簡易檢索 / 詳目顯示

研究生: 曾嘉玲
Chia-Ling Tseng
論文名稱: 探討單獨使用新穎化學合成物Yao-ram-2-7或合併使用薑黃素對肝癌細胞的抑制並利用連接網路資料庫比對及證實Yao-ram-2-7之生理功能
To study anticancer effect of a novel compound Yao-ram-2-7 in the presence or absence of phytochemical curcumin on human hepatocellular carcinoma cells and to identify other biological function of Yao-ram-2-7 using Connectivity Map
指導教授: 蘇純立
Su, Chun-Li
學位類別: 碩士
Master
系所名稱: 人類發展與家庭學系
Department of Human Development and Family Studies
論文出版年: 2013
畢業學年度: 101
語文別: 中文
論文頁數: 126
中文關鍵詞: Yao-ram-2-7人類肝癌細胞細胞凋亡細胞自噬薑黃素SorafenibConnectivity Map
英文關鍵詞: Yao-ram-2-7, human hepatocellular carcinoma, apoptosis, autophagy, curcumin, Sorafenib, Connectivity Map
論文種類: 學術論文
相關次數: 點閱:188下載:6
分享至:
查詢本校圖書館目錄 查詢臺灣博碩士論文知識加值系統 勘誤回報
  • 肝癌是世界五大癌症之一,因不易早期發現及預後不佳,使得肝
    癌在癌症所致之死亡率高居不下。根據行政院衛生署統計,肝癌一直
    是國人癌症死因的大宗。治療肝癌方式,以手術和化學治療為主。在
    化學治療方面,藥效常局限於抗藥性的產生使藥效減低,因而促使研
    發更有效的新穎藥物。在本研究團隊自行合成一系列化合物中經
    MTT assay 篩選,發現 Yao-ram-2-7 具有抑制人類肝癌細胞(Hep 3B)
    生長的效用。在本研究中,Yao-ram-2-7 與臨床肝癌標靶用藥 Sorafenib
    在相同的實驗條件下比較,分別處理 Hep 3B 及人類臍靜脈內皮細胞
    (HUVEC)。發現 Yao-ram-2-7 與 Sorafenib 毒殺 Hep 3B 能力相當,
    處理 HUVEC 的安全性測試中,Yao-ram-2-7 毒性較 Sorafenib 弱,顯
    示 Yao-ram-2-7 可能對人體的副作用較小。利用 propidium iodide 染色分析細胞凋亡現象及以 acridine orange 染色分析細胞自噬現象,發現
    Yao-ram-2-7 誘發 Hep 3B 產生細胞凋亡及細胞自噬的比例隨時間和劑
    量增加而增加;利用西方墨點法也確定活化態 caspase 3 蛋白及 LC3-II
    蛋白的表現增加,證實 Yao-ram-2-7 可誘發 Hep 3B 產生細胞凋亡及
    細胞自噬。細胞凋亡實驗結果顯示,相較於 Sorafenib 在高劑量下才
    具有毒殺癌細胞能力,Yao-ram-2-7 在較低劑量下即有效果;細胞自
    噬實驗發現,Yao-ram-2-7 比 Sorafenib 在較低劑量下即可引發細胞產生自噬現象。因營養素可能具有輔助藥物效用,因此本研究也探討具
    有抗癌功用的天然植化素—薑黃素(Curcumin)與 Yao-ram-2-7 或
    Sorafenib 合併使用下,是否對抑制 Hep 3B 細胞生長有更好的效果。
    MTT assay 實驗結果發現 Hep 3B 在 Yao-ram-2-7 與薑黃素同時處理後,抑制細胞生長效果比單獨處理更佳,具有加乘效應;分析細胞週期的
    變化,發現合併使用薑黃素有使 G2/M 期增加的趨勢,使癌細胞分裂
    減少。但在肝癌標靶藥物 Sorafenib 與薑黃素合併使用則發現產生拮
    抗,因此建議臨床使用 Sorafenib 治療的患者不可食用含有薑黃素的
    食物及膳食補充品。另外,本研究透過「連接網路資料庫(Connectivity
    Map;CMAP)」比對,發現 Yao-ram-2-7 可能與 GSK-3 抑制劑
    AR-A014418 作用相似。實驗結果證實 AR-A014418 如 Yao-ram-2-7
    皆可誘發 Hep 3B 產生細胞自噬,Yao-ram-2-7 可抑制 phospho-GSK-3
    及總 GSK-3蛋白表現,顯示 Yao-ram-2-7 的生醫上的其它應用性。
    整體而言,本研究結果發現 Yao-ram-2-7 具有開發為抗癌用藥的潛力,
    提供肝癌病患治療上不同選擇;與薑黃素合併使用能增加藥物的敏感
    性,使化療藥物發揮更好的效果。

    Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide. More than 75% cases of HCC occur in the Asia-Pacific region. High mortality of HCC is due to the difficulty in diagnosis and poor prognosis. Chemotherapy is a traditional choice for inoperable HCC, whereas drug resistant limits the therapeutic effect. Thus, there is an urgent need to develop new potential drugs for HCC. Our research group has synthesized a series of compounds for anti-cancer screening using MTT assay. Yao-ram-2-7 is one of them significantly inhibits the growth of HCC Hep 3B cells. Especially, Yao-ram-2-7 displays less cytotoxicity on normal human umbilical vein endothelial cells than the HCC targeted therapy Sorafenib, suggesting Yao-ram-2-7 is safer than Sorafenib. We further show that Yao-ram-2-7 induces apoptosis of Hep 3B cells in a time- and dose-related manner using propidium iodide staining followed by flow cytometry. Increase of cleavage-caspase 3 expression is observed using Western blotting. Yao-ram-2-7 also induces autophagy of Hep 3B cells characterized by the accumulation of acidic vesicular organelles by flow cytometry after staining the cells with acridine orange. Western blot analysis further observed the conversion of
    autophagy marker from LC3-I to LC3-II. Compared with Sorafenib, Yao-ram-2-7 induces apoptosis and autophagy at a relatively lower dosage for a shorter period of time. Recently, anticancer and chemopreventive effects of phytochemicals such as curcumin have been suggested. In the present study, combination of Yao-ram-2-7 with curcumin promotes growth inhibition of Hep 3B cells and produces an additivity effect. Cell cycle analysis suggests that the decrease in tumor cell proliferation is due to an increase of G2/M arrest. In contrast, addition of curcumin to Sorafenib displays an antagonism effect, suggesting that patients treated with Sorafenib should avoid food and supplements containing curcumin. In addition, we discover that a GSK-3 inhibitor AR-A014418 and Yao-ram-2-7 have similar biological functions since AR-A014418 alters gene expression of Hep 3B cells similarly to Yao-ram-2-7 by using a bioinformatics database Connectivity Map (CMAP). Western blot and flow cytometric analysis confirm that Yao-ram-2-7 behaves like AR-A014418, inducing autophagy and decreasing protein expression of phospho-GSK-3and total GSK-3 These data demonstrate that query gene expression profiles using CMAP is a useful shortcut to reveal molecular action of a small chemical compound. Taken together, our data suggest chemotherapeutic potential of Yao-ram-2-7 on HCC, and addition of curcumin further promots its chemosensitivity.

