研究生: |
劉俊彥 Liu, Chun-Yen |
---|---|
論文名稱: |
透過活化p53引起人類非小細胞肺癌與肝癌細胞凋亡的吲哚喹嚀基藥物與其作用機制的探討 Study of a novel indolylquinoline compound that induces apoptosis in human non-small cell lung cancer and hepatocellular carcinoma cells through p53 activation |
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: | 2016 |
畢業學年度: | 104 |
語文別: | 英文 |
論文頁數: | 121 |
中文關鍵詞: | 肺癌 、p53 、EMMQ 、細胞凋亡 、肝癌 |
DOI URL: | https://doi.org/10.6345/NTNU202203664 |
論文種類: | 學術論文 |
相關次數: | 點閱:115 下載:6 |
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肺癌是全世界癌症中死亡率第一的癌症。非小型細胞肺癌(NSCLC)佔肺癌病患的比例約75%至80%。化療所造成的副作用與抗藥性在肺癌治療中是有待處理的棘手問題。因此發展出新的抗癌藥物對肺癌的病患是有必要的。此篇論文旨在篩選可抑制肺癌細胞生長新穎的合成化合物。透過MTT的分析方式鑑定EMMQ對非小型肺癌細胞的IC50的濃度。數據顯示低濃度的EMMQ即可減少A549和H460此兩種非小型肺癌細胞的生長速率。研究也證明,EMMQ可誘導具有正常p53基因的非小細胞肺癌的細胞凋亡,而且該藥物對p53-null的非小細胞肺癌則無明顯的效果。研究顯示EMMQ會誘導細胞DNA損傷,活化p53蛋白,干擾粒線體的膜電位而釋放細胞色素c,造成Bcl-2的下降,活化caspase-3, 讓PARP裂解而造成的內生性細胞凋亡。活體的實驗證明,EMMQ可以抑制裸鼠異種移植腫瘤的生長。最後,此研究證實EMMQ可在低濃度時活化非小細胞肺癌細胞的p53而造成細胞凋亡。此外,本研究還發現EMMQ可抑制具有正常 p53基因之非小細胞肺癌細胞的細胞轉移。因此本論文的數據顯示EMMQ可能成為一種新穎且有潛力的人類肺癌治療藥物。
肝癌是世界排名第五大常見的癌症。臨床顯示治療這些肝癌腫瘤中的重要的限制是治療過程中化療藥物長久投藥後的失效且肝癌對這些藥物產生抗藥性的問題。因此,開發肝癌治療中所產生化療失效與抗藥性的抗癌藥物是迫切需要的。之前我們已經確認EMMQ於肺癌細胞與活體的模式中是有效治療的效果。在此研究中證明EMMQ可抑制肝癌細胞的細胞生長進而誘導細胞凋亡。 EMMQ誘導的細胞凋亡為wild type p53的肝細胞癌(HCC)細胞,但是對mutant p53和p53-null細胞不敏感。數據顯示此化合物以內源性的途徑方式誘導細胞死亡。研究證明了EMMQ通過兩個主要途徑誘導細胞凋亡。此化合物使HepG2細胞的DNA損傷進而活化p53和γ-H2AX,降低cyclin D1和CDK 2的表現,導致細胞週期於G1期停滯。其次,此化合物使腫瘤抑制基因p53活化,干擾粒線體膜電位,使得ROS產生,Akt與 Bcl-2表現降低,Bax和細胞色素c的釋放,讓caspase-3和PARP裂解。細胞實驗的結果證明,在肝癌的治療上,EMMQ是一個有潛力的抗癌藥物。
Lung cancer is the leading cause of cancer mortality worldwide. NSCLC accounts for about 75% to 80% of lung cancer cases. Chemotherapy adverse side effects and resistance to current anticancer agents have been the pressing problems in the success of lung cancer therapy. Anticancer drugs are in urgent need especially for lung cancer. A program to develop a new anti-lung cancer agent by screening novel synthetic compounds was initiated.
