TRAIL与化疗联合应用诱导淋巴瘤Raji、Jurkat细胞凋亡的实验研究
摘要
肿瘤坏死因子相关的凋亡诱导配体( tumor necrosis factor-related apoptosis-inducing ligand,TRAIL)是肿瘤坏死因子超家族的新成员。TRAIL可诱导肿瘤细胞发生快速、高效的凋亡反应,而对正常细胞无明显毒性。除诱导实体瘤细胞凋亡外,目前研究还表明,TRAIL可诱导淋巴瘤、多发性骨髓瘤、白血病等细胞凋亡。然而体外试验也观察到血液系统恶性肿瘤对重组TRAIL产生耐药的现象,该问题的出现阻碍了TRAIL在临床上的进一步应用。TRAIL治疗淋巴瘤也面临着耐药的困扰。本实验以淋巴瘤细胞系Raji、Jurkat作为研究对象,应用化疗药物顺铂、pCMV-TRAIL表达载体、顺铂联合pCMV-TRAIL表达载体处理上述细胞,观察不同处理方法下细胞的生长状况,以MTT法测定细胞存活率,流式细胞仪及TUNEL染色分析细胞凋亡率,RT-PCR检测细胞周期相关蛋白mRNA表达的变化,免疫印迹法检测凋亡信号,探讨TRAIL联合化疗药物顺铂是否具有协同作用,并试图阐明TRAIL耐药及协同作用的可能机制,为淋巴瘤的治疗提供新的策略及理论依据。
研究结果显示pCMV-TRAIL表达载体及顺铂联合应用处理淋巴瘤细胞系Raji及Jurkat,其细胞存活率均明显低于单药处理组及对照组,而细胞凋亡率则明显高于单药处理组及对照组。RT-PCR检测凋亡相关蛋白cyclin E、CDK2、p27 mRNA表达的变化:DDP化疗组、pCMV-TRAIL重组质粒转染组和联合用药组cyclin E、CDK2表达均低于空质粒转染组和对照组;而p27表达则高于空质粒转染组和对照组。通过免疫印迹法检测survivin、caspase-3、NF-κB等凋亡信号,pCMV-TRAIL重组质粒转染组和联合用药组中caspase-3表达明显增高,而survivin及NF-κB表达则显著降低,且联合用药组NF-κB表达低于pCMV-TRAIL重组质粒转染组。因此,我们认为TRAIL与化疗药物顺铂治疗B、T细胞淋巴瘤具有协同作用,其机制可能与cyclin E、CDK2、p27等调控细胞周期因子以及Survivin、caspase-3、NF-κB等凋亡因子的改变有关。
The Non-Hodgkin lymphomas (NHLs) are a diverse group of hematologic cancers which encompass any lymphoma other than Hodgkin lymphoma.Lymphoma is a type of cancer derived from lymphocytes, a type of white blood cell. Many subtypes of non-Hodgkin lymphoma have been described. Non-Hodgkin lymphomas are treated traditionally by combinations of chemotherapy, immunotherapy and radiation, et al.However, the function of these treatment is limited as well as side effect.
Tumor necrosis factor-related apoptosis-inducing ligand(TRAIL) is a new member in the family of tumor necrosis factors. The death receptors belong to a subset of tumor necrosis factor receptor superfamily members and include Fas (CD95), tumor necrosis factor receptor (TNFR)-1, death receptor 3 (DR3/wsl-1), death receptor 4 (DR4, TRAIL-R1), and death receptor 5 (DR5, TRAIL-R2). The respective ligands bind to these receptors causing trimerization of the receptors and apoptosis. Two of these receptors, DR4 and DR5, have aroused considerable interest and research because of their potential for the treatment of the hematological malignancies. This is due to the observation that combination of TRAIL and DR4 or DR5 selectively can induce apoptosis in tumor cells. There are two major pathways for apoptosis, the mitochondrial or intrinsic apoptotic pathway and the death receptor or extrinsic apoptotic pathway. The intrinsic apoptotic pathway is typically initiated by DNA damage, which causes the upregulation of p53, an increase in the bax:bcl-2 ratio, and the release of cytochrome c from between the inner and outer mitochondrial membranes into the cytosol. Cytochrome c binds to and activates apoptosis-activating factor-1 (Apaf-1) in the cytosol in a process that requires deoxyadenosine triphosphate (dATP), and both caspase 9 and 3 are subsequently activated with the induction of apoptosis. The extrinsic apoptotic pathway is triggered by binding of the death receptor ligands to their cognate receptors. The death receptors for TRAIL, DR4 and DR5, contain cysteine rich repeats in the extracellular domain that bind to TRAIL causing receptor trimerization and subsequent apoptosis. Therefore, TRAIL is promising in treating the hematological malignancies including NHL. However, resistance to TRAIL in tumor cells have blocked its usage in clinical work. Studies have been done to value the combination of TRAIL with chemotheray and to explore the mechanism of TRAIL-resistance.
Cis-platinum complexes is a platinum-based chemotherapy drug used to treat various types of cancers, including sarcomas, some carcinomas (e.g. small cell lung cancer, and ovarian cancer), lymphomas and germ cell tumors. It was the first member of its class, which now also includes carboplatin and oxaliplatin. Platinum complexes are formed in cells, which bind and cause crosslinking of DNA; ultimately triggering apoptosis. Combination of cisplatinum with TRAIL have been proved to be useful to treat some tumors, such as cervical carcinoma, laryngocarcinoma, and so on. Given all the above, in order to investigate the synergistic molecular mechanism of Cisplatin enhancing the TRAIL-induced apoptosis of lymphoma Raji and Jurkat cell lines and provide a novel treatment model of the TRAIL in lymphoma, we design this study. The human lymphoma cell line Raji and Jurkat was treated with Cisplatin, TRAIL, respectively, or in combination. The cytotoxic effect and the rate of apoptosis were determined by MTT and flow cytometry,respectively; the expression of cyclin E(317bp)CDK2(546bp)and p27(237bp)mRNA was determined by reverse transcription-polymerase chain reaction (RT-PCR); and the expression of signal transduetion proteins,such as Caspase-3,NF-κB and Survivin Was detected by Western blot.We get the results that combination with subcytotoxic dose of Cisplatin could reverse the sensitivity of raji and jurkat cells to TRAIL-induced apoptosis,and could down·regulate the expression of cyclin E,CDK2 and survivin, NF-κB; up·regulate the expression of Caspase3 and p27.In conclusion, Cisplatin could sensitize raji and jurkat cells to TRAIL-induced apoptosis.
研究结果显示pCMV-TRAIL表达载体及顺铂联合应用处理淋巴瘤细胞系Raji及Jurkat,其细胞存活率均明显低于单药处理组及对照组,而细胞凋亡率则明显高于单药处理组及对照组。RT-PCR检测凋亡相关蛋白cyclin E、CDK2、p27 mRNA表达的变化:DDP化疗组、pCMV-TRAIL重组质粒转染组和联合用药组cyclin E、CDK2表达均低于空质粒转染组和对照组;而p27表达则高于空质粒转染组和对照组。通过免疫印迹法检测survivin、caspase-3、NF-κB等凋亡信号,pCMV-TRAIL重组质粒转染组和联合用药组中caspase-3表达明显增高,而survivin及NF-κB表达则显著降低,且联合用药组NF-κB表达低于pCMV-TRAIL重组质粒转染组。因此,我们认为TRAIL与化疗药物顺铂治疗B、T细胞淋巴瘤具有协同作用,其机制可能与cyclin E、CDK2、p27等调控细胞周期因子以及Survivin、caspase-3、NF-κB等凋亡因子的改变有关。
The Non-Hodgkin lymphomas (NHLs) are a diverse group of hematologic cancers which encompass any lymphoma other than Hodgkin lymphoma.Lymphoma is a type of cancer derived from lymphocytes, a type of white blood cell. Many subtypes of non-Hodgkin lymphoma have been described. Non-Hodgkin lymphomas are treated traditionally by combinations of chemotherapy, immunotherapy and radiation, et al.However, the function of these treatment is limited as well as side effect.