    第一章 緒論 1 第一節 肝癌 1 一、肝癌的對人類的威脅 1 二、肝癌的致病因子 1 三、肝癌的治療 2 第二節 薑黃素 7 一、薑黃素的背景 7 二、薑黃素與癌症的關係 8 第三節 計畫性細胞死亡 10 一、細胞凋亡 10 二、細胞自噬 16 第四節 細胞週期的意義 21 第五節 新穎化合物 Yao-ram-2-7 23 第六節 連結網路資料庫及 L1000 25 第二章 研究目的 27 第三章 材料與方法 29 第一節 儀器與實驗耗材 29 第二節 藥品與試劑 32 第三節 實驗方法 35 一、細胞培養 35 二、化合物的配製 38 三、細胞毒殺試驗 39 四、細胞週期分析 40 五、檢測細胞自噬比例 42 六、西方墨點法 43 第四章 結果 50 第一節 Yao-ram-2-7 可抑制癌細胞 Hep 3B 的生長,但對人類正 常臍靜脈內皮細胞 HUVEC 傷害較低 50 第二節 Yao-ram-2-7 能誘發 Hep 3B 細胞產生細胞凋亡 55 第三節 Yao-ram-2-7 能誘發 Hep 3B 細胞產生細胞自噬 61 第四節 薑黃素與 Yao-ram-2-7 合併使用對肝癌細胞的影響 64 第五節 薑黃素與 Sorafenib 合併使用對肝癌細胞的影響 73 第六節 驗證連接網路資料庫比對結果 81 第五章 討論 92 第六章 結論 100 第七章 參考文獻 101 附錄 118 Fig. 1 Yao-ram-2-7 is the one of 136 compounds exhibiting anticancer ability. 24 Fig. 2 Effect of Yao-ram-2-7 or Sorafenib on Hep 3B cell viability determined by MTT assay. 52 Fig. 3 Effect of Yao-ram-2-7 or Sorafenib on HUVEC cell viability determined by MTT assay. 53 Fig. 4 Yao-ram-2-7 induced apoptosis of Hep 3B cells in a dose- and time-related manner. 57 Fig. 5 Sorafenib induced apoptosis on Hep 3B cells in a dose- and time-related manner. 59 Fig. 6 Effect of Yao-ram-2-7 on autophagy of Hep 3B cells. 62 Fig. 7 Effect of Sorafenib on autophagy of HCC Hep 3B cells. 63 Fig. 8 Effect of Yao-ram-2-7 with or without curcumin on Hep 3B cell viability determined by MTT assay and the interaction of Yao-ram-2-7 and curcumin determined by the value of q. 68 Fig. 9 The effect of curcumin on Yao-ram-2-7-induced apoptosis. 69 Fig. 10 The change of caspase 3 protein expression in Yao-ram-2-7-treated Hep 3B cells in the presence and absence of curcumin. 71 Fig. 11 The change of LC3 protein expression in Yao-ram-2-7-treated Hep 3B cells in the presence or absence of curcumin. 72 Fig. 12 Effect of Sorafenib with or without curcumin on Hep 3B cell viability determined by MTT assay and the interaction of Sorafenib and curcumin determined by the value of q. 76 Fig. 13 The effect of curcumin on Sorafenib-induced apoptosis. 77 Fig. 14 The change of caspase 3 protein expression in Sorafenib-treated Hep 3B cells in the presence and absence of curcumin. 79 Fig. 15 The change of LC3 protein expression in Sorafenib-treated Hep 3B cells in the presence and absence of curcumin. 80 Fig. 16 Effect of Yao-ram-2-7 or AR-A014418 on Hep 3B cell viability determined by MTT assay. 84 Fig. 17 Effect of AR-A014418 on apoptosis of Hep 3B cells. 85 Fig. 18 The change of caspase 3 protein expression in AR-A014418-treated Hep 3B cell. 87 Fig. 19 Effect of AR-A014418 on autophagy of Hep 3B cells. 88 Fig. 20 The change of LC3 protein expression in AR-A014418-treated Hep 3B cell 89 Fig. 21 The change of phospho-GSK-3α/β protein expression in Yao-ram-2-7-treared Hep 3B cell. 90 Fig. 22 The change of total GSK-3β protein expression in Yao-ram-2-7-treated Hep 3B cell. 91 Table 1 The IC 50 of Yao-ram-2-7 and anticancer drug Sorafenib. 54 Table 2 The percentage of cells at different phases of cell cycle in Fig.4. 58 Table 3 The percentage of cells at different phases of cell cycle in Fig.5 .60 Table 4 The percentages of cells at different phases of cell cycle in Fig. 9 and the value of q 70 Table 5 The percentages of cells at different phases of cell cycle in Fig. 13 and the value of q 78 Table 6 The percentage of cells at different phases of cell cycle in Fig. 17 86 Appendix Fig. 1 Chemical structure of Sorafenib. 118 Appendix Fig. 2 Molecular mechanisms of Sorafenib. 119 Appendix Fig. 3 Curcuma longa Plant and chemical structure of curcumin, an active ingredient of rhizome termeric. 120 Appendix Fig. 4 Curcumin significantly inhibited protein expression of Aurora-A. 121 Appendix Fig. 5 Curcumin enhanced chemosensitivity of human breast cancer cells to Ixabepilone (FDA approved drug for patients with breast cancer). 122 Appendix Fig. 6 The apoptosis pathway. 123 Appendix Fig. 7 The process of autophagy. 124 Appendix Fig. 8 The mammalian cell cycle. 125 Appendix Fig. 9 The chemical of AR-A014418. 126

    Abounit, K., Scarabelli, T. M., & McCauley, R. B. (2012). Autophagy in mammalian
    cells. World J Biol Chem, 3(1), 1-6.
