin E and induction of apoptosis via activation of caspases-3 and -9 in human lung cancer A-549 cells. In Vivo. 2008. 22(2): p. 215-21. 80.Philipp, A., Schneider, A., Vasrik, I., Finke, K., Xiong, Y., et al. Repression of cyclin D1: A novel function of Myc. Mol Cell Biol. 1994. 14(6): p. 4032-43. 81.Berns, K., Hijmans, E.M., and Bernards, R. Repression of c-Myc responsive genes in cycling cells causes G1 arrest through reduction of cyclin E/CDK2 kinase activity. Oncogene. 1997. 15(11): p. 1347-56. 82.Bellacosa, A., Chan, T.O., Ahmed, N.N., Datta, K., Malstrom, S., et al. Akt activation by growth factors is a multiple-step process: The role of the PH domain. Oncogene. 1998. 17(3): p. 313-25. 83.Liao, Y. and Hung, M.C. Physiological regulation of Akt activity and stability. Am J Transl Res. 2010. 2(1): p. 19-42. 84.Hart, J.R. and Vogt, P.K. Phosphorylation of Akt: A mutational analysis. Oncotarget. 2011. 2(6): p. 467-76. 85.Vincent, E.E., Elder, D.J., Thomas, E.C., Phillips, L., Morgan, C., et al. Akt phosphorylation on Thr308 but not on Ser473 correlates with Akt protein kinase activity in human non-small cell lung cancer. Br J Cancer. 2011. 104(11): p. 1755-61. 86.Simon, H.U., Haj-Yehia, A., and Levi-Schaffer, F. Role of reactive oxygen species (ROS) in apoptosis induction. Apoptosis. 2000. 5(5): p. 415-8. 87.Redza-Dutordoir, M. and Averill-Bates, D.A. Activation of apoptosis signalling pathways by reactive oxygen species. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 2016. 1863(12): p. 2977-2992. 88.Holzmann, C., Kilch, T., Kappel, S., Dorr, K., Jung, V., et al. Differential redox regulation of Ca2+ signaling and viability in normal and malignant prostate cells. Biophys J. 2015. 109(7): p. 1410-9. 89.Kim, K.Y., Cho, H.J., Yu, S.N., Kim, S.H., Yu, H.S., et al. Interplay of reactive oxygen species, intracellular Ca2+ and mitochondrial homeostasis in the apoptosis of prostate cancer cells by deoxypodophyllotoxin. J Cell Biochem. 2013. 114(5): p. 1124-34. 90.Kim, S.H., Kim, K.Y., Yu, S.N., Park, S.G., Yu, H.S., et al. Monensin induces PC-3 prostate cancer cell apoptosis via ROS production and Ca2+ homeostasis disruption. Anticancer Res. 2016. 36(11): p. 5835-5843. | - |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/79044 | - |
| dc.description.abstract | 人類轉移性去勢療法抗性前列腺癌(metastatic castration-resistant prostate cancer，MCRPC)為一種具侵略性且無法以賀爾蒙療法治療的惡性癌症，故開發能被應用於治療MCRPC的藥物極為重要。本論文共分為兩章，在第一章節中，我們由原先並非用於癌症治療的特定中藥方劑中取得十二個精萃產物E001~E012。利用sulforhodamine B (SRB) assay進行一系列藥物篩選實驗後，發現E002能顯著加乘臨床上廣泛使用於抗癌化學療法的藥物vincristine對於PC-3細胞的生長抑制作用。為了進一步了解其中的抗癌機制，以propidium iodide (PI) 染劑與流式細胞儀觀察細胞分裂情形，發現合併使用E002與vincristine會造成處於sub-G1期的細胞增加，進而造成細胞凋亡。利用西方墨點法的分析，亦可同時觀察到Bcl-2蛋白質家族表現量下降與磷酸化，cleaved-caspase-3及cleaved-PARP增加等與細胞凋亡相關的訊號。合併使用E002與vincristine也能有效增加粒線體膜電位的喪失，顯示了粒線體膜電位流失於其所造成的抗癌機轉中扮演著重要角色。而利用in vivo tubulin assay，我們了解到E002能加強vincristine直接與微管蛋白作用。西方墨點法的結果中合併E002與vincristine能顯著增加MPM-2蛋白質表現量，此結果證實了該組合對於磷酸化微管蛋白的影響。而在第二章節中，短柄香苦草(Hyptis brevipes)中的天然物成分(-)-brevipolide H具有複雜的結構與抗癌活性。根據SRB assay的數據，(-)-brevipolide H能有效抑制PC-3的生長 (GI50=2.72±0.15μM)，且其抑制癌細胞生長的效果隨濃度增加。而colony formation的結果顯示(-)-brevipolide H長時間作用(一週)抑制PC-3細胞生長的效果更為明顯(GI50=0.37±0.06 μM)。利用carboxyfluoresceinsuccinimidyl ester (CFSE) 染劑與流式細胞儀觀察，可以觀察到(-)-brevipolide H能有效抑制PC-3細胞的增生情形。以PI染劑與流式細胞儀觀察觀察細胞分裂情形，證實(-)-brevipolide H會造成細胞週期停滯於G0/G1期與並引發細胞凋亡。西方墨點法與免疫螢光染色的分析結果亦顯示了細胞週期調控相關蛋白如c-Myc、cyclin D1及cyclin E表現量下降等與細胞週期停滯於G0/G1期的相關訊號。此外，(-)-brevipolide H透過抑制磷酸化作用位點來抑制Akt/mTOR/p70S6K/4E-BP1的訊息傳遞路徑。以轉染技術過量表現myristylated-Akt後我們發現myristylated-Akt可以逆轉原先(-)-brevipolide H對於Akt/mTOR/p70S6K/4E-BP1訊息傳遞路徑的抑制，代表Akt於(-)-brevipolide H的抗癌作用機轉中扮演重要角色。進一步研究後發現，(-)-brevipolide H短時間內透過引發細胞內氧化壓力(Oxidative stress，ROS)與細胞內鈣離子的過載來調控Akt/mTOR/p70S6K/4E-BP1訊息傳遞路徑中的訊號。(-)-Brevipolide H亦藉由降低Bcl-2 家族蛋白的表現量與造成粒線體膜電位的喪失來引發細胞凋亡。綜合第一及第二章節的研究結果，顯示了合併E002與vincristine能經由提升抗微管蛋白活性、粒線體膜電位的喪失與caspase蛋白的活化來抑制PC-3細胞的生長，最終導致mitotic arrest及細胞凋亡的發生。而(-)-brevipolide經由造成細胞內ROS與鈣離子增加，對於Akt/mTOR/p70S6K/4E-BP1訊息的抑制及降低細胞週期調控蛋白來抑制PC-3細胞的增生並造成G0/G1 arrest與細胞凋亡。 | zh_TW |
