簡易檢索 / 詳目顯示

回結果列表
研究生： 王景平
Wang, Jing-Ping
論文名稱： 活化p53調控人類非小型肺癌細胞凋亡的藥物與機制
Drugs in tumor suppressor gene p53-activated apoptosis of human non-small cell lung cancer cells
指導教授： 方剛
Fang, Kang
學位類別： 博士
Doctor
系所名稱： 生命科學系
Department of Life Science
論文出版年： 2015
畢業學年度： 103
語文別： 英文
論文頁數： 82
中文關鍵詞： p53 、Akt 、teroxirone 、ellipticine 、NSCLC cells (非小型肺癌細胞) 、ROS
英文關鍵詞： p53, Akt, teroxirone, ellipticine, NSCLC cells, ROS
論文種類： 學術論文
相關次數： 點閱：151  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

    • Part I
    本論文發現三環化合物 (Teroxirone) 在低濃度下能抑制人類非小型肺癌細胞 (NSCLC cells) 的增生，不論在體外實驗或體內實驗都能具有顯著的效果。藥物所誘發的p53依賴型的細胞凋亡 (p53-dependent apoptosis) 是經由破壞癌細胞內的DNA結構所引發的，讓癌細胞p53上升，進而活化下游caspase-3，導致最終的細胞凋亡。而caspase-3的抑制劑 (DEVD-CHO) 或是利用 si-RNA p53抑制細胞內的p53，皆能抑制藥物所引發的細胞凋亡現象。另外，此藥物在缺失p53的細胞H1299 cells中，也能引起些微的細胞毒性。在體內實驗中，此藥物對於裸鼠身上的癌細胞也具有顯著抑制生長的功效。進一步發現，此藥物會引發癌細胞內的氧化壓力、產生活性氧化物 (ROS)、讓細胞內的粒腺體外膜崩壞，進而產生p53依賴型的內生性細胞凋亡 (intrinsic apoptosis pathway)。而利用ROS的抑制劑 (NAC) 進行處理後，也會抑制藥物所引發的細胞凋亡現象。由結果顯示，此藥物在低濃度時就能引發癌細胞的細胞凋亡並會顯著抑制癌細胞增生的結果，在未來可以是一個具有潛力治療人類非小型肺癌細胞的藥物。
    Part II
    玫瑰樹鹼 (Ellipticine) 是一種DNA拓樸異構酶II抑制劑，能夠有效的抑制人類非小型肺癌細胞 (NSCLC cells) 的增生。之前研究指出，此藥物能讓p53及Akt活化且共同轉移至細胞核內，並可藉由磷酸化AktS473去誘導癌細胞產生細胞自噬 (autophagy)，進而引發細胞死亡。另外，此藥物也可抑制能穩定表現p53功能的細胞株 (利用轉殖wild-type p53質體進入原本缺失p53的細胞株 (H1299 cells) 內，並讓其穩定表現 p53功能的細胞株) 的生長。在本研究中，我們進一步發現到，將AktS473的磷酸化位點突變成alanine以及利用shRNA p53去knockdown p53後，皆能抑制玫瑰樹鹼對於p53和Akt的活化以及轉移至細胞核內的程度，也能同時減少細胞凋亡的產生。因此，p53能夠讓此誘導細胞凋亡，並且能協助磷酸化AktS473進入細胞核內，進而引發細胞自噬作用，導致細胞死亡。本研究指出，玫瑰樹鹼能活化p53及磷酸化AktS473，並藉由這兩者間的協同作用去抑制癌細胞的生長。對於原本只有DNA拓樸異構酶II抑制功能的藥物，能提供另一個治療癌症抑制的新思維。

    Part I
    In this study, we demonstrated that the growth of human non-small cell lung cancer (NSCLC) cells H460 and A549 cells can be inhibited by low concentrations of an epoxide derivative, teroxirone, in both in vitro and in vivo models. The cytotoxicity was mediated by apoptotic cell death through DNA damage. The onset of ultimate apoptosis is dependent on the status of p53. Teroxirone caused transient elevation of p53 that activates downstream p21 and procaspase-3 cleavage. The presence of caspase-3 inhibitor reverted apoptotic phenotype. Furthermore, we showed the cytotoxicity of teroxirone in H1299 cells with stable ectopic expression of p53, but not those of mutant p53. A siRNA-mediated knockdown of p53 expression attenuated drug sensitivity. The in vivo experiments demonstrated that teroxirone suppressed growth of xenograft tumors in nude mice. Being a potential therapeutic agent by restraining cell growth through apoptotic death at low concentrations, teroxirone provides a feasible perspective in reversing tumorigenic phenotype of human lung cancer cells. The results indicated that low concentrations of teroxirone suppressed the growth of human non-small cell lung cancer cells. The induced apoptotic cell death can be reverted by caspase-3 inhibitor, DEVD-CHO. The reduced cell viability is closely related to p53-activated apoptosis. Furthermore, we also found that teroxirone-induced p53-dependent apoptosis was through regulating intrinsic pathway via ROS generation and mitochondria dysfunction, which can reverted by antioxidant NAC. Teroxirone provides a good candidate for lung cancer treatment by suppressing cellular proliferation.
    Part II
    Topoisomerase II inhibitor ellipticine effectively suppressed the growth of human non-small cell lung cancer (NSCLC) epithelial cells. Previously, we reported the drug activity was consummated through parallel nucleus migration of p53 and Akt in A549 cells. While inducing cell death, the drug activity was proved related to autophagy through phosphorylated Akt at S473. In addition, ellipticine induced cytotoxicity in p53-null H1299 cells with stable expression of ectopic p53. In this work, we further demonstrated that dominant-negative AktS473A or p53 shRNA inhibited ellipticine-mediated translocalization of p53 and Akt and attenuated apoptotic cell death in A549 cells. The presence of p53 predates ellipticine-mediated apoptotic cell death, assists in nucleus translocation of phosphorylated Akt and activation of autophagy pathway. Growth inhibition through collaborating p53 and phosphorylated Akt473 in lung epithelial cancer cells provided a new perspective of the topoisomerase inhibitor as an effective cancer therapy agent.