Tumor necrosis factor-related apoptosis-inducing ligand(TRAIL) is a new member in the family of tumor necrosis factors. The death receptors belong to a subset of tumor necrosis factor receptor superfamily members and include Fas (CD95), tumor necrosis factor receptor (TNFR)-1, death receptor 3 (DR3/wsl-1), death receptor 4 (DR4, TRAIL-R1), and death receptor 5 (DR5, TRAIL-R2). The respective ligands bind to these receptors causing trimerization of the receptors and apoptosis. Two of these receptors, DR4 and DR5, have aroused considerable interest and research because of their potential for the treatment of the hematological malignancies. This is due to the observation that combination of TRAIL and DR4 or DR5 selectively can induce apoptosis in tumor cells. There are two major pathways for apoptosis, the mitochondrial or intrinsic apoptotic pathway and the death receptor or extrinsic apoptotic pathway. The intrinsic apoptotic pathway is typically initiated by DNA damage, which causes the upregulation of p53, an increase in the bax:bcl-2 ratio, and the release of cytochrome c from between the inner and outer mitochondrial membranes into the cytosol. Cytochrome c binds to and activates apoptosis-activating factor-1 (Apaf-1) in the cytosol in a process that requires deoxyadenosine triphosphate (dATP), and both caspase 9 and 3 are subsequently activated with the induction of apoptosis. The extrinsic apoptotic pathway is triggered by binding of the death receptor ligands to their cognate receptors. The death receptors for TRAIL, DR4 and DR5, contain cysteine rich repeats in the extracellular domain that bind to TRAIL causing receptor trimerization and subsequent apoptosis. Therefore, TRAIL is promising in treating the hematological malignancies including NHL. However, resistance to TRAIL in tumor cells have blocked its usage in clinical work. Studies have been done to value the combination of TRAIL with chemotheray and to explore the mechanism of TRAIL-resistance.
Cis-platinum complexes is a platinum-based chemotherapy drug used to treat various types of cancers, including sarcomas, some carcinomas (e.g. small cell lung cancer, and ovarian cancer), lymphomas and germ cell tumors. It was the first member of its class, which now also includes carboplatin and oxaliplatin. Platinum complexes are formed in cells, which bind and cause crosslinking of DNA; ultimately triggering apoptosis. Combination of cisplatinum with TRAIL have been proved to be useful to treat some tumors, such as cervical carcinoma, laryngocarcinoma, and so on. Given all the above, in order to investigate the synergistic molecular mechanism of Cisplatin enhancing the TRAIL-induced apoptosis of lymphoma Raji and Jurkat cell lines and provide a novel treatment model of the TRAIL in lymphoma, we design this study. The human lymphoma cell line Raji and Jurkat was treated with Cisplatin, TRAIL, respectively, or in combination. The cytotoxic effect and the rate of apoptosis were determined by MTT and flow cytometry,respectively; the expression of cyclin E(317bp)CDK2(546bp)and p27(237bp)mRNA was determined by reverse transcription-polymerase chain reaction (RT-PCR); and the expression of signal transduetion proteins,such as Caspase-3,NF-κB and Survivin Was detected by Western blot.We get the results that combination with subcytotoxic dose of Cisplatin could reverse the sensitivity of raji and jurkat cells to TRAIL-induced apoptosis,and could down·regulate the expression of cyclin E,CDK2 and survivin, NF-κB; up·regulate the expression of Caspase3 and p27.In conclusion, Cisplatin could sensitize raji and jurkat cells to TRAIL-induced apoptosis.
引文
[1] Clarke CA and Glaser SL. Changing incidence of non-Hodgkin lymphomas in the United States. Cancer 2002; 94: 2015–2023.
[2] Secchiero P, Vaccarezza M, Gonelli A, Zauli G. TNF-related apoptosis-inducing ligand (TRAIL): a potential candidate forcombined treatment of hematological malignancies. CurrPharm Des 2004; 10: 3673– 3681.
[3] Wen J H ,Ramadevi N ,Ngugen D ,et al . Antileukemic Drugs Increase Deat h Receptor 5 Levels and EnhanceApo22L2In2 duced Apoptosis of Human Acute Leukemia Cells[J ] . Blood ,2000,96 (12) :3900 - 3 906.
[4] Liu Q, Hilsenbeck S, Gazitt Y. Arsenic trioxide-induced apoptosis in myeloma cells: p53-dependent G1 or G2/M cell cycle arrest, activation of caspase-8 or caspase-9, and synergy with APO2/TRAIL. Blood 2003; 101: 4078– 4087.
[5] Georgakis GV, Li Y, Humphreys R, Andreeff M, O’Brien S,Younes M, et al. Activity of selective fully human agonistic antibodies to the TRAIL death receptors TRAIL-R1 and TRAIL-R2 in primary and cultured lymphoma cells: induction of apoptosis and enhancement of doxorubicin- and bortezomib-induced cell death. Br J Haematol 2005; 130: 501– 510.
[6] Yee L, FanaleM, Dimick K, Calvert S, Robbins C, Ing J, et al. A phase 1B safety and pharmacokinetic (PK) study of recombinant human Apo2L/TRAIL in combination with rituximab in patients with low grade non-Hodgkin lymphoma. American Society of Clinical Oncology ASCO) 2007; Abstract 8078.
[7] Falschlehner C, Emmerich CH, Gerlach B, Walczak H.TRAIL signalling: decisions between life and death. Int J Biochem Cell Biol 2007;39:1462– 1475.
[8] Lee TJ, Jung EM, Lee JT, Kim S, Park JW, Choi KS, et al.Mithramycin A sensitizes cancer cells to TRAIL-mediated apoptosis by down-regulation of XIAP gene promoter through Sp1 sites. Mol Cancer Ther 2006;5:2737– 2746.
[9]王才智;凌斌;席玉玲等.TRAIL联合化疗药物对子宫内膜癌细胞增殖及凋亡的影响。现代妇产科进展,2008;11:817-819.
[10]黄涛;吕刚;李建华等.TRAIL与顺铂联用对人骨肉瘤细胞杀伤作用的实验研究。中国组织化学与细胞化学杂志,2005;2:191-195.
[11]余晓燕;陈鸿雁. TRAIL联合化疗药物诱导喉癌HEP-2细胞株凋亡的研究。重庆医科大学学报,2008;8:51-953.
[12] Wiley SR, Schooley PJ, Smolak WS, et al. Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity , 1995;3(6):673-682.
[13] Cha SS, Kim MS, Choi YH, et al. A resolution crystal structure of human TRAIL, a cytokine with selective antitumor activity. Immunity, 1999, 11(2):253-261.
[14] Bodmer JL, Meier P, Tschopp J, et al. Cysteine 230 is essential for the structure and activity of the cytotoxic ligand TRAIL. Biol Chem, 2000, 275(27):20632-20637.
[15] pierings DC, De Vries EG, Vellenga E, et al. Tissue distribution of the death ligand TRAIL and its receptors . Histochem Cytochem,2004, 52(6):821-831.
[16]范青林,宋礼华,魏伟. TRAIL的诱导肿瘤细胞凋亡与临床[J ].中国药理学通报,2003 ,19 (9) :976 - 981.
[17] Pan Q, Liu B, Liu J, Cai R, Wang Y, Qian C. Synergistic induction of tumor cell death by combining cisplatin with an oncolytic adenovirus carrying TRAIL. Mol Cell Biochem 2007;304:315-323.
[18] Ashkenazi A, Pai RC, Fong S, Leung S, Lawrence DA,Marsters SA, et al. Safety and antitumor activity of recombinant soluble Apo2 ligand. J Clin Invest 1999;104:155-162.
