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TRAIL in Cancer Therapy

  • Chapter
Death Receptors in Cancer Therapy

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

Death receptors and their ligands have recently garnered much attention for therapeutic intervention of tumor progression. In clinical oncology, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptors are the most prominent duos in the death-receptor-ligand guild for their ability to specifically eliminate cancer cells without any deleterious effect on normal cells. Although in recent years five TRAIL receptors have been identified and a number of checkpoints involved in the TRAIL pathway are known, a well defined signaling pathway remains elusive and appears to be very complex. In spite of TRAIL possessing a high therapeutic index, some tumor cells evade TRAIL-mediated cell death by utilizing a plethora of different regulators, such as cellular FLICE- inhibitory protein (c-FLIP), caspase-8, NF-κB, Akt, and/or decoy receptors, which either stall or shunt death signaling by mechanisms that remain poorly understood. Interestingly, a number of recent reports suggest that a key to the success of TRAIL in cancer therapy is to use it in conjunction with chemo- or radiotherapy. Such a concept of combination therapy is gaining ground in eliminating tumors that are refractory to treatment with TRAIL, ionizing radiation, or chemotherapeutic agents alone. Results from preclinical studies on TRAIL have been very promising for cancer treatment; however, outcome from phase I/II clinical trials is eagerly awaited to assess its safety. Time will show whether TRAIL will be the foremost weapon in the clinical oncologist’s arsenal to eradicate tumors.

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References

  1. Wyllie AH, Kerr JF, Currie AR. Cell death: the significance of apoptosis. Int Rev Cytol 1980;68:251–306.

    PubMed  CAS  Google Scholar 

  2. Strasser A, O’Connor L, Dixit VM. Apoptosis signaling. Annu Rev Biochem 2000;69:217–245.

    PubMed  CAS  Google Scholar 

  3. Shi Y. Mechanisms of caspase activation and inhibition during apoptosis. Mol Cell 2002;9:459–470.

    PubMed  CAS  Google Scholar 

  4. Kaufmann SH, Gores GJ. Apoptosis in cancer: cause and cure. Bioessays 2000;22:1007–1017.

    PubMed  CAS  Google Scholar 

  5. Ashkenazi A. Targeting death and decoy receptors of the tumour-necrosis factor superfamily. Nat Rev Cancer 2002;2:420–430.

    PubMed  CAS  Google Scholar 

  6. Siegel RM, Chan FK, Chun HJ, Lenardo MJ. The multifaceted role of Fas signaling in immune cell homeostasis and autoimmunity. Nat Immunol 2000;1:469–474.

    PubMed  CAS  Google Scholar 

  7. Krammer PH. CD95’s deadly mission in the immune system. Nature 2000;407:789–795.

    PubMed  CAS  Google Scholar 

  8. Wiley SR, Schooley K, Smolak PJ, et al. Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 1995;3:673–682.

    PubMed  CAS  Google Scholar 

  9. Pitti RM, Marsters SA, Ruppert S, Donahue CJ, Moore A, Ashkenazi A. Induction of apoptosis by Apo2 ligand, a new member of the tumor necrosis factor cytokine family. J Biol Chem 1996;271:12687–2690.

    PubMed  CAS  Google Scholar 

  10. Ashkenazi A, Dixit VM. Apoptosis control by death and decoy receptors. Curr Opin Cell Biol 1999;11:255–260.

    PubMed  CAS  Google Scholar 

  11. Ashkenazi A, Pai RC, Fong S, et al. Safety and antitumor activity of recombinant soluble Apo2 ligand. J Clin Invest 1999;104:155–162.

    PubMed  CAS  Google Scholar 

  12. Walczak H, Miller RE, Ariail K, et al. Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nat Med 1999;5:157–163.

    PubMed  CAS  Google Scholar 

  13. Hymowitz SG, O’Connell MP, Ultsch MH, et al. A unique zinc-binding site revealed by a high-resolution X-ray structure of homotrimeric Apo2L/TRAIL. Biochemistry 2000;39:633–640.

    PubMed  CAS  Google Scholar 

  14. Hymowitz SG, Christinger HW, Fuh G, et al. Triggering cell death: the crystal structure of Apo2L/TRAIL in a complex with death receptor 5. Mol Cell 1999;4:563–571.

    PubMed  CAS  Google Scholar 

  15. Bodmer JL, Meier P, Tschopp J, Schneider P. Cysteine 230 is essential for the structure and activity of the cytotoxic ligand TRAIL. J Biol Chem 2000;275:20,632–20,637.

    PubMed  CAS  Google Scholar 

  16. Sheridan JP, Marsters SA, Pitti RM, et al. Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science 1997;277:818–821.

    PubMed  CAS  Google Scholar 

  17. Pan G, Ni J, Wei YF, Yu G, Gentz R, Dixit VM. An antagonist decoy receptor and a death domain-containing receptor for TRAIL. Science 1997;277:815–818.