    Part I Page 中文摘要..................................................1 Abstract.................................................2 Introduction.............................................3 Lung cancer..............................................3 Apoptosis................................................4 Tumor suppressor gene p53................................5 Teroxirone...............................................6 Production of ROS trigged the activation of apoptosis....7 Purpose..................................................8 Materials and methods....................................8 Chemicals................................................8 Cell culture.............................................8 Cell viability determination.............................9 Comet assay..............................................10 Flow cytometry and determinations for cell cycle analysis and apoptosis determination..............................11 Analysis of cytochrome c release.........................11 Western blot analysis....................................12 Results..................................................13 Teroxirone-damaged DNA suppressed cell proliferation in A549 and H460 cells,but not in H1299 cells...............13 The increased annexin V and PI-positive cells by teroxirone in both H460 and A549 cells...................13 The inducible PARP cleavage and expression mitosis regulators, p53 and p21Waf1/Cip1 (p21), accounted for the apoptotic cell death in H460 and A549 cells....................................................14 Release of cytochrome c in H460 and A549 cells when treated with teroxirone..........................................14 Caspase-3 inhibitor blocked teroxirone-mediated apoptosis................................................15 Teroxirone-induced apoptosis is dependent on p53 status...................................................15 Down-regulation of p53 proteins attenuated the onset of teroxirone-induced cell death in NSCLC cells...........................................16 Teroxirone enhances mitochondrial membrane potential drop in NSCLC cells...........................................16 To evaluated the intracellular ROS production by teroxirone in human NSCLC cells.....................................17 NAC suppressed the effect of ROS generation on cell cycle distribution in NSCLC cells..............................17 Teroxirone induces the p53-dependent apoptosis of NSCLC cells in a ROS-dependent manner..........................18 Production of ROS mediated the release of cytochrome c in NSCLC cells..............................................18 Figures and legends......................................20 Figure 1.................................................20 Figure 2.................................................22 Figure 3.................................................24 Figure 4-1...............................................26 Figure 4-2...............................................27 Figure 5.................................................29 Figure 6.................................................31 Figure 7.................................................32 Figure 8.................................................34 Figure 9.................................................35 Figure 10................................................37 Figure 11................................................38 Figure 12................................................39 Discussion...............................................40 Part II 中文摘要..................................................46 