[19] Yoo J, Choi S, Hwang KS, et al. Adeno-associated virus-mediated gene transfer of a secreted form of TRAIL inhibits tumor growth and occurrence in an experimental tumor model. Gene Med,2006,8(2):163-174.
[20] Kim CY, Jeong M, Mushiake H, et al. Cancer gene therapy using a novel secretable trimeric TRAIL . Gene Ther,2006,13(4):330-338.
[21] Kimberley F C ,Screaton Q R. Following a TRAIL :Update on a Ligand and it sFive Receptors [ J ] . Cell Research , 2004 , 14(5) :359 - 372.
[22] Ashkenazi A, Dixit VM. Apoptosis control by death and decoy receptors. Curr Opin Cell Biol 1999;11:255– 260.
[23] Waiant H. TNF2Related Apoptosis Inducing Ligang ( TRAIL) and it s Receptors in Tumor Surveillance[J ] . Apoptosis ,2002 ,7(5) :449 - 459.
[24] Siegmund D,Mauri D,Peters N,et a1.Fas-associeated death domain protein(FADD)and caspase-8 mediate up-regulation of c-Fos by Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)via a FLICE inhibitory protein(FLIP)-regulated pathway.J Biol Chem.2001.276(35):32585-32590.
[25] Jia L,Pat wari Y.Kelsey SM, et at.TRAIl -induced apoptosis in type t leukemic cells is not enhanced by overexpression of bax.Biochem Biophys Res Comnmn,2001,283(5):1037-1045.
[26] Shetty S, Gladden JB, Henson ES, Hu X, Villanueva J,Haney N, et al. Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) up-regulates death receptor 5 (DR5) mediated by NFkB activation in epithelial derived cell lines.Apoptosis 2002;7:413– 420.
[27] Aggarwal BB, Bhardwaj U, Takada Y. Regulation of TRAIL induced apoptosis by ectopic expression of antiapoptotic factors. Vitam Horm 2004;67:453– 483.
[28] Baritaki S, Huerta-Yepez S, Sakai T, Spandidos DA,Bonavida B. Chemotherapeutic drugs sensitize cancer cells to TRAIL-mediated apoptosis: up-regulation of DR5 and inhibition of Yin Yang 1. Mol Cancer Ther 2007;6:1387–1399.
[29] Baritaki S, Huerta-Yepez S, Sakai T, Spandidos DA,Bonavida B. Chemotherapeutic drugs sensitize cancer cells to TRAIL-mediated apoptosis: up-regulation of DR5 and inhibition of Yin Yang 1. Mol Cancer Ther 2007;6:1387–1399.
[30] Abdollahi T,Robertson NM,Abdollahi A.et a1.Identification of interleukin 8 as an inhibitor of tumor necrosis factor-related apoptosis·inducingligand-induced apoptosis in the ovarian carcinoma cell line OVCAR3.Cancer Res, 2003.63(15):452l-4526.
[31] W ilson C, Wilson T , Johnston PG, Longley DB, Waugh DJ. Interleukin-8 signaling attenuates TRAIL- and chemotherapy-induced apoptosis through transcriptional regulation of c-FLIP in prostate cancer cells.Mol Cancer Ther. 2008; 7(9):2649-2661.
[32] Meng RD, El-Deiry WS. p53-independent upregulation of KILLER/DR5 TRAIL receptor expression by glucocorticoids and interferon-γ. Exp Cell Res 2001; 262:154– 169.
[33] Yang D, Wang S, Brooks C, Dong Z, Schoenlein PV, Kumar V, Ouyang X, Xiong H, Lahat G, Hayes-Jordan A, Lazar A, Pollock R, Lev D, Liu K. IFN regulatory factor 8 sensitizes soft tissue sarcoma cells to death receptor-initiated apoptosis via repression of FLICE-like protein expression. Cancer Res. 2009 1;69(3):1080-1088.
[34] Ashkenazi A, Pai RC, Fong S, et al. Safety and antitumor activity of recombinant soluble Apo2 ligand. Clin invest, 1999, 104(2):155-162.
[35] B ucur O,Ray S,Bucur MC,et al. APO2 ligand/tumor necrosis factor-related apoptosis-inducing ligand in prostate cancer therapy .Front Biosci, 2006, (11) :1549-1568 .
[36] M erchant MS,Yang X,Melchionda F,et al. Interferon gamma en-hancesthe effectiveness of tumor necrosis factor-related apoptosis-in-ducingligand receptor agonists in a xenograft models of Ewing‘s sarcoma .cancer res. 2004,64, 64 :8349-8356 .
[37] Georgakis GV, Li Y, Humphreys R, Andreeff M, O’Brien S,Younes M, et al. Activity of selective fully human agonistic antibodies to the TRAIL death receptors TRAIL-R1 and TRAIL-R2 in primary and cultured lymphoma cells: induction of apoptosis and enhancement of doxorubicin- and bortezomib-induced cell death. Br J Haematol 2005;130:501– 510.
[38] Cha SS, Sung BJ, Kim YA, et al. Crystal structure of TRAIL-DR5 complexidentifies a critical role of the unique frame insertion in conferring recognition specificity . Biol Chem, 2000, 275(40):31171-31177.
[39] Sikic BI, Wakelee HA, Mehren MV, Lewis N, Calvert AH,Plummer ER, et al. A phase 1b study to access the safety of lexatumumab, a human monoclonal antibody that activates TRAIL-R2 in combination with gemitabine, pemetrexed, doxorubicin, or FOLFIRI. American Society of Clinical Oncology (ASCO) 2007;Abstract 14006.
[40] Cytotoxicity and radiosensitization effect of TRA-8 on radioresistant human larynx squamous carcinoma cells.Wu F, Hu Y, Long J, Zhou YJ, Zhong YH, Liao ZK, Liu SQ, Zhou FX, Zhou YF, Xie CH.Oncol Rep. 2009;21(2):461-465.
[41] Daniel D, Yang B, Lawrence DA, Totpal K, Balter I, Lee WP, Gogineni A, Cole MJ, Yee SF, Ross S, Ashkenazi A. Cooperation of the proapoptotic receptor agonist hApo2L/TRAIL with the CD20 antibody rituximab against non-Hodgkin lymphoma xenografts. Blood. 2007 ;110(12):4037-4046.
[42] Nguyen T, Thomas W, Zhang XD, Gray C, Hersey P.Immunologically- mediated tumour cell apoptosis: the role of TRAIL in T cell and cytokine-mediated responses to melanoma. Forum (Genova) 2000; 10: 243- 252.
[43] Zauli G, Secchiero P. The role of the TRAIL/TRAIL receptors system in hematopoiesis and endothelial cell biology.Cytokine Growth Factor Rev 2006;17:245-257.
[44] Sedger LM, Glaccum MB, Schuh JC, Kanaly ST,Williamson E, Kayagaki N, et al. Characterization of the in vivo function of TNF-a-related apoptosis-inducing ligand,TRAIL/Apo2L, using TRAIL/Apo2L gene-deficient mice.Eur J Immunol 2002;32:2246-2254.
[45] Rubio-Moscardo F, Blesa D, Mestre C, Siebert R, Balasas T,Benito A, et al. Characterization of 8p21.3 chromosomal deletions in B-cell lymphoma: TRAIL-R1 and TRAIL-R2 as candidate dosage-dependent tumor suppressor genes. Blood 2005;106:3214-3222.
[46] Wolf S, Mertens D, Pscherer A, Schroeter P, Winkler D,Grone HJ, et al. Ala228 variant of trail receptor 1 affecting the ligand binding site is associated with chronic lymphocytic leukemia, mantle cell lymphoma, prostate cancer, head and neck squamous cell carcinoma and bladder cancer. Int J Cancer 2006;118:1831-1835.
