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研究生:黃瀚立
研究生(外文):Han-Li Huang
論文名稱:MPT0E028在人類大腸直腸癌與B細胞淋巴癌之抗癌機轉探討
論文名稱(外文):Evaluation of the anticancer mechanisms of MPT0E028 in human colorectal cancer and B-cell lymphoma
指導教授:鄧哲明鄧哲明引用關係潘秀玲潘秀玲引用關係
指導教授(外文):Che-Ming TengShiow-Lin Pan
口試委員:陳慶士黃德富劉景平顏茂雄
口試委員(外文):Ching-Shih ChenTur-Fu HuangJing-Ping LiouMao-Hsiung Yen
口試日期:2015-03-09
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:藥理學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2015
畢業學年度:103
語文別:英文
論文頁數:120
中文關鍵詞:MPT0E028組蛋白去乙醯酶(HDAC)Akt大腸直腸癌B細胞淋巴癌細胞凋亡
外文關鍵詞:MPT0E028histone deacetylase (HDAC)Aktcolorectal cancerB-cell lymphomaapoptosis
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隨著人民平均壽命延長及生活習慣的改變,癌症發生率仍持續上升,根據台灣衛生福利部國民健康署統計,癌症已為國人十大死因之首達三十年。為有效治療癌症,藥物開發在癌症領域中仍是相當重要的課題,其中組蛋白去乙醯酶(histone deacetylase, HDAC)為近期相當重要的藥物作用標的。本實驗室和台北醫學大學劉景平教授及潘秀玲副教授合作發展一個新穎的組蛋白去乙醯酶抑制劑MPT0E028,本篇論文即在探MPT0E028在人類大腸直腸癌及B細胞淋巴癌之抗癌機轉。
本篇論文第一部分,我們著重在探討MPT0E028在人類大腸直腸癌中的抗癌機轉及HDAC抑制效果。MPT0E028可以抑制許多癌細胞的生長,尤其對於HCT116細胞最為敏感。相對於第一個被FDA認可的HDAC抑制劑SAHA,MPT0E028可產生較強的細胞凋亡作用及HDAC抑制效果。在HCT116異體移植體內實驗中,MPT0E028可延緩並抑制腫瘤生長,相對於SAHA也具有較強的抑癌效果。
本篇論文第二部分,我們著重在探討MPT0E028在人類B細胞淋巴癌中的抗癌機轉及MPT0E028作用下,HDAC及Akt之間的關係。根據kinome diversity screen實驗結果發現,MPT0E028具有可直接接合並抑制Akt的能力;而我們也發現,HDAC及Akt皆對MPT0E028所引發的細胞凋亡作用具有貢獻,並且為獨立作用,並顯示相對於SAHA具有較強的效果。除體外實驗,B細胞淋巴癌動物模式體內實驗中也發現MPT0E028可以延長存活率並且抑制腫瘤生長。
綜合而言,我們的結果顯示MPT0E028具獨特性而有潛力成為癌症治療的新選擇。

The incidence rate of cancer is increasing as more people live to an old age and as lifestyle changes. According to Health Promotion Administration, Ministry of Health and Welfare in Taiwan, cancer has been the first place of ten leading deaths for thirty-two years. In order to cure cancer efficaciously, drug development is still an important issue in cancer therapy. Histone deacetylase inhibitor (HDAC) has been an important drug target in recent years. Our lab cooperates with Professor Jing-Ping Liou (Taipei Medical University) and Associate Professor Shiow-Lin Pan (Taipei Medical University) to develop a novel HDAC inhibitor MPT0E028. In this thesis, we investigated the anticancer mechanism of MPT0E028 in human colorectal cancer and B-cell lymphoma.
In the first part of this thesis, we focus on the antiproliferation effect and the anti-HDAC potency of MPT0E028 in human colorectal carcinoma. MPT0E028 can inhibit a panel of cancer cells, especially most potent in HCT116 cells. MPT0E028 can induce stronger apoptosis effect and HDAC enzyme inhibition in vitro compared to SAHA, the first therapeutic HDAC inhibitor approved by FDA. HCT116 xenograft tumor growth was delayed and inhibited under treatment of MPT0E028 in vivo, which also showed a better antitumor efficacy than SAHA.