Abstract.................................................47 Introduction.............................................48 Topoisomerace II inhibitor...............................48 Ellipticine..............................................49 PI3K/Akt signaling pathway...............................49 Purpose..................................................50 Materials and methods....................................51 Chemicals................................................51 Transfection of constructs...............................51 Immunofluorescence analysis..............................52 Results..................................................52 The suppressed cell viabilities and the increased sub-G1 cell populations can be reverted by dominant-negative AktS473A.................................................52 AktS473A abrogated ellipticine sensitivity in H1299 cells with ectopic p53.........................................53 Dominant-negative AktS473A inhibited ellipticine induced nucleus translocation of p53 and Akt in A549 cells.......54 Knock-down of p53 inhibited ellipticine-induced nucleus translocation of Akt.....................................55 The enhanced autophagy during ellipticine-induced apoptosis was deactivated by AktS473A..............................55 Figures and legends......................................57 Figure 1.................................................57 Figure 2.................................................59 Figure 3-1...............................................61 Figure 3-2...............................................62 Figure 4-1...............................................64 Figure 4-2...............................................66 Figure 5.................................................67 Figure 6.................................................69 Discussion...............................................71 References...............................................75

    1. Herbst RS, Heymach JV, Lippman SM (2008) Lung cancer. N Engl J Med 359: 1367-1380.
    2. Saintigny P, Burger JA (2012) Recent advances in non-small cell lung cancer biology and clinical management. Discov Med 13: 287-297.
    3. Erridge SC, Moller H, Price A, Brewster D (2007) International comparisons of survival from lung cancer: pitfalls and warnings. Nat Clin Pract Oncol 4: 570-577.
    4. Jemal A, Thun MJ, Ries LA, Howe HL, Weir HK, et al. (2008) Annual report to the nation on the status of cancer, 1975-2005, featuring trends in lung cancer, tobacco use, and tobacco control. J Natl Cancer Inst 100: 1672-1694.
    5. Pao W, Chmielecki J (2010) Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. Nat Rev Cancer 10: 760-774.
    6. Charoensinphon N, Qiu P, Dong P, Zheng J, Ngauv P, et al. (2013) 5-demethyltangeretin inhibits human nonsmall cell lung cancer cell growth by inducing G2/M cell cycle arrest and apoptosis. Mol Nutr Food Res 57: 2103-2111.
    7. Rathos MJ, Khanwalkar H, Joshi K, Manohar SM, Joshi KS (2013) Potentiation of in vitro and in vivo antitumor efficacy of doxorubicin by cyclin-dependent kinase inhibitor P276-00 in human non-small cell lung cancer cells. BMC Cancer 13: 29.
    8. Santana-Davila R, Szabo A, Arce-Lara C, Williams CD, Kelley MJ, et al. (2014) Cisplatin versus carboplatin-based regimens for the treatment of patients with metastatic lung cancer. An analysis of Veterans Health Administration data. J Thorac Oncol 9: 702-709.
    9. Pace E, Melis M, Siena L, Bucchieri F, Vignola AM, et al. (2000) Effects of gemcitabine on cell proliferation and apoptosis in non-small-cell lung cancer (NSCLC) cell lines. Cancer Chemother Pharmacol 46: 467-476.
    10. Bates S, Vousden KH (1999) Mechanisms of p53-mediated apoptosis. Cell Mol Life Sci 55: 28-37.
    11. Lowe SW, Lin AW (2000) Apoptosis in cancer. Carcinogenesis 21: 485-495.
    12. Kerr JF, Winterford CM, Harmon BV (1994) Apoptosis. Its significance in cancer and cancer therapy. Cancer 73: 2013-2026.