[47] Zhang L, Fang B. Mechanisms of resistance to TRAILinduced apoptosis in cancer. Cancer Gene Ther 2005;12:228-237.
[48] Gomez-Benito M, Martinez-Lorenzo MJ, Anel A, Marzo I,Naval J. Membrane expression of DR4, DR5 and caspase-8 levels, but not Mcl-1, determine sensitivity of human myeloma cells to Apo2L/TRAIL. Exp Cell Res 2007;313:2378-2388.
[49] Secchiero P, Vaccarezza M, Gonelli A, Zauli G. TNF-related apoptosis-inducing ligand (TRAIL): a potential candidate for combined treatment of hematological malignancies. Curr Pharm Des 2004;10:3673-3681.
[50] Zhang L, Fang B. Mechanisms of resistance to TRAILinduced apoptosis in cancer. Cancer Gene Ther 2005;12:228-237.
[51] Falschlehner C, Emmerich CH, Gerlach B, Walczak H.TRAIL signalling: decisions between life and death. Int J Biochem Cell Biol 2007;39:1462-1475.
[52] Pedersen IM, Kitada S, Leoni LM, Zapata JM, Karras JG,Tsukada N, et al. Protection of CLL B cells by a follicular dendritic cell line is dependent on induction of Mcl-1. Blood 2002;100:1795-1801.
[53] Saxena A, Viswanathan S, Moshynska O, Tandon P,Sankaran K, Sheridan DP. Mcl-1 and Bcl-2/Bax ratio are associated with treatment response but not with Rai stage in Bcell chronic lymphocytic leukemia. Am J Hematol 2004; 75:22-33.
[54] J ohnston JB, Paul JT, Neufeld NJ, Haney N, Kropp DM, Hu X, et al. Role of myeloid cell factor-1 (Mcl-1) in chronic lymphocytic leukemia. Leuk Lymphoma 2004;45:2017-2027.
[55] G elinas C, White E. BH3-only proteins in control: specificity regulates MCL-1and BAK-mediated apoptosis. Genes Dev 2005;19:1263-1268.
[56] K aufmann SH, Steensma DP. On the TRAIL of a new therapyfor leukemia. Leukemia 2005;19:2195-2202.
[57] Yagita H, Takeda K, Hayakawa Y, Smyth MJ, Okumura K. TRAIL and its receptors as targets for cancer therapy. Cancer Sci 2004;95:777-783.
[58] Shrader M, Pino MS, Lashinger L, Bar-Eli M, Adam L,Dinney CP, et al. Gefitinib reverses TRAIL resistance in human bladder cancer cell lines via inhibition of AKTmediated X-linked inhibitor of apoptosis protein expression.Cancer Res 2007;67:1430-1435.
[59] Kelley SK, Ashkenazi A. Targeting death receptors in cancer with Apo2L/TRAIL. Curr Opin Pharmacol 2004;4:333-339.
[60] Wang S, El-Deiry WS. TRAIL and apoptosis induction by TNF-family death receptors. Oncogene 2003;22:8628-8633.
[61] Lee TJ, Jung EM, Lee JT, Kim S, Park JW, Choi KS, et al.Mithramycin A sensitizes cancer cells to TRAIL-mediated apoptosis by down-regulation of XIAP gene promoter through Sp1 sites. Mol Cancer Ther 2006; 5:2737-2746.
[62] Kim DM, Koo SY, Jeon K, Kim MH, Lee J, Hong CY, et al. Rapid induction of apoptosis by combination of flavopiridol and tumor necrosis factor (TNF)-a or TNF-related apoptosisinducing ligand in human cancer cell lines. Cancer Res 2003;63:621-626.
[63] A kay C, Gazitt Y. Arsenic trioxide selectively induces early and extensive apoptosis via the APO2/caspase-8 pathway engaging the mitochondrial pathway in myeloma cells with mutant p53. Cell Cycle 2003;2:358-368.
[64] L iu Q, Hilsenbeck S, Gazitt Y. Arsenic trioxide-induced apoptosis in myeloma cells: p53-dependent G1 or G2/M cell cycle arrest, activation of caspase-8 or caspase-9, and synergy with APO2/TRAIL. Blood 2003;101:4078-4087.
[65] Johnston JB, Kabore AF, Strutinsky J, Hu X, Paul JT,Kropp DM, et al. Role of the TRAIL/APO2-L death receptors in chlorambucil- and fludarabine-induced apoptosis in chronic lymphocytic leukemia. Oncogene 2003;22:8356-8369.
[66] MacFarlane M, Inoue S, Kohlhaas SL, Majid A, Harper N,Kennedy DB, et al. Chronic lymphocytic leukemic cells exhibit apoptotic signaling via TRAIL-R1. Cell Death Differ 2005; 12:773-782.
[67] Insinga A, Monestiroli S, Ronzoni S, Gelmetti V, Marchesi F,Viale A, et al. Inhibitors of histone deacetylases induce tumorselective apoptosis through activation of the death receptorpathway. Nat Med 2005;11:71-76.
[68] Sayers T J, Murphy W J. Combining proteasome inhibition with TNF-related apoptosis-inducing ligand (Apo2L/TRAIL) for cancer therapy. Cancer Immunol Immunother,2006, 55(1):76-84.
[69] Nencioni A, Wille L, Dal Bello G, et al. Cooperative cytotoxicity of proteasome inhibitors and tumor necrosis factor related apoptosis-inducing ligand in chemoresistant Bcl-2-overexpressing cells. Clin Cancer Res, 2005, 11(11): 4259-4265.
[70] Kabore AF, Sun J, Hu X, McCrea K, Johnston JB, Gibson S.The TRAIL apoptotic pathway mediates proteasome inhibitor induced apoptosis in primary chronic lymphocytic leukemia cells. Apoptosis, 2006;11:1175-1193.
[71] Balsas P, López-Royuela N, Galán-Malo P, Anel A, Marzo I, Naval J,Cooperation between Apo2L/TRAIL and bortezomib in multiple myeloma apoptosis.Biochem Pharmacol. 2009;77(5):804-812.
[72] Wendt J, Von Haefen C, Hemmati P, et al. TRAIL sensitizes for ionizing irradiation-induced apoptosis through an entirely Bax-dependent mitochondrial cell death pathway. Oncogene,2005,24(25):4052-4064.
[73] Shankar S , Singh TR , Srivastava RK, Ionizing radiation enhances the therapeutic potential of TRAIL in prostate cancer in vitro and in vivo: Intracellular mechanisms . Prostate , 2004, 61(1):35-49.
[74] Shankar S, Singh TR, Chen X, et al. The sequential treatment with ionizing radiation followed by TRAIL/Apo-2L reduces tumor growth and induces apoptosis of breast tumor xenografts in nude mice. Int J Oncol, 2004,24(5):1133-1140.
[75] Gong B, Almasan. A. Apo2 ligand/TNF-related apoptosis-inducing ligand and death receptor 5 mediate the apoptotic signaling induced by ionizing radiation in leukemic cells.Cancer Res. 2000 Oct 15;60(20):5754-5760.
[76] Wissink EH, Verbrugge I, Vink SR,et, al. TRAIL enhances efficacy of radiotherapy in a p53 mutant, Bcl-2 overexpressing lymphoid malignancy. Radiother Oncol. 2006 ,80(2):214-222.
[77] Unnithan J, Macklis RM. TRAIL induction by radiation in lymphoma patients. Cancer Invest. 2004;22(4):522-525.
[78] Georgakis GV, Li Y, Humphreys R, Andreeff M, O’Brien S,Younes M, et al. Activity of selective fully human agonistic antibodies to the TRAIL death receptors TRAIL-R1 and TRAIL-R2 in primary and cultured lymphoma cells: induction of apoptosis and enhancement of doxorubicin- and bortezomib- induced cell death. Br J Haematol 2005;130:501-510.