| dc.description.abstract | Metastatic castration-resistant prostate cancer (MCRPC) is a type of progressive prostate cancer unresponsive to hormone therapy. Therefore, maximizing treatment options for MCRPC is of importance. This thesis is divided into two chapters. In the first chapter, E002 is a partial-purified extract derived from one traditional Chinese medicine formula used for the treatment of cancer unrelated diseases. The data demonstrated that the combinatorial treatment of E002 and vincristine, one of the chemotherapeutic drugs clinically used to treat several cancers, induced a concentration-dependent and synergistic inhibition of cell proliferation in MCRPC PC-3 by the sulforhodamine B (SRB) assay. To investigate the mechanism, the flow cytofluorometric analysis of cell cycle with propidium iodide (PI) staining demonstrated that combination of E002 and vincristine caused a synergistic increase of sub-G1 population that was confirmed accordingly by phosphorylation of Bcl-2 family proteins (Bcl-2 and Bcl-xL), activation of caspase-3, and the cleavage of caspase-9 and PARP-1. Furthermore, the synergistic loss of mitochondrial membrane potential (ΔΨm) was induced by combinatorial treatment of E002 and vincristine, indicating the role of mitochondrial stress in the sensitization mechanism. Moreover, combinatorial treatment of E002 and vincristine was found to directly interact with tubulins through performing the in vivo tubulin assay. The sensitization effect was validated by a synergistic increase of phosphorylated mitotic proteins identified by MPM-2 antibody. In the second chapter of the thesis, a total synthesis has been performed successfully to obtain (-)-brevipolide H, which is a natural component from Hyptis brevipes, with complex structure and cytotoxic activity. The data demonstrated that (-)-brevipolide H induced a concentration-dependent inhibition of cell proliferation with a GI50 of 2.72±0.15 μM in MCRPC PC-3 by the SRB assay. A long-term exposure to (-)-brevipolide H resulted in a stronger anti-proliferative effect against anchorage-dependent colony formation with a GI50 of 0.37±0.06 μM. Flow cytometric analysis of cell division by carboxyfluoresceinsuccinimidyl ester (CFSE) staining also confirmed the anti-proliferative effect of (-)-brevipolide H. Furthermore, flow cytofluorometric analysis of cell cycle with PI staining showed arrest of the cell cycle at G0/G1 phase to (-)-brevipolide H action and an induction of subsequent cell apoptosis. The G0/G1 arrest was validated to be attributed to the down-regulated protein expressions of c-Myc, cyclin D1 and cyclin E by using Western blotting and confocal immunofluorescence microscopic examination. Moreover, (-)-brevipolide H inhibited the signaling pathway of Akt/mTOR/p70S6K/4E-BP1 through the inhibition of phosphorylation at several stimulatory sites. Overexpression of myristylated-Akt, a constitutively activated Akt, partly rescued the Akt/mTOR signaling cascades to (-)-brevipolide H action. Of note, (-)-brevipolide H induced an increase of intracellular Ca2+ levels and ROS production. It also induced the down-regulation of anti-apoptotic Bcl-2 family proteins (Bcl-2 and Bcl-xL) and the loss of mitochondrial membrane