    Anderluh, M., Cesar, J., Stefanic, P., Kikelj, D., Janes, D., Murn, J., et al. (2005).
    Design and synthesis of novel platelet fibrinogen receptor antagonists with
    2H-1,4-benzoxazine-3(4H)-one scaffold. A systematic study. Eur J Med Chem,
    40(1), 25-49.
    Arii, S., Yamaoka, Y., Futagawa, S., Inoue, K., Kobayashi, K., Kojiro, M., et al.
    (2000). Results of surgical and nonsurgical treatment for small-sized
    hepatocellular carcinomas: a retrospective and nationwide survey in Japan.
    The Liver Cancer Study Group of Japan. Hepatology, 32(6), 1224-1229.
    Ban, J. O., Kwak, D. H., Oh, J. H., Park, E. J., Cho, M. C., Song, H. S., et al. (2010).
    Suppression of NF-kappaB and GSK-3beta is involved in colon cancer cell
    growth inhibition by the PPAR agonist troglitazone. Chem Biol Interact,
    188(1), 75-85.
    Bellance, N., Lestienne, P., & Rossignol, R. (2009). Mitochondria: from bioenergetics
    to the metabolic regulation of carcinogenesis. Front Biosci, 14, 4015-4034.
    Benn, J., Su, F., Doria, M., & Schneider, R. J. (1996). Hepatitis B virus HBx protein
    induces transcription factor AP-1 by activation of extracellular
    signal-regulated and c-Jun N-terminal mitogen-activated protein kinases. J
    Virol, 70(8), 4978-4985.
    Bhat, R., Xue, Y., Berg, S., Hellberg, S., Ormo, M., Nilsson, Y., et al. (2003).
    Structural insights and biological effects of glycogen synthase kinase
    3-specific inhibitor AR-A014418. J Biol Chem, 278(46), 45937-45945.
    Bilim, V., Ougolkov, A., Yuuki, K., Naito, S., Kawazoe, H., Muto, A., et al. (2009).
    Glycogen synthase kinase-3: a new therapeutic target in renal cell carcinoma.
    Br J Cancer, 101(12), 2005-2014.
    Block, T. M., Mehta, A. S., Fimmel, C. J., & Jordan, R. (2003). Molecular viral
    oncology of hepatocellular carcinoma. Oncogene, 22(33), 5093-5107.
    Bolden, J. E., Peart, M. J., & Johnstone, R. W. (2006). Anticancer activities of histone
    deacetylase inhibitors. Nat Rev Drug Discov, 5(9), 769-784.
    Brouet, I., & Ohshima, H. (1995). Curcumin, an Anti-tumor Promoter and
    Anti-inflammatory Agent, Inhibits Induction of Nitric Oxide Synthase in
    Activated Macrophages. Biochemical and Biophysical Research
    Communications, 206(2), 533-540.
    Buckle, D. R., Rockell, C. J., Smith, H., & Spicer, B. A. (1986). Studies on
    1,2,3-triazoles. 13. (Piperazinylalkoxy)
    [1]benzopyrano[2,3-d]-1,2,3-triazol-9(1H)-ones with combined
    H1-antihistamine and mast cell stabilizing properties. J Med Chem, 29(11),
    2262-2267.
    Budihardjo, I., Oliver, H., Lutter, M., Luo, X., & Wang, X. (1999). Biochemical
    pathways of caspase activation during apoptosis. Annu Rev Cell Dev Biol, 15,
    269-290.
    Buscarini, L., Buscarini, E., Di Stasi, M., Vallisa, D., Quaretti, P., & Rocca, A. (2001).
    Percutaneous radiofrequency ablation of small hepatocellular carcinoma:
    long-term results. Eur Radiol, 11(6), 914-921.
    Cagnol, S., & Chambard, J. C. (2010). ERK and cell death: mechanisms of
    ERK-induced cell death--apoptosis, autophagy and senescence. FEBS J,
    277(1), 2-21.
    Cao, J., Liu, Y., Jia, L., Zhou, H. M., Kong, Y., Yang, G., et al. (2007). Curcumin
    induces apoptosis through mitochondrial hyperpolarization and mtDNA
    damage in human hepatoma G2 cells. Free Radic Biol Med, 43(6), 968-975.
    Center, M. M., & Jemal, A. (2011). International trends in liver cancer incidence rates.
    Cancer Epidemiol Biomarkers Prev, 20(11), 2362-2368.
    Chang, C.-P., Yang, M.-C., Liu, H.-S., Lin, Y.-S., & Lei, H.-Y. (2007). Concanavalin A
    induces autophagy in hepatoma cells and has a therapeutic effect in a murine
    in situ hepatoma model. Hepatology, 45(2), 286-296.
    Chau, B. N., Cheng, E. H. Y., Kerr, D. A., & Hardwick, J. M. (2000). Aven, a Novel
    Inhibitor of Caspase Activation, Binds Bcl-xL and Apaf-1. Molecular cell,
    6(1), 31-40.