[79] Maddipatla S, Hernandez-Ilizaliturri FJ, Knight J,Czuczman MS. Augmented antitumor activity against B-cell lymphoma by a combination of monoclonal antibodies targeting TRAIL-R1 and CD20.Clin Cancer Res.2007;13(15pt1): 4556-4564.
[80] Nimmanapalli R, Porosnicu M, Nguyen D, Worthington E,O’Bryan E, Perkins C, et al. Cotreatment with STI-571enhances tumor necrosis factor a-related apoptosis-inducing ligand (TRAIL or apo-2L)-induced apoptosis of Bcr-Abl positive human acute leukemia cells. Clin Cancer Res 2001;7:350-357.
[81] Georgakis G V, Li Y, Rassidakis G Z, et al. Inhibition of heat shock protein 90 function by 17-allylamino-17-demethoxygeldanamycinin Hodgkin’s lymphoma cells down-regulates Akt kinase, dephosphorylates extracellular signal- regulated kinase, and induces cell cycle arrest and cell death. Clin Cancer Res, 2006, 12(2): 584-590.
[82] Ma Y L, Lakshmikanthan V, Lewis R W, et al. Sensitization of TRAIL- resistant cells by inhibition of heat shock protein 90 with low-dose geldanamycin. Mol Cancer Ther, 2006,5:170-178.
[83] Wu XX,Kakehi Y.Enhancement of lexatumumab-induced apoptosis in humansolid cancer cells by cisplatin in caspase-dependent manner.Clin Cancer Res.2009;15(6):2039-2047.
[84] Blagosklonny MV, Pardee AB. The restriction point of the cell cycle. Cell Cycle 2002;1:103-110.
[85] Nath N, Wang S, Betts V, Knudsen E, Chellappan S. Apoptotic and mitogenic stimuli inactivate Rb by differential utilization of p38 and cyclin-dependent kinases. Oncogene 2003;22:5986-5994.
[86] Bryja V, Pachernik J, Faldikova L, Krejci P, Pogue R, Nevriva I, Dvorak P, Hampl A. The role of p27(Kip1) in maintaining the levels of D-type cyclins in vivo. Biochim Biophys Acta 2004;1691:105-116.
[87] Favrot M, Coll JL, Louis N, Negoescu A. Cell death and cancer: Replacement of apoptotic genes and inactivation of death suppressor genes in therapy. Gene Ther 1998;5:728-739.
[88] Kim TY, Kim WI, Smith RE, Kay ED. Role of p27(Kip1) in cAMP- and TGF-beta2-mediated antiproliferation in rabbit corneal endothelial cells. Invest Ophthalmol Vis Sci 2001; 42:3142-3149.
[89] Shimizu T, Takahashi N, Tachibana K, Takeda K. Complex regulation of CDK2 and G1 arrest during neuronal differentiation of human prostatic cancer TSU-Prl cells by staurosporine. Anticancer Res 2001;21:893-898.
[90] e Koning JP, Soede-Bobok AA, Ward AC, Schelen AM, Antonissen C, van Leeuwen D, Lowenberg B, Touw IP. STAT3- mediated differentiation and survival and of myeloid cells in response to granulocyte colony-stimulating factor:role for the cyclin-dependent kinase inhibitor p27(Kip1). Oncogene 2000; 19:3290-3298.
[91] Alisi A, Leoni S, Piacentani A, Conti Devirgiliis L. Retinoic acid modulates the cell-cycle in fetal rat hepatocytes and HepG2 cells by regulating cyclin-cdk activities. Liver Int 2003; 23:179-186.
[92] Shetty S, Gladden JB, Henson ES, et al. Tumor necrosis factor-related apoptosis inducing ligand(TRAIL) up-regulateds death receptor 5(DR5) mediated by NFkappaB activation in epithelial derived cell lines.Apoptosis. 2002;7(5):413-420.
[93] Devereaux QL, Takahashi R, Salvesen GS, et al. X-linked IAP is a direct inhibitor of cell-death proteases. Nature 1997,388: 300-304.
[94] Altieri DC, Marchisio PC, Marchisio C. Survivin apoptosis: an interloper between cell death and cell proliferation in cancer. Lab Invest, 1999, 79(11):1327.
[95] Shankar SL, Mani S ,O′Guin KN, et al. survivin inhibition induces human neural tumor cell death through caspase-independent and dependent pathways[J].J Neurochem,2001,79(2):426-436.
[96] Jin Y, Wei Y, Xiong L, et al. Differential regulation of survivin by p53 contributes to cell cycle dependent apoptosis[J].Cell Res,2005,15(5):361-370.
[97] Mesri M, Wall NR, Li J, et al. Cancer gene therapy using a Survivin mutant adenovirus[J].J Clin Invest,2001,108(7):981-990.
[98] Bobayashi K,Hatano M,Otaki M,et al.Expression of a murine homologue of the inhibitor of apoptosis protein is related to cell proliferation[J].Proc Natl Acad Sci USA,1999,96(4):1457-1462.
[99]唐发清.Survivin研究进展[J].国外医学:生理、病理科学与临床分册.2001,21(2):87-88.
[100] Papapetropoulos A,Fulton D,Mahboubi K,et al.Angiopoietin-1 inhibits endothelial cell apoptosis via the Akt/Survivin pathway[J].J Biol Chem,2000, 275(13):9102-9105.
[101] O′Connor DS,Schechner JS,Adida C,et al.Control of apoptosis during angiogenesis by survivin express in endothelial cell[J].Am J Pathol,2000, 156(2):393-398.
[102]杨柳芹,房殿春.胃癌细胞NF-κB和Survivin的表达对TRAIL抗瘤作用的影响[J].第三军医大学学报,2004, 26(7):584-586.
[103] Lu M, Strohecker A, Chen F, et al. Aspirin sentitizes cancer cells to TRAIL-induced apoptosis by reducing surviving levels. Clin Cancer Res. 2008; 14(10):3168-3176.
[2] Secchiero P, Vaccarezza M, Gonelli A, Zauli G. TNF-related apoptosis-inducing ligand (TRAIL): a potential candidate forcombined treatment of hematological malignancies. CurrPharm Des 2004; 10: 3673– 3681.
[3] Wen J H ,Ramadevi N ,Ngugen D ,et al . Antileukemic Drugs Increase Deat h Receptor 5 Levels and EnhanceApo22L2In2 duced Apoptosis of Human Acute Leukemia Cells[J ] . Blood ,2000,96 (12) :3900 - 3 906.
[4] Liu Q, Hilsenbeck S, Gazitt Y. Arsenic trioxide-induced apoptosis in myeloma cells: p53-dependent G1 or G2/M cell cycle arrest, activation of caspase-8 or caspase-9, and synergy with APO2/TRAIL. Blood 2003; 101: 4078– 4087.
[5] Georgakis GV, Li Y, Humphreys R, Andreeff M, O’Brien S,Younes M, et al. Activity of selective fully human agonistic antibodies to the TRAIL death receptors TRAIL-R1 and TRAIL-R2 in primary and cultured lymphoma cells: induction of apoptosis and enhancement of doxorubicin- and bortezomib-induced cell death. Br J Haematol 2005; 130: 501– 510.
[6] Yee L, FanaleM, Dimick K, Calvert S, Robbins C, Ing J, et al. A phase 1B safety and pharmacokinetic (PK) study of recombinant human Apo2L/TRAIL in combination with rituximab in patients with low grade non-Hodgkin lymphoma. American Society of Clinical Oncology ASCO) 2007; Abstract 8078.
[7] Falschlehner C, Emmerich CH, Gerlach B, Walczak H.TRAIL signalling: decisions between life and death. Int J Biochem Cell Biol 2007;39:1462– 1475.
[8] Lee TJ, Jung EM, Lee JT, Kim S, Park JW, Choi KS, et al.Mithramycin A sensitizes cancer cells to TRAIL-mediated apoptosis by down-regulation of XIAP gene promoter through Sp1 sites. Mol Cancer Ther 2006;5:2737– 2746.