    PubMed  CAS  Google Scholar 

  18. Walczak H, Degli-Esposti MA, Johnson RS, et al. TRAIL-R2: a novel apoptosis-mediating receptor for TRAIL. Embo J 1997;16:5386–5397.

    PubMed  CAS  Google Scholar 

  19. Degli-Esposti MA, Dougall WC, Smolak PJ, Waugh JY, Smith CA, Goodwin RG. The novel receptor TRAIL-R4 induces NF-kappaB and protects against TRAIL-mediated apoptosis, yet retains an incomplete death domain. Immunity 1997;7:813–820.

    PubMed  CAS  Google Scholar 

  20. Degli-Esposti MA, Smolak PJ, Walczak H, et al. Cloning and characterization of TRAIL-R3, a novel member of the emerging TRAIL receptor family. J Exp Med 1997;186:1165–1170.

    PubMed  CAS  Google Scholar 

  21. Pan G, O’Rourke K, Chinnaiyan AM, et al. The receptor for the cytotoxic ligand TRAIL. Science 1997;276:111–113.

    PubMed  CAS  Google Scholar 

  22. Emery JG, McDonnell P, Burke MB, et al. Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J Biol Chem 1998;273:14,363–14,367.

    PubMed  CAS  Google Scholar 

  23. Igney FH, Krammer PH. Death and anti-death: tumour resistance to apoptosis. Nat Rev Cancer 2002;2:277–288.

    PubMed  CAS  Google Scholar 

  24. Kischkel FC, Hellbardt S, Behrmann I, et al. Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. Embo J 1995;14:5579–5588.

    PubMed  CAS  Google Scholar 

  25. Kischkel FC, Lawrence DA, Tinel A, et al. Death receptor recruitment of endogenous caspase-10 and apoptosis initiation in the absence of caspase-8. J Biol Chem 2001;276:46,639–46,646.

    PubMed  CAS  Google Scholar 

  26. Muzio M, Chinnaiyan AM, Kischkel FC, et al. FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex. Cell 1996;85:817–827.

    PubMed  CAS  Google Scholar 

  27. Krueger A, Baumann S, Krammer PH, Kirchhoff S. FLICE-inhibitory proteins: regulators of death receptor-mediated apoptosis. Mol Cell Biol 2001;21:8247–8254.

    PubMed  CAS  Google Scholar 

  28. Griffith TS, Chin WA, Jackson GC, Lynch DH, Kubin MZ. Intracellular regulation of TRAIL-induced apoptosis in human melanoma cells. J Immunol 1998;161:2833–2840.

    PubMed  CAS  Google Scholar 

  29. Hernandez A, Wang QD, Schwartz SA, Evers BM. Sensitization of human colon cancer cells to TRAIL-mediated apoptosis. J Gastrointest Surg 2001;5:56–65.

    PubMed  CAS  Google Scholar 

  30. Green DR, Reed JC. Mitochondria and apoptosis. Science 1998;281:1309–1312.

    PubMed  CAS  Google Scholar 

  31. Gross A, McDonnell JM, Korsmeyer SJ. BCL-2 family members and the mitochondria in apoptosis. Genes Dev 1999;13:1899–1911.

    PubMed  CAS  Google Scholar 

  32. Verhagen AM, Ekert PG, Pakusch M, et al. Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell 2000;102:43–53.

    PubMed  CAS  Google Scholar 

  33. Du C, Fang M, Li Y, Li L, Wang X. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 2000;102:33–42.

    PubMed  CAS  Google Scholar 

  34. Zou H, Li Y, Liu X, Wang X. An APAF-1.cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9. J Biol Chem 1999;274:11,549–11,556.

    PubMed  CAS  Google Scholar 

  35. Ekert PG, Silke J, Hawkins CJ, Verhagen AM, Vaux DL. DIABLO promotes apoptosis by removing MIHA/XIAP from processed caspase 9. J Cell Biol 2001;152:483–490.

    PubMed  CAS  Google Scholar 

  36. Petak I, Houghton JA. Shared pathways: death receptors and cytotoxic drugs in cancer therapy. Pathol Oncol Res 2001;7:95–106.

    PubMed  CAS  Google Scholar 

  37. Fulda S, Meyer E, Friesen C, Susin SA, Kroemer G, Debatin KM. Cell type specific involvement of death receptor and mitochondrial pathways in drug-induced apoptosis. Oncogene 2001;20:1063–1075.

    PubMed  CAS  Google Scholar 

  38. Korsmeyer SJ, Wei MC, Saito M, Weiler S, Oh KJ, Schlesinger PH. Pro-apoptotic cascade activates BID, which oligomerizes BAK or BAX into pores that result in the release of cytochrome c. Cell Death Differ 2000;7:1166–1173.

    PubMed  CAS  Google Scholar 

  39. El-Deiry WS. Insights into cancer therapeutic design based on p53 and TRAIL receptor signaling. Cell Death Differ 2001;8:1066–1075.