    Chen, D.-S., Kuo, G. C., Sung, J.-L., Lai, M.-Y., Sheu, J.-C., Chen, P.-J., et al. (1990).
    Hepatitis C Virus Infection in an Area Hyperendemic for Hepatitis B and
    Chronic Liver Disease: The Taiwan Experience. Journal of Infectious Diseases,
    162(4), 817-822.
    Chen, J., Tang, X., Zhi, J., Cui, Y., Yu, H., Tang, E., et al. (2006). Curcumin protects
    PC12 cells against 1-methyl-4-phenylpyridinium ion-induced apoptosis by
    bcl-2-mitochondria-ROS-iNOS pathway. Apoptosis, 11(6), 943-953.
    Cheng, C. Y., Lin, Y. H., & Su, C. C. (2010). Curcumin inhibits the proliferation of
    human hepatocellular carcinoma J5 cells by inducing endoplasmic reticulum
    stress and mitochondrial dysfunction. Int J Mol Med, 26(5), 673-678.
    Choi, M. J., Jung, K. H., Kim, D., Lee, H., Zheng, H. M., Park, B. H., et al. (2011).
    Anti-cancer effects of a novel compound HS-113 on cell growth, apoptosis,
    and angiogenesis in human hepatocellular carcinoma cells. Cancer Lett,
    306(2), 190-196.
    Choueiri, T. K., Schutz, F. A., Je, Y., Rosenberg, J. E., & Bellmunt, J. (2010). Risk of
    arterial thromboembolic events with sunitinib and sorafenib: a systematic
    review and meta-analysis of clinical trials. J Clin Oncol, 28(13), 2280-2285.
    Coates, J. M., Galante, J. M., & Bold, R. J. (2010). Cancer therapy beyond apoptosis:
    autophagy and anoikis as mechanisms of cell death. J Surg Res, 164(2),
    301-308.
    Cohen, G. M. (1997). Caspases: the executioners of apoptosis. Biochem J, 326 ( Pt 1),
    1-16.
    Colotta, F., Allavena, P., Sica, A., Garlanda, C., & Mantovani, A. (2009).
    Cancer-related inflammation, the seventh hallmark of cancer: links to genetic
    instability. Carcinogenesis, 30(7), 1073-1081.
    Duvoix, A., Blasius, R., Delhalle, S., Schnekenburger, M., Morceau, F., Henry, E., et
    al. (2005). Chemopreventive and therapeutic effects of curcumin. Cancer
    Letters, 223(2), 181-190.
    Duvoix, A., Morceau, F., Schnekenburger, M., Delhalle, S., Galteau, M. M., Dicato,
    M., et al. (2003). Curcumin-induced cell death in two leukemia cell lines:
    K562 and Jurkat. Ann N Y Acad Sci, 1010, 389-392.
    Escudier, B., Eisen, T., Stadler, W. M., Szczylik, C., Oudard, S., Siebels, M., et al.
    (2007). Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med,
    356(2), 125-134.
    Fischer, P. M., Glover, D. M., & Lane, D. P. (2004). Targeting the cell cycle. Drug
    Discovery Today: Therapeutic Strategies, 1(4), 417-423.
    Gauthier, A., & Ho, M. (2012). Role of sorafenib in the treatment of advanced
    hepatocellular carcinoma: An update. Hepatology Research, n/a-n/a.
    Genin, M. J., Allwine, D. A., Anderson, D. J., Barbachyn, M. R., Emmert, D. E., Garmon, S. A., et al. (2000). Substituent effects on the antibacterial activity of
    nitrogen-carbon-linked (azolylphenyl)oxazolidinones with expanded activity
    against the fastidious gram-negative organisms Haemophilus influenzae and
    Moraxella catarrhalis. J Med Chem, 43(5), 953-970.
    Goel, A., & Aggarwal, B. B. (2010). Curcumin, the golden spice from Indian saffron,
    is a chemosensitizer and radiosensitizer for tumors and chemoprotector and
    radioprotector for normal organs. Nutr Cancer, 62(7), 919-930.
    Goel, A., & Aggarwal, B. B. (2010). Curcumin, the Golden Spice From Indian Saffron,
    Is a Chemosensitizer and Radiosensitizer for Tumors and Chemoprotector and
    Radioprotector for Normal Organs. [Article]. Nutrition & Cancer, 62(7),
    919-930.
    Gottesman, M. M., Fojo, T., & Bates, S. E. (2002). Multidrug resistance in cancer:
    role of ATP-dependent transporters. [10.1038/nrc706]. Nat Rev Cancer, 2(1),
    48-58.
    Green, A. S., Chapuis, N., Lacombe, C., Mayeux, P., Bouscary, D., & Tamburini, J.
    (2011). LKB1/AMPK/mTOR signaling pathway in hematological
    malignancies: from metabolism to cancer cell biology. Cell Cycle, 10(13),
    2115-2120.
    Hanahan, D., & Weinberg, Robert A. (2011). Hallmarks of Cancer: The Next
    Generation. Cell, 144(5), 646-674.
    Hartwell, L. H., & Kastan, M. B. (1994). Cell cycle control and cancer. Science,
    266(5192), 1821-1828.
    He, C., & Levine, B. (2010). The Beclin 1 interactome. Curr Opin Cell Biol, 22(2),
    140-149.
    Hill, M. M., Adrain, C., Duriez, P. J., Creagh, E. M., & Martin, S. J. (2004). Analysis of the composition, assembly kinetics and activity of native Apaf-1
    apoptosomes. EMBO J, 23(10), 2134-2145.
    Hoeflich, K. P., Luo, J., Rubie, E. A., Tsao, M. S., Jin, O., & Woodgett, J. R. (2000).
    Requirement for glycogen synthase kinase-3beta in cell survival and
    NF-kappaB activation. Nature, 406(6791), 86-90.
    Hour, T.-C., Chen, J., Huang, C.-Y., Guan, J.-Y., Lu, S.-H., & Pu, Y.-S. (2002).