[9]王才智;凌斌;席玉玲等.TRAIL联合化疗药物对子宫内膜癌细胞增殖及凋亡的影响。现代妇产科进展,2008;11:817-819.
[10]黄涛;吕刚;李建华等.TRAIL与顺铂联用对人骨肉瘤细胞杀伤作用的实验研究。中国组织化学与细胞化学杂志,2005;2:191-195.
[11]余晓燕;陈鸿雁. TRAIL联合化疗药物诱导喉癌HEP-2细胞株凋亡的研究。重庆医科大学学报,2008;8:51-953.
[12] Wiley SR, Schooley PJ, Smolak WS, et al. Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity , 1995;3(6):673-682.
[13] Cha SS, Kim MS, Choi YH, et al. A resolution crystal structure of human TRAIL, a cytokine with selective antitumor activity. Immunity, 1999, 11(2):253-261.
[14] Bodmer JL, Meier P, Tschopp J, et al. Cysteine 230 is essential for the structure and activity of the cytotoxic ligand TRAIL. Biol Chem, 2000, 275(27):20632-20637.
[15] pierings DC, De Vries EG, Vellenga E, et al. Tissue distribution of the death ligand TRAIL and its receptors . Histochem Cytochem,2004, 52(6):821-831.
[16]范青林,宋礼华,魏伟. TRAIL的诱导肿瘤细胞凋亡与临床[J ].中国药理学通报,2003 ,19 (9) :976 - 981.
[17] Pan Q, Liu B, Liu J, Cai R, Wang Y, Qian C. Synergistic induction of tumor cell death by combining cisplatin with an oncolytic adenovirus carrying TRAIL. Mol Cell Biochem 2007;304:315-323.
[18] Ashkenazi A, Pai RC, Fong S, Leung S, Lawrence DA,Marsters SA, et al. Safety and antitumor activity of recombinant soluble Apo2 ligand. J Clin Invest 1999;104:155-162.
[19] Yoo J, Choi S, Hwang KS, et al. Adeno-associated virus-mediated gene transfer of a secreted form of TRAIL inhibits tumor growth and occurrence in an experimental tumor model. Gene Med,2006,8(2):163-174.
[20] Kim CY, Jeong M, Mushiake H, et al. Cancer gene therapy using a novel secretable trimeric TRAIL . Gene Ther,2006,13(4):330-338.
[21] Kimberley F C ,Screaton Q R. Following a TRAIL :Update on a Ligand and it sFive Receptors [ J ] . Cell Research , 2004 , 14(5) :359 - 372.
[22] Ashkenazi A, Dixit VM. Apoptosis control by death and decoy receptors. Curr Opin Cell Biol 1999;11:255– 260.
[23] Waiant H. TNF2Related Apoptosis Inducing Ligang ( TRAIL) and it s Receptors in Tumor Surveillance[J ] . Apoptosis ,2002 ,7(5) :449 - 459.
[24] Siegmund D,Mauri D,Peters N,et a1.Fas-associeated death domain protein(FADD)and caspase-8 mediate up-regulation of c-Fos by Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)via a FLICE inhibitory protein(FLIP)-regulated pathway.J Biol Chem.2001.276(35):32585-32590.
[25] Jia L,Pat wari Y.Kelsey SM, et at.TRAIl -induced apoptosis in type t leukemic cells is not enhanced by overexpression of bax.Biochem Biophys Res Comnmn,2001,283(5):1037-1045.
[26] Shetty S, Gladden JB, Henson ES, Hu X, Villanueva J,Haney N, et al. Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) up-regulates death receptor 5 (DR5) mediated by NFkB activation in epithelial derived cell lines.Apoptosis 2002;7:413– 420.
[27] Aggarwal BB, Bhardwaj U, Takada Y. Regulation of TRAIL induced apoptosis by ectopic expression of antiapoptotic factors. Vitam Horm 2004;67:453– 483.
[28] Baritaki S, Huerta-Yepez S, Sakai T, Spandidos DA,Bonavida B. Chemotherapeutic drugs sensitize cancer cells to TRAIL-mediated apoptosis: up-regulation of DR5 and inhibition of Yin Yang 1. Mol Cancer Ther 2007;6:1387–1399.
[29] Baritaki S, Huerta-Yepez S, Sakai T, Spandidos DA,Bonavida B. Chemotherapeutic drugs sensitize cancer cells to TRAIL-mediated apoptosis: up-regulation of DR5 and inhibition of Yin Yang 1. Mol Cancer Ther 2007;6:1387–1399.
[30] Abdollahi T,Robertson NM,Abdollahi A.et a1.Identification of interleukin 8 as an inhibitor of tumor necrosis factor-related apoptosis·inducingligand-induced apoptosis in the ovarian carcinoma cell line OVCAR3.Cancer Res, 2003.63(15):452l-4526.
[31] W ilson C, Wilson T , Johnston PG, Longley DB, Waugh DJ. Interleukin-8 signaling attenuates TRAIL- and chemotherapy-induced apoptosis through transcriptional regulation of c-FLIP in prostate cancer cells.Mol Cancer Ther. 2008; 7(9):2649-2661.
[32] Meng RD, El-Deiry WS. p53-independent upregulation of KILLER/DR5 TRAIL receptor expression by glucocorticoids and interferon-γ. Exp Cell Res 2001; 262:154– 169.
[33] Yang D, Wang S, Brooks C, Dong Z, Schoenlein PV, Kumar V, Ouyang X, Xiong H, Lahat G, Hayes-Jordan A, Lazar A, Pollock R, Lev D, Liu K. IFN regulatory factor 8 sensitizes soft tissue sarcoma cells to death receptor-initiated apoptosis via repression of FLICE-like protein expression. Cancer Res. 2009 1;69(3):1080-1088.
[34] Ashkenazi A, Pai RC, Fong S, et al. Safety and antitumor activity of recombinant soluble Apo2 ligand. Clin invest, 1999, 104(2):155-162.
[35] B ucur O,Ray S,Bucur MC,et al. APO2 ligand/tumor necrosis factor-related apoptosis-inducing ligand in prostate cancer therapy .Front Biosci, 2006, (11) :1549-1568 .
[36] M erchant MS,Yang X,Melchionda F,et al. Interferon gamma en-hancesthe effectiveness of tumor necrosis factor-related apoptosis-in-ducingligand receptor agonists in a xenograft models of Ewing‘s sarcoma .cancer res. 2004,64, 64 :8349-8356 .
[37] Georgakis GV, Li Y, Humphreys R, Andreeff M, O’Brien S,Younes M, et al. Activity of selective fully human agonistic antibodies to the TRAIL death receptors TRAIL-R1 and TRAIL-R2 in primary and cultured lymphoma cells: induction of apoptosis and enhancement of doxorubicin- and bortezomib-induced cell death. Br J Haematol 2005;130:501– 510.
[38] Cha SS, Sung BJ, Kim YA, et al. Crystal structure of TRAIL-DR5 complexidentifies a critical role of the unique frame insertion in conferring recognition specificity . Biol Chem, 2000, 275(40):31171-31177.
[39] Sikic BI, Wakelee HA, Mehren MV, Lewis N, Calvert AH,Plummer ER, et al. A phase 1b study to access the safety of lexatumumab, a human monoclonal antibody that activates TRAIL-R2 in combination with gemitabine, pemetrexed, doxorubicin, or FOLFIRI. American Society of Clinical Oncology (ASCO) 2007;Abstract 14006.
[40] Cytotoxicity and radiosensitization effect of TRA-8 on radioresistant human larynx squamous carcinoma cells.Wu F, Hu Y, Long J, Zhou YJ, Zhong YH, Liao ZK, Liu SQ, Zhou FX, Zhou YF, Xie CH.Oncol Rep. 2009;21(2):461-465.