EMMQ was selected by MTT cell viability assay. The cell growth rate of A549 and H460 NSCLC cells was reduced by a low concentration of EMMQ treatment. Our study revealed that EMMQ induced apoptosis in NSCLC cells with wild-type p53, while the drug is less potent to against p53-null cells. The study elucidated that EMMQ-induced apoptosis is was mediated through the intrinsic pathway involving DNA damage, activation of p53, interference of mitochondrial ΔΨm that led to release of cytochrome c and down regulation Bcl-2, activation of caspase family proteins, and finally cleavage of PARP polymerase cleavage.
In vivo study showed that EMMQ reduced tumorigenesis and significantly suppressed growth rate of xenograft tumors in nude mice. In addition, metastasis studies demonstrated that EMMQ may inhibit wild-type p53 cells migration at low concentration. In conclusion, EMMQ was demonstrated as an effective p53 regulator in NSCLC cells. Our findings indicate that EMMQ may serve as a promising new and potential therapeutic agent for human lung cancer.
Human liver cancer is the fifth most frequently diagnosed cancer worldwide. The important limitation in the clinical battle against this tumor is its marked intrinsic and acquired refractivity to the available chemotherapies. Anticancer agents effective against chemo-resistant cells are greatly needed for liver cancer treatment. Previously, our study have identified EMMQ as an effective drug in the treatment of lung cancer cells in vitro and in animal models. In this work, results show EMMQ treatment may inhibit cell growth and induce apoptosis in HCC. EMMQ induced apoptosis in HCC cells with wild-typed p53, and is less potent in cells with mutant p53 and in p53-null. The study also demonstrated that EMMQ induces apoptosis through two major pathways. First, the compound induced cell death through the intrinsic pathway by first damaging DNA increasing expression of p53 and γ-H2AX and decreasing cyclin D1 and CDK 2, finally leading to G1 arrest in HepG2 cells as studied cell cycle. Second, the tumor suppressor gene p53 was activated following a reduction of ΔΨm, ROS generation and down-regulating Akt, Bcl-2, Bax, cytochrome c, caspase-3 and cleavage of PARP, the critical events leading to cell death in HepG2 cells treated with EMMQ. The in vitro findings indicate that EMMQ is a promising candidate for the treatment of liver cancer.
1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics. CA Cancer J Clin 2011, 61:69-90.
2. Hamid MS, Shameem R, Gafoor K, George J, Mina B, Sullivan K: Non-Small-Cell Lung Cancer Clinicopathologic Features and Survival Outcomes in Asian Pacific Islanders Residing in the United States: A SEER Analysis. J Cancer Epidemiol 2015, 2015:269304.
3. Raz DJ, Gomez SL, Chang ET, Kim JY, Keegan TH, Pham J, Kukreja J, Hiatt RA, Jablons DM: Epidemiology of non-small cell lung cancer in Asian Americans: incidence patterns among six subgroups by nativity. J Thorac Oncol 2008, 3:1391-1397.
4. Siegel R, Ward E, Brawley O, Jemal A: Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 2011, 61:212-236.
5. Cheng I, Le GM, Noone AM, Gali K, Patel M, Haile RW, Wakelee HA, Gomez SL: Lung cancer incidence trends by histology type among Asian American, Native Hawaiian, and Pacific Islander populations in the United States, 1990-2010. Cancer Epidemiol Biomarkers Prev 2014, 23:2250-2265.
6. Alberg AJ, Brock MV, Samet JM: Epidemiology of lung cancer: looking to the future. J Clin Oncol 2005, 23:3175-3185.
7. Pathak AK, Bhutani M, Mohan A, Guleria R, Bal S, Kochupillai V: Non small cell lung cancer (NSCLC): current status and future prospects. Indian J Chest Dis Allied Sci 2004, 46:191-203.
8. Dela Cruz CS, Tanoue LT, Matthay RA: Lung cancer: epidemiology, etiology, and prevention. Clin Chest Med 2011, 32:605-644.
9. Ganti AK, West WW, Lackner RP, Kessinger A: Current concepts in the diagnosis and management of small-cell lung cancer. Oncology (Williston Park) 2010, 24:1034-1039.