    Curcumin enhances cytotoxicity of chemotherapeutic agents in prostate cancer
    cells by inducing p21WAF1/CIP1 and C/EBPβ expressions and suppressing
    NF-κB activation. The Prostate, 51(3), 211-218.
    Inoki, K., Ouyang, H., Zhu, T., Lindvall, C., Wang, Y., Zhang, X., et al. (2006). TSC2
    integrates Wnt and energy signals via a coordinated phosphorylation by
    AMPK and GSK3 to regulate cell growth. Cell, 126(5), 955-968.
    Jacobs, K. M., Bhave, S. R., Ferraro, D. J., Jaboin, J. J., Hallahan, D. E., & Thotala, D.
    (2012). GSK-3beta: A Bifunctional Role in Cell Death Pathways. Int J Cell
    Biol, 2012, 930710.
    Je, Y., Schutz, F. A., & Choueiri, T. K. (2009). Risk of bleeding with vascular
    endothelial growth factor receptor tyrosine-kinase inhibitors sunitinib and
    sorafenib: a systematic review and meta-analysis of clinical trials. Lancet
    Oncol, 10(10), 967-974.
    Kamb, A., Gruis, N. A., Weaver-Feldhaus, J., Liu, Q., Harshman, K., Tavtigian, S. V.,
    et al. (1994). A cell cycle regulator potentially involved in genesis of many
    tumor types. Science (New York, N.Y.), 264(5157), 436-440.
    Kang, J., Chen, J., Shi, Y., Jia, J., & Zhang, Y. (2005). Curcumin-induced histone
    hypoacetylation: the role of reactive oxygen species. Biochem Pharmacol,
    69(8), 1205-1213.
    Kataoka, T., Schroter, M., Hahne, M., Schneider, P., Irmler, M., Thome, M., et al.
    (1998). FLIP prevents apoptosis induced by death receptors but not by
    perforin/granzyme B, chemotherapeutic drugs, and gamma irradiation. J
    Immunol, 161(8), 3936-3942.
    Kerr, J. F., Winterford, C. M., & Harmon, B. V. (1994). Apoptosis. Its significance in
    cancer and cancer therapy. Cancer, 73(8), 2013-2026.
    Kerr, J. F., Wyllie, A. H., & Currie, A. R. (1972). Apoptosis: a basic biological
    phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer,
    26(4), 239-257.
    Kerr, J. F. R. (1972). Shrinkage necrosis of adrenal cortical cells. The Journal of
    Pathology, 107(3), 217-219.
    Kim, D.-H., Sarbassov, D. D., Ali, S. M., King, J. E., Latek, R. R.,
    Erdjument-Bromage, H., et al. (2002). mTOR Interacts with Raptor to Form a
    Nutrient-Sensitive Complex that Signals to the Cell Growth Machinery. Cell,
    110(2), 163-175.
    Kim, M. J., Kim, D. E., Jeong, I. G., Choi, J., Jang, S., Lee, J. H., et al. (2012). HDAC
    inhibitors synergize antiproliferative effect of sorafenib in renal cell carcinoma
    cells. Anticancer Res, 32(8), 3161-3168.
    Kischkel, F. C., Hellbardt, S., Behrmann, I., Germer, M., Pawlita, M., Krammer, P. H.,
    et al. (1995). Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins
    form a death-inducing signaling complex (DISC) with the receptor. EMBO J,
    14(22), 5579-5588.
    Kiso, Y., Suzuki, Y., Watanabe, N., Oshima, Y., & Hikino, H. (1983). Antihepatotoxic
    Principles of Curcuma longa Rhizomes1. Planta medica, 49(11), 185-187.
    Kondo, Y., Kanzawa, T., Sawaya, R., & Kondo, S. (2005). The role of autophagy in cancer development and response to therapy. [10.1038/nrc1692]. Nat Rev
    Cancer, 5(9), 726-734.
    Kroemer, G., & Jaattela, M. (2005). Lysosomes and autophagy in cell death control.
    Nat Rev Cancer, 5(11), 886-897.
    Kuan N, P. J. E. (1998). Apoptosis: Programmed cell death. Archives of Surgery,
    133(7), 773-775.
    Kuwana, T., & Newmeyer, D. D. (2003). Bcl-2-family proteins and the role of
    mitochondria in apoptosis. Curr Opin Cell Biol, 15(6), 691-699.
    Lamb, J., Crawford, E. D., Peck, D., Modell, J. W., Blat, I. C., Wrobel, M. J., et al.
    (2006). The Connectivity Map: using gene-expression signatures to connect
    small molecules, genes, and disease. Science, 313(5795), 1929-1935.
    Lencioni, R., Pinto, F., Armillotta, N., Bassi, A. M., Moretti, M., Di Giulio, M., et al.
    (1997). Long-term results of percutaneous ethanol injection therapy for
    hepatocellular carcinoma in cirrhosis: a European experience. Eur Radiol, 7(4),
    514-519.
    Lev-Ari, S., Starr, A., Vexler, A., Karaush, V., Loew, V., Greif, J., et al. (2006).
    Inhibition of pancreatic and lung adenocarcinoma cell survival by curcumin is
    associated with increased apoptosis, down-regulation of COX-2 and EGFR
    and inhibition of Erk1/2 activity. Anticancer Res, 26(6B), 4423-4430.
    Li, J., Hou, N., Faried, A., Tsutsumi, S., Takeuchi, T., & Kuwano, H. (2009).
    Inhibition of Autophagy by 3-MA Enhances the Effect of 5-FU-Induced
    Apoptosis in Colon Cancer Cells. Annals of Surgical Oncology, 16(3),
    761-771.
    Li, J., Hou, N., Faried, A., Tsutsumi, S., Takeuchi, T., & Kuwano, H. (2009).
    Inhibition of autophagy by 3-MA enhances the effect of 5-FU-induced apoptosis in colon cancer cells. Ann Surg Oncol, 16(3), 761-771.
    Liang, C., & Jung, J. U. (2010). Autophagy genes as tumor suppressors. Current
    Opinion in Cell Biology, 22(2), 226-233.