[41] Daniel D, Yang B, Lawrence DA, Totpal K, Balter I, Lee WP, Gogineni A, Cole MJ, Yee SF, Ross S, Ashkenazi A. Cooperation of the proapoptotic receptor agonist hApo2L/TRAIL with the CD20 antibody rituximab against non-Hodgkin lymphoma xenografts. Blood. 2007 ;110(12):4037-4046.
[42] Nguyen T, Thomas W, Zhang XD, Gray C, Hersey P.Immunologically- mediated tumour cell apoptosis: the role of TRAIL in T cell and cytokine-mediated responses to melanoma. Forum (Genova) 2000; 10: 243- 252.
[43] Zauli G, Secchiero P. The role of the TRAIL/TRAIL receptors system in hematopoiesis and endothelial cell biology.Cytokine Growth Factor Rev 2006;17:245-257.
[44] Sedger LM, Glaccum MB, Schuh JC, Kanaly ST,Williamson E, Kayagaki N, et al. Characterization of the in vivo function of TNF-a-related apoptosis-inducing ligand,TRAIL/Apo2L, using TRAIL/Apo2L gene-deficient mice.Eur J Immunol 2002;32:2246-2254.
[45] Rubio-Moscardo F, Blesa D, Mestre C, Siebert R, Balasas T,Benito A, et al. Characterization of 8p21.3 chromosomal deletions in B-cell lymphoma: TRAIL-R1 and TRAIL-R2 as candidate dosage-dependent tumor suppressor genes. Blood 2005;106:3214-3222.
[46] Wolf S, Mertens D, Pscherer A, Schroeter P, Winkler D,Grone HJ, et al. Ala228 variant of trail receptor 1 affecting the ligand binding site is associated with chronic lymphocytic leukemia, mantle cell lymphoma, prostate cancer, head and neck squamous cell carcinoma and bladder cancer. Int J Cancer 2006;118:1831-1835.
[47] Zhang L, Fang B. Mechanisms of resistance to TRAILinduced apoptosis in cancer. Cancer Gene Ther 2005;12:228-237.
[48] Gomez-Benito M, Martinez-Lorenzo MJ, Anel A, Marzo I,Naval J. Membrane expression of DR4, DR5 and caspase-8 levels, but not Mcl-1, determine sensitivity of human myeloma cells to Apo2L/TRAIL. Exp Cell Res 2007;313:2378-2388.
[49] Secchiero P, Vaccarezza M, Gonelli A, Zauli G. TNF-related apoptosis-inducing ligand (TRAIL): a potential candidate for combined treatment of hematological malignancies. Curr Pharm Des 2004;10:3673-3681.
[50] Zhang L, Fang B. Mechanisms of resistance to TRAILinduced apoptosis in cancer. Cancer Gene Ther 2005;12:228-237.
[51] Falschlehner C, Emmerich CH, Gerlach B, Walczak H.TRAIL signalling: decisions between life and death. Int J Biochem Cell Biol 2007;39:1462-1475.
[52] Pedersen IM, Kitada S, Leoni LM, Zapata JM, Karras JG,Tsukada N, et al. Protection of CLL B cells by a follicular dendritic cell line is dependent on induction of Mcl-1. Blood 2002;100:1795-1801.
[53] Saxena A, Viswanathan S, Moshynska O, Tandon P,Sankaran K, Sheridan DP. Mcl-1 and Bcl-2/Bax ratio are associated with treatment response but not with Rai stage in Bcell chronic lymphocytic leukemia. Am J Hematol 2004; 75:22-33.
[54] J ohnston JB, Paul JT, Neufeld NJ, Haney N, Kropp DM, Hu X, et al. Role of myeloid cell factor-1 (Mcl-1) in chronic lymphocytic leukemia. Leuk Lymphoma 2004;45:2017-2027.
[55] G elinas C, White E. BH3-only proteins in control: specificity regulates MCL-1and BAK-mediated apoptosis. Genes Dev 2005;19:1263-1268.
[56] K aufmann SH, Steensma DP. On the TRAIL of a new therapyfor leukemia. Leukemia 2005;19:2195-2202.
[57] Yagita H, Takeda K, Hayakawa Y, Smyth MJ, Okumura K. TRAIL and its receptors as targets for cancer therapy. Cancer Sci 2004;95:777-783.
[58] Shrader M, Pino MS, Lashinger L, Bar-Eli M, Adam L,Dinney CP, et al. Gefitinib reverses TRAIL resistance in human bladder cancer cell lines via inhibition of AKTmediated X-linked inhibitor of apoptosis protein expression.Cancer Res 2007;67:1430-1435.
[59] Kelley SK, Ashkenazi A. Targeting death receptors in cancer with Apo2L/TRAIL. Curr Opin Pharmacol 2004;4:333-339.
[60] Wang S, El-Deiry WS. TRAIL and apoptosis induction by TNF-family death receptors. Oncogene 2003;22:8628-8633.
[61] Lee TJ, Jung EM, Lee JT, Kim S, Park JW, Choi KS, et al.Mithramycin A sensitizes cancer cells to TRAIL-mediated apoptosis by down-regulation of XIAP gene promoter through Sp1 sites. Mol Cancer Ther 2006; 5:2737-2746.
[62] Kim DM, Koo SY, Jeon K, Kim MH, Lee J, Hong CY, et al. Rapid induction of apoptosis by combination of flavopiridol and tumor necrosis factor (TNF)-a or TNF-related apoptosisinducing ligand in human cancer cell lines. Cancer Res 2003;63:621-626.
[63] A kay C, Gazitt Y. Arsenic trioxide selectively induces early and extensive apoptosis via the APO2/caspase-8 pathway engaging the mitochondrial pathway in myeloma cells with mutant p53. Cell Cycle 2003;2:358-368.
[64] L iu Q, Hilsenbeck S, Gazitt Y. Arsenic trioxide-induced apoptosis in myeloma cells: p53-dependent G1 or G2/M cell cycle arrest, activation of caspase-8 or caspase-9, and synergy with APO2/TRAIL. Blood 2003;101:4078-4087.
[65] Johnston JB, Kabore AF, Strutinsky J, Hu X, Paul JT,Kropp DM, et al. Role of the TRAIL/APO2-L death receptors in chlorambucil- and fludarabine-induced apoptosis in chronic lymphocytic leukemia. Oncogene 2003;22:8356-8369.
[66] MacFarlane M, Inoue S, Kohlhaas SL, Majid A, Harper N,Kennedy DB, et al. Chronic lymphocytic leukemic cells exhibit apoptotic signaling via TRAIL-R1. Cell Death Differ 2005; 12:773-782.
[67] Insinga A, Monestiroli S, Ronzoni S, Gelmetti V, Marchesi F,Viale A, et al. Inhibitors of histone deacetylases induce tumorselective apoptosis through activation of the death receptorpathway. Nat Med 2005;11:71-76.
[68] Sayers T J, Murphy W J. Combining proteasome inhibition with TNF-related apoptosis-inducing ligand (Apo2L/TRAIL) for cancer therapy. Cancer Immunol Immunother,2006, 55(1):76-84.
[69] Nencioni A, Wille L, Dal Bello G, et al. Cooperative cytotoxicity of proteasome inhibitors and tumor necrosis factor related apoptosis-inducing ligand in chemoresistant Bcl-2-overexpressing cells. Clin Cancer Res, 2005, 11(11): 4259-4265.
[70] Kabore AF, Sun J, Hu X, McCrea K, Johnston JB, Gibson S.The TRAIL apoptotic pathway mediates proteasome inhibitor induced apoptosis in primary chronic lymphocytic leukemia cells. Apoptosis, 2006;11:1175-1193.
[71] Balsas P, López-Royuela N, Galán-Malo P, Anel A, Marzo I, Naval J,Cooperation between Apo2L/TRAIL and bortezomib in multiple myeloma apoptosis.Biochem Pharmacol. 2009;77(5):804-812.