10. Alberg AJ, Samet JM: Epidemiology of lung cancer. Chest 2003, 123:21S-49S.
11. Degterev A, Yuan J: Expansion and evolution of cell death programmes. Nat Rev Mol Cell Biol 2008, 9:378-390.
12. Elmore S: Apoptosis: a review of programmed cell death. Toxicol Pathol 2007, 35:495-516.
13. Elmore S: Apoptosis: A Review of Programmed Cell Death. Toxicologic pathology 2007, 35:495-516.
14. Pietenpol JA, Stewart ZA: Cell cycle checkpoint signaling: cell cycle arrest versus apoptosis. Toxicology 2002, 181-182:475-481.
15. Thompson CB: Apoptosis in the pathogenesis and treatment of disease. Science 1995, 267:1456-1462.
16. Wong RS: Apoptosis in cancer: from pathogenesis to treatment. J Exp Clin Cancer Res 2011, 30:87.
17. Levine AJ: The p53 tumor suppressor gene and gene product. Princess Takamatsu Symp 1989, 20:221-230.
18. Baker SJ, Fearon ER, Nigro JM, Hamilton SR, Preisinger AC, Jessup JM, vanTuinen P, Ledbetter DH, Barker DF, Nakamura Y, et al: Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science 1989, 244:217-221.
19. Linke SP, Clarkin KC, Di Leonardo A, Tsou A, Wahl GM: A reversible, p53-dependent G0/G1 cell cycle arrest induced by ribonucleotide depletion in the absence of detectable DNA damage. Genes Dev 1996, 10:934-947.
20. Taylor WR, Stark GR: Regulation of the G2/M transition by p53. Oncogene 2001, 20:1803-1815.
21. Concin N, Stimpfl M, Zeillinger C, Wolff U, Hefler L, Sedlak J, Leodolter S, Zeillinger R: Role of p53 in G2/M cell cycle arrest and apoptosis in response to gamma-irradiation in ovarian carcinoma cell lines. Int J Oncol 2003, 22:51-57.
22. Liu L, Bernard D, Wang S: Case Study: discovery of inhibitors of the MDM2-p53 protein-protein interaction. Methods Mol Biol 2015, 1278:567-585.
23. Moll UM, Petrenko O: The MDM2-p53 interaction. Mol Cancer Res 2003, 1:1001-1008.
24. Burns PA, Kemp CJ, Gannon JV, Lane DP, Bremner R, Balmain A: Loss of heterozygosity and mutational alterations of the p53 gene in skin tumours of interspecific hybrid mice. Oncogene 1991, 6:2363-2369.
25. Fischer M, Steiner L, Engeland K: The transcription factor p53: not a repressor, solely an activator. Cell Cycle 2014, 13:3037-3058.
26. Soussi T, Beroud C: Significance of TP53 mutations in human cancer: a critical analysis of mutations at CpG dinucleotides. Hum Mutat 2003, 21:192-200.
27. Rand A, Glenn KS, Alvares CP, White MB, Thibodeau SM, Karnes WE, Jr.: p53 functional loss in a colon cancer cell line with two missense mutations (218leu and 248trp) on separate alleles. Cancer Lett 1996, 98:183-191.
28. Innocente SA, Abrahamson JL, Cogswell JP, Lee JM: p53 regulates a G2 checkpoint through cyclin B1. Proc Natl Acad Sci U S A 1999, 96:2147-2152.
29. Lakin ND, Jackson SP: Regulation of p53 in response to DNA damage. Oncogene 1999, 18:7644-7655.
30. Touboul E, Lagrange JL, Theobald S, Astoul P, Baldeyrou P, Bardet E, Bazelly B, Brechot J, Breton JL, Douillard JY, et al: [Standards, Options and Recommendations for the management of stage I or II primary bronchial cancers treated exclusively with radiotherapy]. Cancer Radiother 2001, 5:452-463.
31. Maione P, Rossi A, Sacco PC, Bareschino MA, Schettino C, Gridelli C: Advances in chemotherapy in advanced non-small-cell lung cancer. Expert Opin Pharmacother 2010, 11:2997-3007.
32. Adamo V, Franchina T, Adamo B, Denaro N, Gambadauro P, Chiofalo G, Scimone A, Caristi N, Russo A, Giordano A: Gefitinib in lung cancer therapy: clinical results, predictive markers of response and future perspectives. Cancer Biol Ther 2009, 8:206-212.