    13. McConkey DJ, Aguilar-Santelises M, Hartzell P, Eriksson I, Mellstedt H, et al. (1991) Induction of DNA fragmentation in chronic B-lymphocytic leukemia cells. J Immunol 146: 1072-1076.
    76
    14. Martin SJ, Green DR (1995) Protease activation during apoptosis: death by a thousand cuts? Cell 82: 349-352.
    15. Enari M, Sakahira H, Yokoyama H, Okawa K, Iwamatsu A, et al. (1998) A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature 391: 43-50.
    16. Thompson CB (1995) Apoptosis in the pathogenesis and treatment of disease. Science 267: 1456-1462.
    17. Hussain SP, Harris CC (1998) Molecular epidemiology of human cancer: contribution of mutation spectra studies of tumor suppressor genes. Cancer Res 58: 4023-4037.
    18. Mogi A, Kuwano H (2011) TP53 mutations in nonsmall cell lung cancer. J Biomed Biotechnol 2011: 583929.
    19. Fridman JS, Lowe SW (2003) Control of apoptosis by p53. Oncogene 22: 9030-9040.
    20. Lowe SW, Ruley HE, Jacks T, Housman DE (1993) p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 74: 957-967.
    21. Ames MM, Kovach JS, Rubin J (1984) Pharmacological characterization of teroxirone, a triepoxide antitumor agent, in rats, rabbits, and humans. Cancer Res 44: 4151-4156.
    22. Atassi G, Dumont P, Fisher U, Zeidler M, Budnowski M (1984) Preclinical evaluation of the anti tumour activity of new epoxyde derivatives. Cancer Treat Rev 11 Suppl A: 99-110.
    23. Neidhart JA, Derocher D, Grever MR, Kraut EH, Malspeis L (1984) Phase I trial of teroxirone. Cancer Treat Rep 68: 1115-1119.
    24. Nicaise C, Rozencweig M, Crespeigne N, Dodion P, Gerard B, et al. (1986) Phase I study of triglycidylurazol given on a 5-day i.v. schedule. Cancer Treat Rep 70: 599-603.
    25. Rubin J, Kovach JS, Ames MM, Moertel CG, Creagan ET, et al. (1987) Phase I study of two schedules of teroxirone. Cancer Treat Rep 71: 489-492.
    26. Piccart M, Rozencweig M, Dodion P, Cumps E, Crespeigne N, et al. (1981) Phase I clinical trial with alpha 1,3,5- triglycidyl-s-triazinetrione (NSC-296934). Eur J Cancer Clin Oncol 17: 1263-1266.
    27. Mates JM, Sanchez-Jimenez FM (2000) Role of reactive oxygen species in apoptosis: implications for cancer therapy. Int J Biochem Cell Biol 32: 157-170.
    28. Simon HU, Haj-Yehia A, Levi-Schaffer F (2000) Role of reactive oxygen species (ROS) in apoptosis induction. Apoptosis 5: 415-418.
    29. Brodska B, Holoubek A (2011) Generation of reactive oxygen species during
    77
    apoptosis induced by DNA-damaging agents and/or histone deacetylase inhibitors. Oxid Med Cell Longev 2011: 253529.
    30. von Harsdorf R, Li PF, Dietz R (1999) Signaling pathways in reactive oxygen species-induced cardiomyocyte apoptosis. Circulation 99: 2934-2941.
    31. Herrera B, Alvarez AM, Sanchez A, Fernandez M, Roncero C, et al. (2001) Reactive oxygen species (ROS) mediates the mitochondrial-dependent apoptosis induced by transforming growth factor (beta) in fetal hepatocytes. Faseb j 15: 741-751.
    32. Crespo R, Villaverde ML, Girotti JR, Guerci A, Juarez MP, et al. (2011) Cytotoxic and genotoxic effects of defence secretion of Ulomoides dermestoides on A549 cells. J Ethnopharmacol 136: 204-209.