    Liu, H. S., Ke, C. S., Cheng, H. C., Huang, C. Y., & Su, C. L. (2011).
    Curcumin-induced mitotic spindle defect and cell cycle arrest in human
    bladder cancer cells occurs partly through inhibition of aurora A. Mol
    Pharmacol, 80(4), 638-646.
    Liu, T., Kuljaca, S., Tee, A., & Marshall, G. M. (2006). Histone deacetylase inhibitors:
    multifunctional anticancer agents. Cancer Treat Rev, 32(3), 157-165.
    Llovet, J. M., Bruix, J., & Gores, G. J. (2000). Surgical resection versus
    transplantation for early hepatocellular carcinoma: clues for the best strategy.
    Hepatology, 31(4), 1019-1021.
    Llovet, J. M., Ricci, S., Mazzaferro, V., Hilgard, P., Gane, E., Blanc, J.-F., et al. (2008).
    Sorafenib in Advanced Hepatocellular Carcinoma. New England Journal of
    Medicine, 359(4), 378-390.
    Llovet, J. M., Sala, M., Castells, L., Suarez, Y., Vilana, R., Bianchi, L., et al. (2000).
    Randomized controlled trial of interferon treatment for advanced
    hepatocellular carcinoma. Hepatology, 31(1), 54-58.
    Macchiarulo, A., Costantino, G., Fringuelli, D., Vecchiarelli, A., Schiaffella, F., &
    Fringuelli, R. (2002). 1,4-Benzothiazine and 1,4-benzoxazine imidazole
    derivatives with antifungal activity: a docking study. Bioorg Med Chem,
    10(11), 3415-3423.
    Majno, G., & Joris, I. (1995). Apoptosis, oncosis, and necrosis. An overview of cell
    death. Am J Pathol, 146(1), 3-15.
    Manov, I., Pollak, Y., Broneshter, R., & Iancu, T. C. (2011). Inhibition of doxorubicin-induced autophagy in hepatocellular carcinoma Hep3B cells by
    sorafenib--the role of extracellular signal-regulated kinase counteraction.
    FEBS J, 278(18), 3494-3507.
    McNally, S. J., Harrison, E. M., Ross, J. A., Garden, O. J., & Wigmore, S. J. (2007).
    Curcumin induces heme oxygenase 1 through generation of reactive oxygen
    species, p38 activation and phosphatase inhibition. Int J Mol Med, 19(1),
    165-172.
    Mizushima, N., Levine, B., Cuervo, A. M., & Klionsky, D. J. (2008). Autophagy
    fights disease through cellular self-digestion. [10.1038/nature06639]. Nature,
    451(7182), 1069-1075.
    Mulcahy, M. F. (2005). Management of hepatocellular cancer. Curr Treat Options
    Oncol, 6(5), 423-435.
    Nanji, A. A., Jokelainen, K., Tipoe, G. L., Rahemtulla, A., Thomas, P., & Dannenberg,
    A. J. (2003). Curcumin prevents alcohol-induced liver disease in rats by
    inhibiting the expression of NF-kappa B-dependent genes. American journal
    of physiology. Gastrointestinal and liver physiology, 284(2), G321-327.
    Newmeyer, D. D., Bossy-Wetzel, E., Kluck, R. M., Wolf, B. B., Beere, H. M., &
    Green, D. R. (2000). Bcl-xL does not inhibit the function of Apaf-1. Cell
    Death Differ, 7(4), 402-407.
    Noda, T., & Ohsumi, Y. (1998). Tor, a phosphatidylinositol kinase homologue,
    controls autophagy in yeast. J Biol Chem, 273(7), 3963-3966.
    Notarbartolo, M., Poma, P., Perri, D., Dusonchet, L., Cervello, M., & D'Alessandro, N.
    (2005). Antitumor effects of curcumin, alone or in combination with cisplatin
    or doxorubicin, on human hepatic cancer cells. Analysis of their possible
    relationship to changes in NF-kB activation levels and in IAP gene expression.
    Cancer Lett, 224(1), 53-65.
    Notarbartolo, M., Poma, P., Perri, D., Dusonchet, L., Cervello, M., & D'Alessandro, N.
    (2005). Antitumor effects of curcumin, alone or in combination with cisplatin
    or doxorubicin, on human hepatic cancer cells. Analysis of their possible
    relationship to changes in NF-kB activation levels and in IAP gene expression.
    Cancer Letters, 224(1), 53-65.
    Nurse, P., Masui, Y., & Hartwell, L. (1998). Understanding the cell cycle. Nat Med,
    4(10), 1103-1106.
    Okano, J.-i., Fujise, Y., Abe, R., Imamoto, R., & Murawaki, Y. (2011).
    Chemoprevention against hepatocellular carcinoma. Clinical Journal of
    Gastroenterology, 4(4), 185-197.
    Ong, G. Y., Changchien, C. S., Lee, C. M., Wang, J. H., Tung, H. D., Chuah, S. K., et
    al. (2004). Liver abscess complicating transcatheter arterial embolization: a
    rare but serious complication. A retrospective study after 3878 procedures. Eur
    J Gastroenterol Hepatol, 16(8), 737-742.
    Ou, D. L., Shen, Y. C., Liang, J. D., Liou, J. Y., Yu, S. L., Fan, H. H., et al. (2009).
    Induction of Bim expression contributes to the antitumor synergy between
    sorafenib and mitogen-activated protein kinase/extracellular signal-regulated
    kinase kinase inhibitor CI-1040 in hepatocellular carcinoma. Clin Cancer Res,
    15(18), 5820-5828.
    Ougolkov, A. V., Bone, N. D., Fernandez-Zapico, M. E., Kay, N. E., & Billadeau, D.
    D. (2007). Inhibition of glycogen synthase kinase-3 activity leads to epigenetic
    silencing of nuclear factor kappaB target genes and induction of apoptosis in
    chronic lymphocytic leukemia B cells. Blood, 110(2), 735-742.