33. Souquet PJ, Geriniere L: [Combinations of platinum salts and gemcitabine in the treatment of non-small-cell lung cancer]. Bull Cancer 2002, 89 Spec No:S80-84.
34. Wright CM, van der Merwe M, DeBrot AH, Bjornsti MA: DNA topoisomerase I domain interactions impact enzyme activity and sensitivity to camptothecin. J Biol Chem 2015, 290:12068-12078.
35. Toffalorio F, Giovannetti E, De Pas T, Radice D, Pelosi G, Manzotti M, Minocci D, Spaggiari L, Spitaleri G, Noberasco C, et al: Expression of gemcitabine- and cisplatin-related genes in non-small-cell lung cancer. Pharmacogenomics J 2010, 10:180-190.
36. Li W, Zhang M, Xu L, Lin D, Cai S, Zou F: The apoptosis of non-small cell lung cancer induced by cisplatin through modulation of STIM1. Exp Toxicol Pathol 2013, 65:1073-1081.
37. Dhanikula AB, Panchagnula R: Localized paclitaxel delivery. Int J Pharm 1999, 183:85-100.
38. Rose WC: Taxol: a review of its preclinical in vivo antitumor activity. Anticancer Drugs 1992, 3:311-321.
39. Orr GA, Verdier-Pinard P, McDaid H, Horwitz SB: Mechanisms of Taxol resistance related to microtubules. Oncogene 2003, 22:7280-7295.
40. Boyle DA, Goldspiel BR: A review of paclitaxel (Taxol) administration, stability, and compatibility issues. Clin J Oncol Nurs 1998, 2:141-145.
41. Das GC, Holiday D, Gallardo R, Haas C: Taxol-induced cell cycle arrest and apoptosis: dose-response relationship in lung cancer cells of different wild-type p53 status and under isogenic condition. Cancer Lett 2001, 165:147-153.
42. Croft SL, Sundar S, Fairlamb AH: Drug resistance in leishmaniasis. Clin Microbiol Rev 2006, 19:111-126.
43. Neves LO, Talhari AC, Gadelha EP, Silva Junior RM, Guerra JA, Ferreira LC, Talhari S: A randomized clinical trial comparing meglumine antimoniate, pentamidine and amphotericin B for the treatment of cutaneous leishmaniasis by Leishmania guyanensis. An Bras Dermatol 2011, 86:1092-1101.
44. Ramesh C, Kavala V, Raju BR, Kuo C-W, Yao C-F: Novel synthesis of indolylquinoline derivatives via the C-alkylation of Baylis–Hillman adducts. Tetrahedron Letters 2009, 50:4037-4041.
45. Wang JP, Lin KH, Liu CY, Yu YC, Wu PT, Chiu CC, Su CL, Chen KM, Fang K: Teroxirone inhibited growth of human non-small cell lung cancer cells by activating p53. Toxicol Appl Pharmacol 2013, 273:110-120.
46. Agarwal C, Singh RP, Agarwal R: Grape seed extract induces apoptotic death of human prostate carcinoma DU145 cells via caspases activation accompanied by dissipation of mitochondrial membrane potential and cytochrome c release. Carcinogenesis 2002, 23:1869-1876.
47. Chipuk JE, Green DR: How do BCL-2 proteins induce mitochondrial outer membrane permeabilization? Trends Cell Biol 2008, 18:157-164.
48. Desagher S, Martinou JC: Mitochondria as the central control point of apoptosis. Trends Cell Biol 2000, 10:369-377.
49. Petty TJ, Emamzadah S, Costantino L, Petkova I, Stavridi ES, Saven JG, Vauthey E, Halazonetis TD: An induced fit mechanism regulates p53 DNA binding kinetics to confer sequence specificity. EMBO J 2011, 30:2167-2176.
50. Xue G, Hemmings BA: PKB/Akt-dependent regulation of cell motility. J Natl Cancer Inst 2013, 105:393-404.
51. Fotheringham JA, Coalson NE, Raab-Traub N: Epstein-Barr virus latent membrane protein-2A induces ITAM/Syk- and Akt-dependent epithelial migration through alphav-integrin membrane translocation. J Virol 2012, 86:10308-10320.