    33. Tice RR, Agurell E, Anderson D, Burlinson B, Hartmann A, et al. (2000) Single cell gel/comet assay: guidelines for in vitro and in vivo genetic toxicology testing. Environ Mol Mutagen 35: 206-221.
    34. Gualtieri M, Rigamonti L, Galeotti V, Camatini M (2005) Toxicity of tire debris extracts on human lung cell line A549. Toxicol In Vitro 19: 1001-1008.
    35. Lim SW, Ting KN, Bradshaw TD, Zeenathul NA, Wiart C, et al. (2011) Acalypha wilkesiana extracts induce apoptosis by causing single strand and double strand DNA breaks. J Ethnopharmacol 138: 616-623.
    36. Simbulan-Rosenthal CM, Rosenthal DS, Iyer S, Boulares H, Smulson ME (1999) Involvement of PARP and poly(ADP-ribosyl)ation in the early stages of apoptosis and DNA replication. Mol Cell Biochem 193: 137-148.
    37. Chiu CC, Lin CH, Fang K (2005) Etoposide (VP-16) sensitizes p53-deficient human non-small cell lung cancer cells to caspase-7-mediated apoptosis. Apoptosis 10: 643-650.
    38. Riley T, Sontag E, Chen P, Levine A (2008) Transcriptional control of human p53-regulated genes. Nat Rev Mol Cell Biol 9: 402-412.
    39. Toledo F, Wahl GM (2006) Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nat Rev Cancer 6: 909-923.
    40. Boehme KA, Kulikov R, Blattner C (2008) p53 stabilization in response to DNA damage requires Akt/PKB and DNA-PK. Proc Natl Acad Sci U S A 105: 7785-7790.
    41. Christophorou MA, Martin-Zanca D, Soucek L, Lawlor ER, Brown-Swigart L, et al. (2005) Temporal dissection of p53 function in vitro and in vivo. Nat Genet 37: 718-726.
    42. Christophorou MA, Ringshausen I, Finch AJ, Swigart LB, Evan GI (2006) The pathological response to DNA damage does not contribute to p53-mediated tumour suppression. Nature 443: 214-217.
    78
    43. Siddiqui-Jain A, Bliesath J, Macalino D, Omori M, Huser N, et al. (2012) CK2 inhibitor CX-4945 suppresses DNA repair response triggered by DNA-targeted anticancer drugs and augments efficacy: mechanistic rationale for drug combination therapy. Mol Cancer Ther 11: 994-1005.
    44. Meek DW (2009) Tumour suppression by p53: a role for the DNA damage response? Nat Rev Cancer 9: 714-723.
    45. Ling S, Lin WC (2011) EDD inhibits ATM-mediated phosphorylation of p53. J Biol Chem 286: 14972-14982.
    46. Offer H, Erez N, Zurer I, Tang X, Milyavsky M, et al. (2002) The onset of p53-dependent DNA repair or apoptosis is determined by the level of accumulated damaged DNA. Carcinogenesis 23: 1025-1032.
    47. Dash BC, El-Deiry WS (2005) Phosphorylation of p21 in G2/M promotes cyclin B-Cdc2 kinase activity. Mol Cell Biol 25: 3364-3387.
    48. Hsu YL, Kuo PL, Lin CC (2004) The proliferative inhibition and apoptotic mechanism of Saikosaponin D in human non-small cell lung cancer A549 cells. Life Sci 75: 1231-1242.
    49. An J, Gao Y, Wang J, Zhu Q, Ma Y, et al. (2012) Flavokawain B induces apoptosis of non-small cell lung cancer H460 cells via Bax-initiated mitochondrial and JNK pathway. Biotechnol Lett 34: 1781-1788.
    50. Oliver PG, LoBuglio AF, Zinn KR, Kim H, Nan L, et al. (2008) Treatment of human colon cancer xenografts with TRA-8 anti-death receptor 5 antibody alone or in combination with CPT-11. Clin Cancer Res 14: 2180-2189.