In the second part of this thesis, we focus on the antitumor effect of MPT0E028 in human B-cell lymphoma and the relationship between HDACs and Akt under the treatment of MPT0E028. According to kinome diversity screen data, MPT0E028 was found to exhibit direct Akt targeting ability. We revealed that both its inhibitory activity on HDAC and Akt contribute to MPT0E028-induced apoptosis, which functioned independently and showed stronger effect than SAHA. Besides in vitro experiment, in vivo study also showed that MPT0E028 may prolong the survival rate and inhibit tumor growth in B-cell lymphoma model.
Taken together, our results demonstrated that MPT0E028 has unique properties and may be a potential and promising anti-cancer therapeutic option.

口試委員會審定書………………………………………………………………….………………..i
誌謝………………………………………………………………….....…………….………………….ii
Abbreviations……………………………………………………………………….……………….iv
中文摘要…………………………………………………………………….……….…………..…...1
Abstract ……………………………………………………………………………………………....3
Chapter 1 Introduction………………………………………….…………..…..5
1.1 Research Motivation and Aim………………………….……5
1.2 Literature Reviews………………………………….…….…………...7
Chapter 2 Materials and Methods……………………………………...39
2.1 Materials…………………………………………………………….……….…………..39
2.2 Methods…………………………………………………………….……….….………...40
Chapter 3 Anticancer Activity of MPT0E028, a Novel Potent Histone Deacetylase Inhibitors, in
Human Colorectal Cancer HCT116 Cells in vitro and in vivo
中文摘要……………………………………………………………….….….……....…………..52
Abstract……………………………………………………………….…….……....…………….53
3.1 Results………………………….……………………….…….……..….…………….54
3.2 Discussion……………………………………………………..…….………...……59
Chapter 4 Novel Histone Deacetylase Inhibitor, MPT0E028, Displays Potent Growth-Inhibitory
Activity against Human B-cell Lymphoma in vitro and in vivo
中文摘要…………………………………………………………………....………..………....…76
Abstract…………………………………………………………………………....…...………….77
4.1 Results…………………………………………………………………..……….……....78
4.2 Discussion………………………………………………………...…….………....85
Chapter 5 Conclusion and Perspectives………….…….…………105
Publications………………..……………………………………………….…………….....113
References………………………………………………………………….…………..…….....114

Bali, P., P. George, et al. (2004). "Superior activity of the combination of histone deacetylase inhibitor LAQ824 and the FLT-3 kinase inhibitor PKC412 against human acute myelogenous leukemia cells with mutant FLT-3." Clin Cancer Res 10(15): 4991-4997.
Bali, P., M. Pranpat, et al. (2005). "Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90: a novel basis for antileukemia activity of histone deacetylase inhibitors." J Biol Chem 280(29): 26729-26734.
Blagosklonny, M. V., R. Robey, et al. (2002). "Histone Deacetylase Inhibitors All Induce p21 but Differentially Cause Tubulin Acetylation, Mitotic Arrest, and Cytotoxicity." Mol Cancer Ther 1(11): 937-941.
Blagosklonny, M. V., S. Trostel, et al. (2005). "Depletion of mutant p53 and cytotoxicity of histone deacetylase inhibitors." Cancer Res 65(16): 7386-7392.
Boland, C. R. and A. Goel (2005). "Somatic evolution of cancer cells." Semin Cancer Biol 15(6): 436-450.
Bolden, J. E., M. J. Peart, et al. (2006). "Anticancer activities of histone deacetylase inhibitors." Nat Rev Drug Discov 5(9): 769-784.
Bruserud, O., C. Stapnes, et al. (2007). "Histone deacetylase inhibitors in cancer treatment: a review of the clinical toxicity and the modulation of gene expression in cancer cells." Current Pharmaceutical Biotechnology 8(6): 388-400.