52. Irie HY, Pearline RV, Grueneberg D, Hsia M, Ravichandran P, Kothari N, Natesan S, Brugge JS: Distinct roles of Akt1 and Akt2 in regulating cell migration and epithelial-mesenchymal transition. J Cell Biol 2005, 171:1023-1034.
53. Amini-Nik S, Cambridge E, Yu W, Guo A, Whetstone H, Nadesan P, Poon R, Hinz B, Alman BA: beta-Catenin-regulated myeloid cell adhesion and migration determine wound healing. J Clin Invest 2014, 124:2599-2610.
54. Liang CC, Park AY, Guan JL: In vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitro. Nat Protoc 2007, 2:329-333.
55. Ardizzoni A, Boni L, Tiseo M, Fossella FV, Schiller JH, Paesmans M, Radosavljevic D, Paccagnella A, Zatloukal P, Mazzanti P, et al: Cisplatin- versus carboplatin-based chemotherapy in first-line treatment of advanced non-small-cell lung cancer: an individual patient data meta-analysis. J Natl Cancer Inst 2007, 99:847-857.
56. Tardito S, Isella C, Medico E, Marchio L, Bevilacqua E, Hatzoglou M, Bussolati O, Franchi-Gazzola R: The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem 2009, 284:24306-24319.
57. Shi A, Nguyen TA, Battina SK, Rana S, Takemoto DJ, Chiang PK, Hua DH: Synthesis and anti-breast cancer activities of substituted quinolines. Bioorg Med Chem Lett 2008, 18:3364-3368.
58. Sedic M, Poznic M, Gehrig P, Scott M, Schlapbach R, Hranjec M, Karminski-Zamola G, Pavelic K, Kraljevic Pavelic S: Differential antiproliferative mechanisms of novel derivative of benzimidazo[1,2-alpha]quinoline in colon cancer cells depending on their p53 status. Mol Cancer Ther 2008, 7:2121-2132.
59. Ding Y, Nguyen TA: PQ1, a quinoline derivative, induces apoptosis in T47D breast cancer cells through activation of caspase-8 and caspase-9. Apoptosis 2013, 18:1071-1082.
60. Bernzweig J, Heiniger B, Prasain K, Lu J, Hua DH, Nguyen TA: Anti-breast cancer agents, quinolines, targeting gap junction. Med Chem 2011, 7:448-453.
61. Khan N, Mukhtar H: Dietary agents for prevention and treatment of lung cancer. Cancer Lett 2015, 359:155-164.
62. Nakamura Y, Yogosawa S, Izutani Y, Watanabe H, Otsuji E, Sakai T: A combination of indol-3-carbinol and genistein synergistically induces apoptosis in human colon cancer HT-29 cells by inhibiting Akt phosphorylation and progression of autophagy. Mol Cancer 2009, 8:100.
63. Cetintas VB, Kucukaslan AS, Kosova B, Tetik A, Selvi N, Cok G, Gunduz C, Eroglu Z: Cisplatin resistance induced by decreased apoptotic activity in non-small-cell lung cancer cell lines. Cell Biol Int 2012, 36:261-265.
64. Li QQ, Wang G, Huang F, Li JM, Cuff CF, Reed E: Sensitization of lung cancer cells to cisplatin by beta-elemene is mediated through blockade of cell cycle progression: antitumor efficacies of beta-elemene and its synthetic analogs. Med Oncol 2013, 30:488.
65. Lindahl T, Modrich P, Sancar A: The 2015 Nobel Prize in Chemistry The Discovery of Essential Mechanisms that Repair DNA Damage. J Assoc Genet Technol 2016, 42:37-41.
66. Chang CW, Chen CR, Huang CY, Shu WY, Chiang CS, Hong JH, Hsu IC: Comparative transcriptome profiling of an SV40-transformed human fibroblast (MRC5CVI) and its untransformed counterpart (MRC-5) in response to UVB irradiation. PLoS One 2013, 8:e73311.
67. Chipuk JE, Kuwana T, Bouchier-Hayes L, Droin NM, Newmeyer DD, Schuler M, Green DR: Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science 2004, 303:1010-1014.
68. Mihara M, Erster S, Zaika A, Petrenko O, Chittenden T, Pancoska P, Moll UM: p53 has a direct apoptogenic role at the mitochondria. Mol Cell 2003, 11:577-590.