    51. Khan M, Zheng B, Yi F, Rasul A, Gu Z, et al. (2012) Pseudolaric Acid B induces caspase-dependent and caspase-independent apoptosis in u87 glioblastoma cells. Evid Based Complement Alternat Med 2012: 957568.
    52. Weigel TL, Lotze MT, Kim PK, Amoscato AA, Luketich JD, et al. (2000) Paclitaxel-induced apoptosis in non-small cell lung cancer cell lines is associated with increased caspase-3 activity. J Thorac Cardiovasc Surg 119: 795-803.
    53. Yan KH, Yao CJ, Chang HY, Lai GM, Cheng AL, et al. (2010) The synergistic anticancer effect of troglitazone combined with aspirin causes cell cycle arrest and apoptosis in human lung cancer cells. Mol Carcinog 49: 235-246.
    54. Wang JP, Lin KH, Liu CY, Yu YC, Wu PT, et al. (2013) Teroxirone inhibited growth of human non-small cell lung cancer cells by activating p53. Toxicol Appl Pharmacol 273: 110-120.
    55. Fulda S, Debatin KM (2006) Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy. Oncogene 25: 4798-4811.
    56. Ricci JE, Munoz-Pinedo C, Fitzgerald P, Bailly-Maitre B, Perkins GA, et al. (2004)
    79
    Disruption of mitochondrial function during apoptosis is mediated by caspase cleavage of the p75 subunit of complex I of the electron transport chain. Cell 117: 773-786.
    57. Cantley LC (2002) The phosphoinositide 3-kinase pathway. Science 296: 1655-1657.
    58. Xu H, Li X, Ding W, Zeng X, Kong H, et al. (2015) Deguelin induces the apoptosis of lung cancer cells through regulating a ROS driven Akt pathway. Cancer Cell Int 15: 25.
    59. Nitiss JL (2009) Targeting DNA topoisomerase II in cancer chemotherapy. Nat Rev Cancer 9: 338-350.
    60. Ganapathi RN, Ganapathi MK (2013) Mechanisms regulating resistance to inhibitors of topoisomerase II. Front Pharmacol 4: 89.
    61. Stiborova M, Sejbal J, Borek-Dohalska L, Aimova D, Poljakova J, et al. (2004) The anticancer drug ellipticine forms covalent DNA adducts, mediated by human cytochromes P450, through metabolism to 13-hydroxyellipticine and ellipticine N2-oxide. Cancer Res 64: 8374-8380.
    62. Kenney S, Vistica DT, Linden H, Boyd MR (1995) Uptake and cytotoxicity of 9-methoxy-N2-methylellipticinium acetate in human brain and non-brain tumor cell lines. Biochem Pharmacol 49: 23-32.
    63. Hagg M, Berndtsson M, Mandic A, Zhou R, Shoshan MC, et al. (2004) Induction of endoplasmic reticulum stress by ellipticine plant alkaloids. Mol Cancer Ther 3: 489-497.
    64. Stiborova M, Rupertova M, Frei E (2011) Cytochrome P450- and peroxidase-mediated oxidation of anticancer alkaloid ellipticine dictates its anti-tumor efficiency. Biochim Biophys Acta 1814: 175-185.
    65. Schwaller MA, Allard B, Lescot E, Moreau F (1995) Protonophoric activity of ellipticine and isomers across the energy-transducing membrane of mitochondria. J Biol Chem 270: 22709-22713.
    66. Stiborova M, Poljakova J, Eckschlager T, Kizek R, Frei E (2012) Analysis of covalent ellipticine- and doxorubicin-derived adducts in DNA of neuroblastoma cells by the (3)(2)P-postlabeling technique. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 156: 115-121.
    67. Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, et al. (2001) Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annu Rev Cell Dev Biol 17: 615-675.
    68. Leslie NR, Biondi RM, Alessi DR (2001) Phosphoinositide-regulated kinases and phosphoinositide phosphatases. Chem Rev 101: 2365-2380.