Buglio, D., G. V. Georgakis, et al. (2008). "Vorinostat inhibits STAT6-mediated TH2 cytokine and TARC production and induces cell death in Hodgkin lymphoma
cell lines." Blood 112(4): 1424-1433.
Chang, J.-Y., H.-P. Hsieh, et al. (2006). "7-Aroyl-aminoindoline-1-sulfonamides as a Novel Class of Potent Antitubulin Agents." Journal of Medicinal Chemistry 49(23): 6656-6659.
Chang, J.-Y., M.-J. Lai, et al. (2010). "Synthesis and biological evaluation of 7-arylindoline-1-benzenesulfonamides as a novel class of potent anticancer agents." MedChemComm 1(2): 152.
Chen, C. H., M. C. Chen, et al. (2014). "Synergistic interaction between the HDAC inhibitor, MPT0E028, and sorafenib in liver cancer cells in vitro and in vivo." Clin Cancer Res 20(5): 1274-1287.
Chen, C. S., S. C. Weng, et al. (2005). "Histone acetylation-independent effect of histone deacetylase inhibitors on Akt through the reshuffling of protein phosphatase 1 complexes." J Biol Chem 280(46): 38879-38887.
Chen, J., F. M. Ghazawi, et al. (2006). "Valproic acid and butyrate induce apoptosis in human cancer cells through inhibition of gene expression of Akt/protein kinase
B." Mol Cancer 5: 71.
Chen, M. C., C. H. Chen, et al. (2013). "The HDAC inhibitor, MPT0E028, enhances erlotinib-induced cell death in EGFR-TKI-resistant NSCLC cells." Cell Death Dis 4: e810.
Cheng, G., S. Park, et al. (2008). "Advances of Akt pathway in human oncogenesis and as a target for anti-cancer drug discovery." Current Cancer Drug Targets 8(1).
Chi, X. Z., J. O. Yang, et al. (2005). "RUNX3 suppresses gastric epithelial cell growth by inducing p21(WAF1/Cip1) expression in cooperation with transforming growth factor {beta}-activated SMAD." Mol Cell Biol 25(18): 8097-8107.
Cross, D. A. E., D. R. Alessi, et al. (1995). "Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B." Nature 378(6559): 785-789.
Darvas, K., S. Rosenberger, et al. (2010). "Histone deacetylase inhibitor-induced sensitization to TNFalpha/TRAIL-mediated apoptosis in cervical carcinoma cells is dependent on HPV oncogene expression." Int J Cancer 127(6): 1384-1392.
Denlinger, C. E., B. K. Rundall, et al. (2005). "Inhibition of phosphatidylinositol 3-kinase/Akt and histone deacetylase activity induces apoptosis in non-small cell lung cancer in vitro and in vivo." J Thorac Cardiovasc Surg 130(5): 1422-1429.
Dokmanovic, M., C. Clarke, et al. (2007). "Histone deacetylase inhibitors: overview and perspectives." Mol Cancer Res 5(10): 981-989.
Ellis, L., S. Ku, et al. (2013). "Combinatorial antitumor effect of HDACs and the PI3K-Akt-mTOR pathway inhibition in a Pten deficient model of prostate cancer." Oncotarget 4(12): 2225-2236.
Engelman, J. A. (2009). "Targeting PI3K signalling in cancer: opportunities, challenges and limitations." Nat Rev Cancer 9(8): 550-562.
Falkenberg, K. J. and R. W. Johnstone (2014). "Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders." Nat Rev Drug
Discov 13(9): 673-691.
Fearnhead, N. S., J. L. Wilding, et al. (2002). "Genetics of colorectal cancer: hereditary aspects and overview of colorectal tumorigenesis." British Medical Bulletin64(1): 27-43.
Fearon, E. R. and B. Vogelstein (1990). "A genetic model for colorectal tumorigenesis." Cell 61(5): 759-767.
Fuino, L., P. Bali, et al. (2003). "Histone deacetylase inhibitor LAQ824 down-regulates Her-2 and sensitizes human breast cancer cells to trastuzumab, taxotere, gemcitabine, and epothilone B." Mol Cancer Ther 2(10): 971-984.