    Panka, D. J., Cho, D. C., Atkins, M. B., & Mier, J. W. (2008). GSK-3beta inhibition enhances sorafenib-induced apoptosis in melanoma cell lines. J Biol Chem,
    283(2), 726-732.
    Patt, Y. Z., Charnsangavej, C., Yoffe, B., Smith, R., Lawrence, D., Chuang, V., et al.
    (1994). Hepatic arterial infusion of floxuridine, leucovorin, doxorubicin, and
    cisplatin for hepatocellular carcinoma: effects of hepatitis B and C viral
    infection on drug toxicity and patient survival. J Clin Oncol, 12(6),
    1204-1211.
    Pattingre, S., Espert, L., Biard-Piechaczyk, M., & Codogno, P. (2008). Regulation of
    macroautophagy by mTOR and Beclin 1 complexes. Biochimie, 90(2),
    313-323.
    Peng, C.-L., Guo, W., Ji, T., Ren, T., Yang, Y., Li, D.-S., et al. (2009). Sorafenib
    induces growth inhibition and apoptosis in human synovial sarcoma cells via
    inhibiting the RAF/MEK/ERK signaling pathway. Cancer Biology & Therapy,
    8(18), 1729-1736.
    Piwocka, K., Jaruga, E., Skierski, J., Gradzka, I., & Sikora, E. (2001). Effect of
    glutathione depletion on caspase-3 independent apoptosis pathway induced by
    curcumin in Jurkat cells. Free Radic Biol Med, 31(5), 670-678.
    Qian, H., Yang, Y., & Wang, X. (2011). Curcumin enhanced adriamycin-induced
    human liver-derived Hepatoma G2 cell death through activation of
    mitochondria-mediated apoptosis and autophagy. European Journal of
    Pharmaceutical Sciences, 43(3), 125-131.
    Sa, G., & Das, T. (2008). Anti cancer effects of curcumin: cycle of life and death:
    BioMed Central Ltd.
    Sadzuka, Y., Nagamine, M., Toyooka, T., Ibuki, Y., & Sonobe, T. (2012). Beneficial
    effects of curcumin on antitumor activity and adverse reactions of doxorubicin. Int J Pharm, 432(1-2), 42-49.
    Sala, M., Varela, M., & Bruix, J. (2004). Selection of candidates with HCC for
    transplantation in the MELD era. Liver Transpl, 10(10 Suppl 2), S4-9.
    Scott, D. W., & Loo, G. (2004). Curcumin-induced GADD153 gene up-regulation in
    human colon cancer cells. Carcinogenesis, 25(11), 2155-2164.
    Scott, R. C., Schuldiner, O., & Neufeld, T. P. (2004). Role and regulation of
    starvation-induced autophagy in the Drosophila fat body. Dev Cell, 7(2),
    167-178.
    Shackelford, D. B., & Shaw, R. J. (2009). The LKB1-AMPK pathway: metabolism
    and growth control in tumour suppression. Nat Rev Cancer, 9(8), 563-575.
    Shi, Y.-H., Ding, Z.-B., Zhou, J., Hui, B., Shi, G.-M., Ke, A.-W., et al. (2011).
    Targeting autophagy enhances sorafenib lethality for hepatocellular carcinoma
    via ER stress-related apoptosis. Autophagy, 7(10), 1159-1172.
    Shinojima, N., Yokoyama, T., Kondo, Y., & Kondo, S. (2007). Roles of the
    Akt/mTOR/p70S6K and ERK1/2 signaling pathways in curcumin-induced
    autophagy. Autophagy, 3(6), 635-637.
    Sim, H. M., Lee, C. Y., Ee, P. L., & Go, M. L. (2008). Dimethoxyaurones: Potent
    inhibitors of ABCG2 (breast cancer resistance protein). Eur J Pharm Sci, 35(4),
    293-306.
    Sinha, S., & Levine, B. (2008). The autophagy effector Beclin 1: a novel BH3-only
    protein. Oncogene, 27 Suppl 1, S137-148.
    Siwak, D. R., Shishodia, S., Aggarwal, B. B., & Kurzrock, R. (2005).
    Curcumin-induced antiproliferative and proapoptotic effects in melanoma cells
    are associated with suppression of IkappaB kinase and nuclear factor kappaB
    activity and are independent of the B-Raf/mitogen-activated/extracellular signal-regulated protein kinase pathway and the Akt pathway. Cancer, 104(4),
    879-890.
    Sreejayan, & Rao, M. N. A. (1997). Nitric Oxide Scavenging by Curcuminoids.
    Journal of Pharmacy and Pharmacology, 49(1), 105-107.
    Srivastava, K. C., Bordia, A., & Verma, S. K. (1995). Curcumin, a major component
    of food spice turmeric (Curcuma longa) inhibits aggregation and alters
    eicosanoid metabolism in human blood platelets. Prostaglandins, Leukotrienes
    and Essential Fatty Acids, 52(4), 223-227.
    Strumberg, D., Richly, H., Hilger, R. A., Schleucher, N., Korfee, S., Tewes, M., et al.
    (2005). Phase I clinical and pharmacokinetic study of the Novel Raf kinase
    and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in
    patients with advanced refractory solid tumors. J Clin Oncol, 23(5), 965-972.
    Syng-Ai, C., Kumari, A. L., & Khar, A. (2004). Effect of curcumin on normal and
    tumor cells: role of glutathione and bcl-2. Mol Cancer Ther, 3(9), 1101-1108.
    Tanida, I., Minematsu-Ikeguchi, N., Ueno, T., & Kominami, E. (2005). Lysosomal
    turnover, but not a cellular level, of endogenous LC3 is a marker for
    autophagy. Autophagy, 1(2), 84-91.
    Thayyullathil, F., Chathoth, S., Hago, A., Patel, M., & Galadari, S. (2008). Rapid
    reactive oxygen species (ROS) generation induced by curcumin leads to
    caspase-dependent and -independent apoptosis in L929 cells. Free Radic Biol
    Med, 45(10), 1403-1412.