    69. Wang W, El-Deiry WS (2008) Restoration of p53 to limit tumor growth. Curr
    80
    Opin Oncol 20: 90-96.
    70. Fang K, Chen SP, Lin CW, Cheng WC, Huang HT (2009) Ellipticine-induced apoptosis depends on Akt translocation and signaling in lung epithelial cancer cells. Lung Cancer 63: 227-234.
    71. Gozuacik D, Kimchi A (2004) Autophagy as a cell death and tumor suppressor mechanism. Oncogene 23: 2891-2906.
    72. Sugikawa E, Hosoi T, Yazaki N, Gamanuma M, Nakanishi N, et al. (1999) Mutant p53 mediated induction of cell cycle arrest and apoptosis at G1 phase by 9-hydroxyellipticine. Anticancer Res 19: 3099-3108.
    73. O'Reilly EK, Kreuzer KN (2002) A unique type II topoisomerase mutant that is hypersensitive to a broad range of cleavage-inducing antitumor agents. Biochemistry 41: 7989-7997.
    74. Peng Y, Li C, Chen L, Sebti S, Chen J (2003) Rescue of mutant p53 transcription function by ellipticine. Oncogene 22: 4478-4487.
    75. Tmejova K, Krejcova L, Hynek D, Adam V, Babula P, et al. (2014) Electrochemical study of ellipticine interaction with single and double stranded oligonucleotides. Anticancer Agents Med Chem 14: 331-340.
    76. Kuo PL, Hsu YL, Chang CH, Lin CC (2005) The mechanism of ellipticine-induced apoptosis and cell cycle arrest in human breast MCF-7 cancer cells. Cancer Lett 223: 293-301.
    77. Martinkova E, Maglott A, Leger DY, Bonnet D, Stiborova M, et al. (2010) alpha5beta1 integrin antagonists reduce chemotherapy-induced premature senescence and facilitate apoptosis in human glioblastoma cells. Int J Cancer 127: 1240-1248.
    78. Savorani C, Manfe V, Biskup E, Gniadecki R (2015) Ellipticine induces apoptosis in T-cell lymphoma via oxidative DNA damage. Leuk Lymphoma 56: 739-747.
    79. Kuo YC, Kuo PL, Hsu YL, Cho CY, Lin CC (2006) Ellipticine induces apoptosis through p53-dependent pathway in human hepatocellular carcinoma HepG2 cells. Life Sci 78: 2550-2557.
    80. Russell EG, O'Sullivan EC, Miller CM, Stanicka J, McCarthy FO, et al. (2014) Ellipticine derivative induces potent cytostatic effect in acute myeloid leukaemia cells. Invest New Drugs 32: 1113-1122.
    81. Xu GW, Mawji IA, Macrae CJ, Koch CA, Datti A, et al. (2008) A high-content chemical screen identifies ellipticine as a modulator of p53 nuclear localization. Apoptosis 13: 413-422.
    82. Crowell JA, Steele VE (2003) AKT and the phosphatidylinositol 3-kinase/AKT pathway: important molecular targets for lung cancer prevention and treatment.
    81
    J Natl Cancer Inst 95: 252-253.
    83. Kim MS, Blake M, Baek JH, Kohlhagen G, Pommier Y, et al. (2003) Inhibition of histone deacetylase increases cytotoxicity to anticancer drugs targeting DNA. Cancer Res 63: 7291-7300.
    84. Maddika S, Bay GH, Kroczak TJ, Ande SR, Maddika S, et al. (2007) Akt is transferred to the nucleus of cells treated with apoptin, and it participates in apoptin-induced cell death. Cell Prolif 40: 835-848.
    85. VanderWeele DJ, Zhou R, Rudin CM (2004) Akt up-regulation increases resistance to microtubule-directed chemotherapeutic agents through mammalian target of rapamycin. Mol Cancer Ther 3: 1605-1613.