Fulda, S. and K. M. Debatin (2006). "Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy." Oncogene 25(34): 4798-4811.
Gatti, L., A. Sevko, et al. (2014). "Histone deacetylase inhibitor-temozolomide co-treatment inhibits melanoma growth through suppression of Chemokine (C-C
motif) ligand 2-driven signals." Oncotarget 5(12): 4516-4528.
Glozak, M. A., N. Sengupta, et al. (2005). "Acetylation and deacetylation of non-histone proteins." Gene 363: 15-23.
Gryder, B. E., Q. H. Sodji, et al. (2012). "Targeted cancer therapy: giving histone deacetylase inhibitors all they need to succeed." Future Medicinal Chemistry 4(4): 505-524.
Gueugnon, F., P.-F. Cartron, et al. (2014). "New histone deacetylase inhibitors improve cisplatin antitumor properties against thoracic cancer cells." Oncotarget 5(12): 4504-4515.
Ha, K., W. Fiskus, et al. (2014). "Histone deacetylase inhibitor treatment induces ‘BRCAness’ and synergistic lethality with PARP inhibitor and cisplatin against human triple negative breast cancer cells." Oncotarget 5(14): 5637-5650.
Hassig, C. A., K. T. Symons, et al. (2008). "KD5170, a novel mercaptoketone-based histone deacetylase inhibitor that exhibits broad spectrum antitumor activity in vitro and in vivo." Mol Cancer Ther 7(5): 1054-1065.
Hennessy, B. T., D. L. Smith, et al. (2005). "Exploiting the PI3K/AKT pathway for cancer drug discovery." Nat Rev Drug Discov 4(12): 988-1004.
Huang, H.-L., H.-Y. Lee, et al. (2012). "Anticancer Activity of MPT0E028, a Novel Potent Histone Deacetylase Inhibitor, in Human Colorectal Cancer HCT116 Cells In Vitro and In Vivo." PLoS One 7(8): e43645.
Johnston, P. B., R. Yuan, et al. (2010). "Targeted therapy in lymphoma." J Hematol Oncol 3: 45.
Juan, L. J., W. J. Shia, et al. (2000). "Histone deacetylases specifically down-regulate p53-dependent gene activation." J Biol Chem 275(27): 20436-20443.
Kazantsev, A. G. and L. M. Thompson (2008). "Therapeutic application of histone deacetylase inhibitors for central nervous system disorders." Nat Rev Drug Discov 7(10): 854-868.
Khosravi-Far, R., E. White, et al. (2007). Histone Deacetylase Inhibitors: Mechanisms and Clinical Significance in Cancer: HDAC Inhibitor-Induced Apoptosis
Programmed Cell Death in Cancer Progression and Therapy, Springer Netherlands. 615: 261-298.117
Kroesen, M., P. R. Gielen, et al. (2014). "HDAC inhibitors and immunotherapy; a double edged sword?" Oncotarget; Vol 5, No 16.
Li, D., N. D. Marchenko, et al. (2011). "SAHA shows preferential cytotoxicity in mutant p53 cancer cells by destabilizing mutant p53 through inhibition of the HDAC6-Hsp90 chaperone axis." Cell Death Differ 18(12): 1904-1913.
Liu, P., H. Cheng, et al. (2009). "Targeting the phosphoinositide 3-kinase pathway in cancer." Nat Rev Drug Discov 8(8): 627-644.
LoPiccolo, J., G. M. Blumenthal, et al. (2008). "Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations." Drug Resist Updat
11(1-2): 32-50.
Ma, X., H. H. Ezzeldin, et al. (2009). "Histone Deacetylase Inhibitors: Current Status and Overview of Recent Clinical Trials." Drugs 69(14): 1911-1934 1910.2165/11315680-000000000-000000000.
Mahadevan, D. and R. I. Fisher (2011). "Novel therapeutics for aggressive non-Hodgkin''s lymphoma." J Clin Oncol 29(14): 1876-1884.
Mann, B. S., J. R. Johnson, et al. (2007). "FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma." Oncologist 12(10):
1247-1252.