69. Moll UM, Wolff S, Speidel D, Deppert W: Transcription-independent pro-apoptotic functions of p53. Curr Opin Cell Biol 2005, 17:631-636.
70. Finucane DM, Bossy-Wetzel E, Waterhouse NJ, Cotter TG, Green DR: Bax-induced caspase activation and apoptosis via cytochrome c release from mitochondria is inhibitable by Bcl-xL. J Biol Chem 1999, 274:2225-2233.
71. Hermanson D, Addo SN, Bajer AA, Marchant JS, Das SG, Srinivasan B, Al-Mousa F, Michelangeli F, Thomas DD, Lebien TW, Xing C: Dual mechanisms of sHA 14-1 in inducing cell death through endoplasmic reticulum and mitochondria. Mol Pharmacol 2009, 76:667-678.
72. Chan G, Kamarudin MN, Wong DZ, Ismail NH, Abdul Latif F, Hasan A, Awang K, Abdul Kadir H: Mitigation of H(2)O(2)-Induced Mitochondrial-Mediated Apoptosis in NG108-15 Cells by Novel Mesuagenin C from Mesua kunstleri (King) Kosterm. Evid Based Complement Alternat Med 2012, 2012:156521.
73. Shi M, Yan SG, Xie ST, Wang HN: Tip30-induced apoptosis requires translocation of Bax and involves mitochondrial release of cytochrome c and Smac/DIABLO in hepatocellular carcinoma cells. Biochim Biophys Acta 2008, 1783:263-274.
74. Malki A, El Ashry el S: In vitro and in vivo efficacy of a novel quinuclidinone derivative against breast cancer. Anticancer Res 2014, 34:1367-1376.
75. Vivanco I, Sawyers CL: The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2002, 2:489-501.
76. Sonderegger S, Haslinger P, Sabri A, Leisser C, Otten JV, Fiala C, Knofler M: Wingless (Wnt)-3A induces trophoblast migration and matrix metalloproteinase-2 secretion through canonical Wnt signaling and protein kinase B/AKT activation. Endocrinology 2010, 151:211-220.
77. Chandrasekar N, Mohanam S, Gujrati M, Olivero WC, Dinh DH, Rao JS: Downregulation of uPA inhibits migration and PI3k/Akt signaling in glioblastoma cells. Oncogene 2003, 22:392-400.
78. Ye M, Hu D, Tu L, Zhou X, Lu F, Wen B, Wu W, Lin Y, Zhou Z, Qu J: Involvement of PI3K/Akt signaling pathway in hepatocyte growth factor-induced migration of uveal melanoma cells. Invest Ophthalmol Vis Sci 2008, 49:497-504.
79. Thiery JP: Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2002, 2:442-454.
80. Nabeshima K, Inoue T, Shimao Y, Sameshima T: Matrix metalloproteinases in tumor invasion: role for cell migration. Pathol Int 2002, 52:255-264.
81. Elewa MA, Al-Gayyar MM, Schaalan MF, Abd El Galil KH, Ebrahim MA, El-Shishtawy MM: Hepatoprotective and anti-tumor effects of targeting MMP-9 in hepatocellular carcinoma and its relation to vascular invasion markers. Clin Exp Metastasis 2015, 32:479-493.
82. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F: Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015, 136:E359-386.
83. Kumar M, Zhao X, Wang XW: Molecular carcinogenesis of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: one step closer to personalized medicine? Cell Biosci 2011, 1:5.
84. Brown KS: Chemotherapy and other systemic therapies for hepatocellular carcinoma and liver metastases. Semin Intervent Radiol 2006, 23:99-108.
85. Cao H, Phan H, Yang LX: Improved chemotherapy for hepatocellular carcinoma. Anticancer Res 2012, 32:1379-1386.
86. Terazawa T, Kondo S, Hosoi H, Morizane C, Shimizu S, Mitsunaga S, Ikeda M, Ueno H, Okusaka T: Transarterial infusion chemotherapy with cisplatin plus S-1 for hepatocellular carcinoma treatment: a phase I trial. BMC Cancer 2014, 14:301.