    86. Cerella C, Grandjenette C, Dicato M, Diederich M (2015) Roles of Apoptosis and Cellular Senescence in Cancer and Aging. Curr Drug Targets.
    87. Djuric Z, Everett CK, Valeriote FA (1992) DNA damage and cytotoxicity in L1210 cells by ellipticine and a structural analogue, N-2-(diethylaminoethyl)-9-hydroxyellipticinium chloride. Cancer Res 52: 1515-1519.
    88. Kingma PS, Osheroff N (1997) Spontaneous DNA damage stimulates topoisomerase II-mediated DNA cleavage. J Biol Chem 272: 7488-7493.
    89. Santi SA, Lee H (2010) The Akt isoforms are present at distinct subcellular locations. Am J Physiol Cell Physiol 298: C580-591.
    90. Feng J, Tamaskovic R, Yang Z, Brazil DP, Merlo A, et al. (2004) Stabilization of Mdm2 via decreased ubiquitination is mediated by protein kinase B/Akt-dependent phosphorylation. J Biol Chem 279: 35510-35517.
    91. Andjelkovic M, Alessi DR, Meier R, Fernandez A, Lamb NJ, et al. (1997) Role of translocation in the activation and function of protein kinase B. J Biol Chem 272: 31515-31524.
    92. Gottlieb TM, Leal JF, Seger R, Taya Y, Oren M (2002) Cross-talk between Akt, p53 and Mdm2: possible implications for the regulation of apoptosis. Oncogene 21: 1299-1303.
    93. Ogawara Y, Kishishita S, Obata T, Isazawa Y, Suzuki T, et al. (2002) Akt enhances Mdm2-mediated ubiquitination and degradation of p53. J Biol Chem 277: 21843-21850.
    94. Chen KC, Yang TY, Wu CC, Cheng CC, Hsu SL, et al. (2014) Pemetrexed induces S-phase arrest and apoptosis via a deregulated activation of Akt signaling pathway. PLoS One 9: e97888.
    95. Brognard J, Clark AS, Ni Y, Dennis PA (2001) Akt/protein kinase B is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation. Cancer Res 61:
    82
    3986-3997.
    96. Moll UM, Petrenko O (2003) The MDM2-p53 interaction. Mol Cancer Res 1: 1001-1008.
    97. Fujiwara K, Iwado E, Mills GB, Sawaya R, Kondo S, et al. (2007) Akt inhibitor shows anticancer and radiosensitizing effects in malignant glioma cells by inducing autophagy. Int J Oncol 31: 753-760.
    98. Takeuchi H, Kondo Y, Fujiwara K, Kanzawa T, Aoki H, et al. (2005) Synergistic augmentation of rapamycin-induced autophagy in malignant glioma cells by phosphatidylinositol 3-kinase/protein kinase B inhibitors. Cancer Res 65: 3336-3346.
    99. Mohapatra P, Preet R, Das D, Satapathy SR, Choudhuri T, et al. (2012) Quinacrine-mediated autophagy and apoptosis in colon cancer cells is through a p53- and p21-dependent mechanism. Oncol Res 20: 81-91.
    100. Polewska J, Skwarska A, Augustin E, Konopa J (2013) DNA-damaging imidazoacridinone C-1311 induces autophagy followed by irreversible growth arrest and senescence in human lung cancer cells. J Pharmacol Exp Ther 346: 393-405.
    101. Seglen PO, Gordon PB (1982) 3-Methyladenine: specific inhibitor of autophagic/lysosomal protein degradation in isolated rat hepatocytes. Proc Natl Acad Sci U S A 79: 1889-1892.
    102. Sourbier C, Lindner V, Lang H, Agouni A, Schordan E, et al. (2006) The phosphoinositide 3-kinase/Akt pathway: a new target in human renal cell carcinoma therapy. Cancer Res 66: 5130-5142.
    103. Welker ME, Kulik G (2013) Recent syntheses of PI3K/Akt/mTOR signaling pathway inhibitors. Bioorg Med Chem 21: 4063-4091.

    下載圖示
    QR CODE