Manning, B. D. and L. C. Cantley (2007). "AKT/PKB signaling: navigating downstream." Cell 129(7): 1261-1274.
Mariadason, J. M. (2008). "HDACs and HDAC inhibitors in colon cancer." Epigenetics 3(1): 28-37.
Marks, P. A. and R. Breslow (2007). "Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug." Nat Biotechnol 25(1):
84-90.
Marks, P. A. and W. S. Xu (2009). "Histone deacetylase inhibitors: Potential in cancer therapy." J Cell Biochem 107(4): 600-608.
Mehrotra, P., J. P. Riley, et al. (2011). "PARP-14 functions as a transcriptional switch for Stat6-dependent gene activation." J Biol Chem 286(3): 1767-1776.
Mercurio, C., S. Minucci, et al. (2010). "Histone deacetylases and epigenetic therapies of hematological malignancies." Pharmacol Res 62(1): 18-34.
Nakagawa, M., Y. Oda, et al. (2007). "Expression profile of class I histone deacetylases in human cancer tissues." Oncol Rep 18: 769-774.
Nishioka, C., T. Ikezoe, et al. (2008). "Blockade of mTOR signaling potentiates the ability of histone deacetylase inhibitor to induce growth arrest and differentiation of acute myelogenous leukemia cells." Leukemia 22(12): 1182159-2168.
Nogai, H., B. Dorken, et al. (2011). "Pathogenesis of non-Hodgkin''s lymphoma." J Clin Oncol 29(14): 1803-1811.
Pal, S. K., K. Reckamp, et al. (2010). "Akt inhibitors in clinical development for the treatment of cancer." Expert Opinion on Investigational Drugs 19(11): 1355-1366.
Patel, J. H., Y. Du, et al. (2004). "The c-MYC oncoprotein is a substrate of the acetyltransferases hGCN5/PCAF and TIP60." Mol Cell Biol 24(24): 10826-10834.
Paull, K., E. Hamel, et al. (1995). Prediction of biochemical mechanism of action from the in vitro antitumor sreen of the National Cancer Institute, in Cancer
Chemotherapeutic Agents. Cancer chemotherapeutic agents. W. Foye. Washington, DC, American Chemical Society.
Peart, M. J., G. K. Smyth, et al. (2005). "Identification and functional significance of genes regulated by structurally different histone deacetylase inhibitors." Proc Natl Acad Sci U S A 102(10): 3697-3702.
Price, T. J., E. Segelov, et al. (2013). "Current opinion on optimal treatment for colorectal cancer." Expert Review of Anticancer Therapy 13(5): 597-611.
Prince, H. M., M. J. Bishton, et al. (2009). "Clinical studies of histone deacetylase
inhibitors." Clin Cancer Res 15(12): 3958-3969.
Rahmani, M., E. Reese, et al. (2005). "Coadministration of histone deacetylase inhibitors and perifosine synergistically induces apoptosis in human leukemia cells through Akt and ERK1/2 inactivation and the generation of ceramide and reactive oxygen species." Cancer Res 65(6): 2422-2432.
Richon, V. M., T. W. Sandhoff, et al. (2000). "Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation." Proc
Natl Acad Sci U S A 97(18): 10014-10019.
Sato, S., N. Fujita, et al. (2000). "Modulation of Akt kinase activity by binding to Hsp90." Proc Natl Acad Sci U S A 97(20): 10832-10837.
Sawas, A., C. Diefenbach, et al. (2011). "New therapeutic targets and drugs in non-Hodgkin''s lymphoma." Curr Opin Hematol 18(4): 280-287.
Shelley L, B. (2002). "Histone modifications in transcriptional regulation." Current Opinion in Genetics & Development 12(2): 142-148.
Shimizu, R., J. Kikuchi, et al. (2010). "HDAC inhibitors augment cytotoxic activity of rituximab by upregulating CD20 expression on lymphoma cells." Leukemi 24(10): 1760-1768.119
Siegel, R., J. Ma, et al. (2014). "Cancer statistics, 2014." CA Cancer J Clin 64(1): 9-29.