87. Jiang L, Zhang Q, Ren H, Ma S, Lu C, Liu B, Liu J, Liang J, Li M, Zhu R: Dihydromyricetin Enhances the Chemo-Sensitivity of Nedaplatin via Regulation of the p53/Bcl-2 Pathway in Hepatocellular Carcinoma Cells. PLoS One 2015, 10:e0124994.
88. Sukowati CH, Rosso N, Croce LS, Tiribelli C: Hepatic cancer stem cells and drug resistance: Relevance in targeted therapies for hepatocellular carcinoma. World J Hepatol 2010, 2:114-126.
89. Lee WY, Cheung CC, Liu KW, Fung KP, Wong J, Lai PB, Yeung JH: Cytotoxic effects of tanshinones from Salvia miltiorrhiza on doxorubicin-resistant human liver cancer cells. J Nat Prod 2010, 73:854-859.
90. Zhang Y, Xue D, Wang X, Lu M, Gao B, Qiao X: Screening of kinase inhibitors targeting BRAF for regulating autophagy based on kinase pathways. Mol Med Rep 2014, 9:83-90.
91. Gauthier A, Ho M: The Role of Sorafenib in the Treatment of Advanced Hepatocellular Carcinoma: An Update. Hepatology research : the official journal of the Japan Society of Hepatology 2013, 43:147-154.
92. Los M, Roodhart JM, Voest EE: Target practice: lessons from phase III trials with bevacizumab and vatalanib in the treatment of advanced colorectal cancer. Oncologist 2007, 12:443-450.
93. Sliesoraitis S, Tawfik B: Bevacizumab-induced bowel perforation. J Am Osteopath Assoc 2011, 111:437-441.
94. Hartmann JT, Kanz L: Sunitinib and periodic hair depigmentation due to temporary c-KIT inhibition. Arch Dermatol 2008, 144:1525-1526.
95. Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, McArthur G, Judson IR, Heinrich MC, Morgan JA, et al: Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 2006, 368:1329-1338.
96. Banin S, Moyal L, Shieh S, Taya Y, Anderson CW, Chessa L, Smorodinsky NI, Prives C, Reiss Y, Shiloh Y, Ziv Y: Enhanced phosphorylation of p53 by ATM in response to DNA damage. Science 1998, 281:1674-1677.
97. Yuan J, Chen J: MRE11-RAD50-NBS1 complex dictates DNA repair independent of H2AX. J Biol Chem 2010, 285:1097-1104.
98. Hamer G, Roepers-Gajadien HL, van Duyn-Goedhart A, Gademan IS, Kal HB, van Buul PP, de Rooij DG: DNA double-strand breaks and gamma-H2AX signaling in the testis. Biol Reprod 2003, 68:628-634.
99. Di Leonardo A, Linke SP, Clarkin K, Wahl GM: DNA damage triggers a prolonged p53-dependent G1 arrest and long-term induction of Cip1 in normal human fibroblasts. Genes Dev 1994, 8:2540-2551.
100. Saha S, Bhattacharjee P, Mukherjee S, Mazumdar M, Chakraborty S, Khurana A, Nayak D, Manchanda R, Chakrabarty R, Das T, Sa G: Contribution of the ROS-p53 feedback loop in thuja-induced apoptosis of mammary epithelial carcinoma cells. Oncol Rep 2014, 31:1589-1598.
101. Macip S, Igarashi M, Berggren P, Yu J, Lee SW, Aaronson SA: Influence of induced reactive oxygen species in p53-mediated cell fate decisions. Mol Cell Biol 2003, 23:8576-8585.
102. Raha S, Robinson BH: Mitochondria, oxygen free radicals, disease and ageing. Trends Biochem Sci 2000, 25:502-508.
103. Ji H, Ding Z, Hawke D, Xing D, Jiang BH, Mills GB, Lu Z: AKT-dependent phosphorylation of Niban regulates nucleophosmin- and MDM2-mediated p53 stability and cell apoptosis. EMBO Rep 2012, 13:554-560.
104. Qian J, Zou Y, Rahman JS, Lu B, Massion PP: Synergy between phosphatidylinositol 3-kinase/Akt pathway and Bcl-xL in the control of apoptosis in adenocarcinoma cells of the lung. Mol Cancer Ther 2009, 8:101-109.