    Thomas, P., Wang, Y. J., Zhong, J. H., Kosaraju, S., O'Callaghan, N. J., Zhou, X. F., et
    al. (2009). Grape seed polyphenols and curcumin reduce genomic instability
    events in a transgenic mouse model for Alzheimer's disease. Mutat Res,
    661(1-2), 25-34. Uddin, S., Hussain, A. R., Manogaran, P. S., Al-Hussein, K., Platanias, L. C.,
    Gutierrez, M. I., et al. (2005). Curcumin suppresses growth and induces
    apoptosis in primary effusion lymphoma. Oncogene, 24(47), 7022-7030.
    van Loo, G., Saelens, X., van Gurp, M., MacFarlane, M., Martin, S. J., &
    Vandenabeele, P. (2002). The role of mitochondrial factors in apoptosis: a
    Russian roulette with more than one bullet. Cell Death Differ, 9(10),
    1031-1042.
    Venkatesan, N. (1998). Curcumin attenuation of acute adriamycin myocardial toxicity
    in rats. British Journal of Pharmacology, 124(3), 425-427.
    Venkatesan, N., Punithavathi, D., & Arumugam, V. (2000). Curcumin prevents
    adriamycin nephrotoxicity in rats. British Journal of Pharmacology, 129(2),
    231-234.
    Wang, L.-Y., Hatch, M., Chen, C.-J., Levin, B., You, S.-L., Lu, S.-N., et al. (1996).
    Aflatoxin exposure and risk of hepatocellular carcinoma in Taiwan.
    International Journal of Cancer, 67(5), 620-625.
    Wang, S., Midgley, C. A., Scaerou, F., Grabarek, J. B., Griffiths, G., Jackson, W., et al.
    (2010). Discovery of N-phenyl-4-(thiazol-5-yl)pyrimidin-2-amine aurora
    kinase inhibitors. J Med Chem, 53(11), 4367-4378.
    Wang, W.-Z., Cheng, J., Luo, J., & Zhuang, S.-M. (2008). Abrogation of G2/M arrest
    sensitizes curcumin-resistant hepatoma cells to apoptosis. FEBS Letters,
    582(18), 2689-2695.
    Wang, W. Z., Cheng, J., Luo, J., & Zhuang, S. M. (2008). Abrogation of G2/M arrest
    sensitizes curcumin-resistant hepatoma cells to apoptosis. FEBS Lett, 582(18),
    2689-2695.
    Weinstein, I. B. (1996). Relevance of cyclin D1 and other molecular markers to cancer chemoprevention. J Cell Biochem Suppl, 25, 23-28.
    Wolf, B. B., Schuler, M., Echeverri, F., & Green, D. R. (1999). Caspase-3 is the
    primary activator of apoptotic DNA fragmentation via DNA fragmentation
    factor-45/inhibitor of caspase-activated DNase inactivation. J Biol Chem,
    274(43), 30651-30656.
    Wu, S., Chen, J. J., Kudelka, A., Lu, J., & Zhu, X. (2008). Incidence and risk of
    hypertension with sorafenib in patients with cancer: a systematic review and
    meta-analysis. Lancet Oncol, 9(2), 117-123.
    Xiao, G. (2007). Autophagy and NF-κB: Fight for fate. Cytokine & Growth
    Factor Reviews, 18(3–4), 233-243.
    Xie, B., Wang, D. H., & Spechler, S. J. (2012). Sorafenib for treatment of
    hepatocellular carcinoma: a systematic review. Dig Dis Sci, 57(5), 1122-1129.
    Yang, F., Lim, G. P., Begum, A. N., Ubeda, O. J., Simmons, M. R., Ambegaokar, S. S.,
    et al. (2005). Curcumin inhibits formation of amyloid beta oligomers and
    fibrils, binds plaques, and reduces amyloid in vivo. The Journal of biological
    chemistry, 280(7), 5892-5901.
    Yang, J., Takahashi, Y., Cheng, E., Liu, J., Terranova, P. F., Zhao, B., et al. (2010).
    GSK-3beta promotes cell survival by modulating Bif-1-dependent autophagy
    and cell death. J Cell Sci, 123(Pt 6), 861-870.
    Yip-Schneider, M. T., Klein, P. J., Wentz, S. C., Zeni, A., Menze, A., & Schmidt, C. M.
    (2009). Resistance to mitogen-activated protein kinase kinase (MEK)
    inhibitors correlates with up-regulation of the MEK/extracellular
    signal-regulated kinase pathway in hepatocellular carcinoma cells. J
    Pharmacol Exp Ther, 329(3), 1063-1070.
    Yoo, H. Y., Patt, C. H., Geschwind, J. F., & Thuluvath, P. J. (2003). The outcome of liver transplantation in patients with hepatocellular carcinoma in the United
    States between 1988 and 2001: 5-year survival has improved significantly
    with time. J Clin Oncol, 21(23), 4329-4335.
    Yousefi, S., & Simon, H. U. (2009). Autophagy in cancer and chemotherapy. Results
    Probl Cell Differ, 49, 183-190.
    Yu, S., Shen, G., Khor, T. O., Kim, J. H., & Kong, A. N. (2008). Curcumin inhibits
    Akt/mammalian target of rapamycin signaling through protein
    phosphatase-dependent mechanism. Mol Cancer Ther, 7(9), 2609-2620.
    Zheng, M., Ekmekcioglu, S., Walch, E. T., Tang, C. H., & Grimm, E. A. (2004).
    Inhibition of nuclear factor-kappaB and nitric oxide by curcumin induces
    G2/M cell cycle arrest and apoptosis in human melanoma cells. Melanoma Res,
    14(3), 165-171.
    Zhou, Y. Y., Wang, H. Y., Tang, Z. G., & Ma, D. L. (1984). [Two new formulae for
    evaluating the effectiveness of drug combinations and the revision of Burgi's
    and Jin's modified Burgi's formulae]. Zhongguo Yao Li Xue Bao, 5(4),
    217-221.

    下載圖示
    QR CODE