[72] Wendt J, Von Haefen C, Hemmati P, et al. TRAIL sensitizes for ionizing irradiation-induced apoptosis through an entirely Bax-dependent mitochondrial cell death pathway. Oncogene,2005,24(25):4052-4064.
[73] Shankar S , Singh TR , Srivastava RK, Ionizing radiation enhances the therapeutic potential of TRAIL in prostate cancer in vitro and in vivo: Intracellular mechanisms . Prostate , 2004, 61(1):35-49.
[74] Shankar S, Singh TR, Chen X, et al. The sequential treatment with ionizing radiation followed by TRAIL/Apo-2L reduces tumor growth and induces apoptosis of breast tumor xenografts in nude mice. Int J Oncol, 2004,24(5):1133-1140.
[75] Gong B, Almasan. A. Apo2 ligand/TNF-related apoptosis-inducing ligand and death receptor 5 mediate the apoptotic signaling induced by ionizing radiation in leukemic cells.Cancer Res. 2000 Oct 15;60(20):5754-5760.
[76] Wissink EH, Verbrugge I, Vink SR,et, al. TRAIL enhances efficacy of radiotherapy in a p53 mutant, Bcl-2 overexpressing lymphoid malignancy. Radiother Oncol. 2006 ,80(2):214-222.
[77] Unnithan J, Macklis RM. TRAIL induction by radiation in lymphoma patients. Cancer Invest. 2004;22(4):522-525.
[78] Georgakis GV, Li Y, Humphreys R, Andreeff M, O’Brien S,Younes M, et al. Activity of selective fully human agonistic antibodies to the TRAIL death receptors TRAIL-R1 and TRAIL-R2 in primary and cultured lymphoma cells: induction of apoptosis and enhancement of doxorubicin- and bortezomib- induced cell death. Br J Haematol 2005;130:501-510.
[79] Maddipatla S, Hernandez-Ilizaliturri FJ, Knight J,Czuczman MS. Augmented antitumor activity against B-cell lymphoma by a combination of monoclonal antibodies targeting TRAIL-R1 and CD20.Clin Cancer Res.2007;13(15pt1): 4556-4564.
[80] Nimmanapalli R, Porosnicu M, Nguyen D, Worthington E,O’Bryan E, Perkins C, et al. Cotreatment with STI-571enhances tumor necrosis factor a-related apoptosis-inducing ligand (TRAIL or apo-2L)-induced apoptosis of Bcr-Abl positive human acute leukemia cells. Clin Cancer Res 2001;7:350-357.
[81] Georgakis G V, Li Y, Rassidakis G Z, et al. Inhibition of heat shock protein 90 function by 17-allylamino-17-demethoxygeldanamycinin Hodgkin’s lymphoma cells down-regulates Akt kinase, dephosphorylates extracellular signal- regulated kinase, and induces cell cycle arrest and cell death. Clin Cancer Res, 2006, 12(2): 584-590.
[82] Ma Y L, Lakshmikanthan V, Lewis R W, et al. Sensitization of TRAIL- resistant cells by inhibition of heat shock protein 90 with low-dose geldanamycin. Mol Cancer Ther, 2006,5:170-178.
[83] Wu XX,Kakehi Y.Enhancement of lexatumumab-induced apoptosis in humansolid cancer cells by cisplatin in caspase-dependent manner.Clin Cancer Res.2009;15(6):2039-2047.
[84] Blagosklonny MV, Pardee AB. The restriction point of the cell cycle. Cell Cycle 2002;1:103-110.
[85] Nath N, Wang S, Betts V, Knudsen E, Chellappan S. Apoptotic and mitogenic stimuli inactivate Rb by differential utilization of p38 and cyclin-dependent kinases. Oncogene 2003;22:5986-5994.
[86] Bryja V, Pachernik J, Faldikova L, Krejci P, Pogue R, Nevriva I, Dvorak P, Hampl A. The role of p27(Kip1) in maintaining the levels of D-type cyclins in vivo. Biochim Biophys Acta 2004;1691:105-116.
[87] Favrot M, Coll JL, Louis N, Negoescu A. Cell death and cancer: Replacement of apoptotic genes and inactivation of death suppressor genes in therapy. Gene Ther 1998;5:728-739.
[88] Kim TY, Kim WI, Smith RE, Kay ED. Role of p27(Kip1) in cAMP- and TGF-beta2-mediated antiproliferation in rabbit corneal endothelial cells. Invest Ophthalmol Vis Sci 2001; 42:3142-3149.
[89] Shimizu T, Takahashi N, Tachibana K, Takeda K. Complex regulation of CDK2 and G1 arrest during neuronal differentiation of human prostatic cancer TSU-Prl cells by staurosporine. Anticancer Res 2001;21:893-898.
[90] e Koning JP, Soede-Bobok AA, Ward AC, Schelen AM, Antonissen C, van Leeuwen D, Lowenberg B, Touw IP. STAT3- mediated differentiation and survival and of myeloid cells in response to granulocyte colony-stimulating factor:role for the cyclin-dependent kinase inhibitor p27(Kip1). Oncogene 2000; 19:3290-3298.
[91] Alisi A, Leoni S, Piacentani A, Conti Devirgiliis L. Retinoic acid modulates the cell-cycle in fetal rat hepatocytes and HepG2 cells by regulating cyclin-cdk activities. Liver Int 2003; 23:179-186.
[92] Shetty S, Gladden JB, Henson ES, et al. Tumor necrosis factor-related apoptosis inducing ligand(TRAIL) up-regulateds death receptor 5(DR5) mediated by NFkappaB activation in epithelial derived cell lines.Apoptosis. 2002;7(5):413-420.
[93] Devereaux QL, Takahashi R, Salvesen GS, et al. X-linked IAP is a direct inhibitor of cell-death proteases. Nature 1997,388: 300-304.
[94] Altieri DC, Marchisio PC, Marchisio C. Survivin apoptosis: an interloper between cell death and cell proliferation in cancer. Lab Invest, 1999, 79(11):1327.
[95] Shankar SL, Mani S ,O′Guin KN, et al. survivin inhibition induces human neural tumor cell death through caspase-independent and dependent pathways[J].J Neurochem,2001,79(2):426-436.
[96] Jin Y, Wei Y, Xiong L, et al. Differential regulation of survivin by p53 contributes to cell cycle dependent apoptosis[J].Cell Res,2005,15(5):361-370.
[97] Mesri M, Wall NR, Li J, et al. Cancer gene therapy using a Survivin mutant adenovirus[J].J Clin Invest,2001,108(7):981-990.
[98] Bobayashi K,Hatano M,Otaki M,et al.Expression of a murine homologue of the inhibitor of apoptosis protein is related to cell proliferation[J].Proc Natl Acad Sci USA,1999,96(4):1457-1462.
[99]唐发清.Survivin研究进展[J].国外医学:生理、病理科学与临床分册.2001,21(2):87-88.
[100] Papapetropoulos A,Fulton D,Mahboubi K,et al.Angiopoietin-1 inhibits endothelial cell apoptosis via the Akt/Survivin pathway[J].J Biol Chem,2000, 275(13):9102-9105.
[101] O′Connor DS,Schechner JS,Adida C,et al.Control of apoptosis during angiogenesis by survivin express in endothelial cell[J].Am J Pathol,2000, 156(2):393-398.
[102]杨柳芹,房殿春.胃癌细胞NF-κB和Survivin的表达对TRAIL抗瘤作用的影响[J].第三军医大学学报,2004, 26(7):584-586.
[103] Lu M, Strohecker A, Chen F, et al. Aspirin sentitizes cancer cells to TRAIL-induced apoptosis by reducing surviving levels. Clin Cancer Res. 2008; 14(10):3168-3176.