Sikandar, S., D. Dizon, et al. (2010). "The Class I Hdac Inhibitor Mgcd0103 Induces Cell Cycle Arrest and Apoptosis in Colon Cancer Initiating Cells by Upregulating Dickkopf-1 and Non-Canonical Wnt Signaling." Oncotarget 1(7): 596-605.
Spange, S., T. Wagner, et al. (2009). "Acetylation of non-histone proteins modulates cellular signalling at multiple levels." Int J Biochem Cell Biol 41(1): 185-198.
Stimson, L., V. Wood, et al. (2009). "HDAC inhibitor-based therapies and haematological malignancy." Ann Oncol 20(8): 1293-1302.
Takai, N. and H. Narahara (2007). "Human endometrial and ovarian cancer cells: histone deacetylase inhibitors exhibit antiproliferative activity, potently induce cell cycle arrest, and stimulate apoptosis." Curr Med Chem. 14(24): 2548-2553.
Talbert, D. R., R. L. Wappel, et al. (2013). "The Role of Myc and the miR-17~92 Cluster in Histone Deacetylase Inhibitor Induced Apoptosis of Solid Tumors." Journal of Cancer Therapy 04(04): 907-918.
Taub, R., I. Kirsch, et al. (1982). "Translocation of the c-myc gene into the immunoglobulin heavy chain locus in human burkitt lymphoma and murine
plasmacytoma cells." Proc Natl Acad Sci U S A 79: 7837-7841.
Taylor, R. C., S. P. Cullen, et al. (2008). "Apoptosis: controlled demolition at the cellular level." Nat Rev Mol Cell Biol 9(3): 231-241.
Thurn, K. T., S. Thomas, et al. (2011). "Rational therapeutic combinations with histone deacetylase inhibitors for the treatment of cancer." Future Oncol 7(2): 263-283.
Tsapis, M., M. Lieb, et al. (2007). "HDAC inhibitors induce apoptosis in glucocorticoid-resistant acute lymphatic leukemia cells despite a switch from the extrinsic to the intrinsic death pathway." Int J Biochem Cell Biol 39(7-8): 1500-1509.
Verheul, H. M., B. Salumbides, et al. (2008). "Combination strategy targeting the hypoxia inducible factor-1 alpha with mammalian target of rapamycin and histone deacetylase inhibitors." Clin Cancer Res 14(11): 3589-3597.
Vivanco, I. and C. L. Sawyers (2002). "The phosphatidylinositol 3-Kinase AKT pathway in human cancer." Nat Rev Cancer 2(7): 489-501.
Wedel, S., L. Hudak, et al. (2011). "Impact of combined HDAC and mTOR inhibition on adhesion, migration and invasion of prostate cancer cells." Clin Exp
Metastasis 28(5): 479-491.
Whittaker, S. J., M. F. Demierre, et al. (2010). "Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma." J Clin Oncol 28(29): 4485-4491.Wilson, A. J., D. S. Byun, et al. (2006). "Histone deacetylase 3 (HDAC3) and other
class I HDACs regulate colon cell maturation and p21 expression and are deregulated in human colon cancer." J Biol Chem 281(19): 13548-13558.
Xu, W. S., R. B. Parmigiani, et al. (2007). "Histone deacetylase inhibitors: molecular mechanisms of action." Oncogene 26(37): 5541-5552.
Zhang, X., X. Chen, et al. (14 June 2012). "Myc represses miR-15a/miR-16-1 expression through recruitment of HDAC3 in mantle cell and other
non-Hodgkin B-cell lymphomas." Oncogene 31: 3002-3008.
Zhu, P., E. Martin, et al. (2004). "Induction of HDAC2 expression upon loss of APC in colorectal tumorigenesis." Cancer Cell 5(5): 455-463.
Zopf, S., D. Neureiter, et al. (2007). "Differential response of p53 and p21 on HDAC inhibitor-mediated apoptosis in HCT116 colon cancer cells in vitro and in vivo." Int J Oncol. 31: 1391-1402.

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