potential indicating the contribution of mitochondrial damage stress to cell apoptosis. In conclusion, the data suggest that combinatorial treatment of E002 and vincristine induces synergistic anticancer activity in PC-3 cells through the sensitization of anti-tubulin activity, mitochondrial stress and caspases activation. In addition, (-)-brevipolide H induces anti-proliferative and apoptotic effects in MCRPC through the intracellular Ca2+ overload and oxidative stress that cooperate with the down-regulation of cell cycle regulators and inhibition of Akt/mTOR/p70S6K pathway, leading to G0/G1 arrest, mitochondrial damage stress and cell apoptosis | en |
| dc.description.provenance | Made available in DSpace on 2021-07-11T15:39:14Z (GMT). No. of bitstreams: 1 ntu-107-R05423014-1.pdf: 13285828 bytes, checksum: bbbbde3418ead6472018d2ca2f6ea3bc (MD5) Previous issue date: 2018 | en |
| dc.description.tableofcontents | 中文摘要 ……………………………………………………………………………………………………………………………Ⅰ
Abstract …………………………………………………………………………………………………………………………Ⅲ List of Abbreviations ………………………………………………………………………………………Ⅴ Contents …………………………………………………………………………………………………………………………Ⅶ List of Figures …………………………………………………………………………………………………… Ⅸ Aim of the Study ……………………………………………………………………………………………………1 Introduction ………………………………………………………………………………………………………………2 Materials and Methods ………………………………………………………………………………………4 Chapter 1. Study of Components from Traditional Chinese Medicine on Anticancer Mechanism in Human Metastatic Castration-Resistant Prostate Cancer ………………………………………………13 1.1 Research Background ………………………………………………………………………14 1.2 Results ………………………………………………………………………………………………………19 1.3 Discussion ………………………………………………………………………………………………24 Chapter 2. Study of Components from Natural Product on Anticancer Mechanism in Human Metastatic Castration-Resistant Prostate Cancer ……………………………………………………………………………45 2.1 Research Background ……………………………………………………………46 2.2 Results ……………………………………………………………………………………………50 2.3 Discussion ……………………………………………………………………………………56 Conclusion ……………………………………………………………………………………………………………………80 References ……………………………………………………………………………………………………………………81 | - |
| dc.language.iso | en | - |
| dc.subject | (-)-Brevipolide H | zh_TW |
| dc.subject | E002 | zh_TW |
| dc.subject | vincristine | zh_TW |
| dc.subject | 前列腺癌 | zh_TW |
| dc.subject | 細胞週期停滯 | zh_TW |
| dc.subject | Akt | zh_TW |
| dc.subject | 微管蛋白 | zh_TW |
| dc.subject | Akt | en |
| dc.subject | (-)-brevipolide H | en |
| dc.subject | E002 | en |
| dc.subject | cell cycle arrest | en |
| dc.subject | tubulin | en |
| dc.subject | vincristine | en |
| dc.subject | prostate cancer | en |
| dc.title | 中藥及天然物成分在人類轉移性去勢療法抗性前列腺癌之抗癌作用機轉研究 | zh_TW |
| dc.title | Study of Components from Traditional Chinese Medicine and Natural Product on Anticancer Mechanism in Human Metastatic Castration-Resistant Prostate Cancer | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 106-2 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 許麗卿;楊家榮;黃聰龍;蕭哲志 | zh_TW |
| dc.contributor.oralexamcommittee | Lih-Ching Hsu;Chia-Ron Yang;Tsong-Long Hwang;George Hsiao | en |
| dc.subject.keyword | (-)-Brevipolide H,E002,vincristine,前列腺癌,細胞週期停滯,Akt,微管蛋白, | zh_TW |
| dc.subject.keyword | (-)-brevipolide H,E002,vincristine,prostate cancer,cell cycle arrest,Akt,tubulin, | en |
| dc.relation.page | 90 | - |
| dc.identifier.doi | 10.6342/NTU201803281 | - |
| dc.rights.note | 未授權 | - |
| dc.date.accepted | 2018-08-14 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 藥學研究所 | - |
| dc.date.embargo-lift | 2023-10-11 | - |
| 顯示於系所單位： | 藥學系 | |
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