    PubMed  CAS  Google Scholar 

  40. LeBlanc H, Lawrence D, Varfolomeev E, et al. Tumor-cell resistance to death receptor-induced apoptosis through mutational inactivation of the proapoptotic Bcl-2 homolog Bax. Nat Med 2002;8:274–281.

    PubMed  CAS  Google Scholar 

  41. Cretney E, Takeda K, Yagita H, Glaccum M, Peschon JJ, Smyth MJ. Increased susceptibility to tumor initiation and metastasis in TNF-related apoptosis-inducing ligand-deficient mice. J Immunol 2002;168:1356–1361.

    PubMed  CAS  Google Scholar 

  42. Takeda K, Smyth MJ, Cretney E, et al. Critical role for tumor necrosis factor-related apoptosis-inducing ligand in immune surveillance against tumor development. J Exp Med 2002;195:161–169.

    PubMed  CAS  Google Scholar 

  43. Johnsen AC, Haux J, Steinkjer B, et al. Regulation of APO-2 ligand/trail expression in NK cells-involvement in NK cell-mediated cytotoxicity. Cytokine 1999;11:664–672.

    PubMed  CAS  Google Scholar 

  44. Jeremias I, Herr I, Boehler T, Debatin KM. TRAIL/Apo-2-ligand-induced apoptosis in human T cells. Eur J Immunol 1998;28:143–152.

    PubMed  CAS  Google Scholar 

  45. Thomas WD, Hersey P. TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis in Fas ligand-resistant melanoma cells and mediates CD4 T cell killing of target cells. J Immunol 1998;161:2195–2200.

    PubMed  CAS  Google Scholar 

  46. Kayagaki N, Yamaguchi N, Nakayama M, et al. Expression and function of TNF-related apoptosis-inducing ligand on murine activated NK cells. J Immunol 1999;163:1906–1913.

    PubMed  CAS  Google Scholar 

  47. Kayagaki N, Yamaguchi N, Nakayama M, et al. Involvement of TNF-related apoptosis-inducing ligand in human CD4+ T cell-mediated cytotoxicity. J Immunol 1999;162:2639–2647.

    PubMed  CAS  Google Scholar 

  48. Martinez-Lorenzo MJ, Alava MA, Gamen S, et al. Involvement of APO2 ligand/TRAIL in activation-induced death of Jurkat and human peripheral blood T cells. Eur J Immunol 1998;28:2714–2725.

    PubMed  CAS  Google Scholar 

  49. Mariani SM, Krammer PH. Surface expression of TRAIL/Apo-2 ligand in activated mouse T and B cells. Eur J Immunol 1998;28:1492–1498.

    PubMed  CAS  Google Scholar 

  50. Griffith TS, Wiley SR, Kubin MZ, Sedger LM, Maliszewski CR, Fanger NA. Monocyte-mediated tumoricidal activity via the tumor necrosis factor-related cytokine, TRAIL. J Exp Med 1999;189:1343–1354.

    PubMed  CAS  Google Scholar 

  51. Kayagaki N, Yamaguchi N, Nakayama M, Eto H, Okumura K, Yagita H. Type I interferons (IFNs) regulate tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression on human T cells: A novel mechanism for the antitumor effects of type I IFNs. J Exp Med 1999;189:1451–1460.

    PubMed  CAS  Google Scholar 

  52. Chen Q, Gong B, Mahmoud-Ahmed AS, et al. Apo2L/TRAIL and Bcl-2-related proteins regulate type I interferon-induced apoptosis in multiple myeloma. Blood 2001;98:2183–2192.

    PubMed  CAS  Google Scholar 

  53. Clarke P, Meintzer SM, Widmann C, Johnson GL, Tyler KL. Reovirus infection activates JNK and the JNK-dependent transcription factor c-Jun. J Virol 2001;75:11,275–11,283.

    PubMed  CAS  Google Scholar 

  54. Secchiero P, Mirandola P, Zella D, et al. Human herpesvirus 7 induces the functional up-regulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) coupled to TRAIL-R1 down-modulation in CD4(+) T cells. Blood 2001;98:2474–2481.

    PubMed  CAS  Google Scholar 

  55. Held J, Schulze-Osthoff K. Potential and caveats of TRAIL in cancer therapy. Drug Resist Updat 2001;4:243–252.

    PubMed  CAS  Google Scholar 

  56. Fricker J. On the TRAIL to a new cancer therapy. Mol Med Today 1999;5:374.

    PubMed  CAS  Google Scholar 

  57. Rieger J, Naumann U, Glaser T, Ashkenazi A, Weller M. APO2 ligand: a novel lethal weapon against malignant glioma? FEBS Lett 1998;427:124–128.

    PubMed  CAS  Google Scholar 

  58. Keane MM, Ettenberg SA, Nau MM, Russell EK, Lipkowitz S. Chemotherapy augments TRAIL-induced apoptosis in breast cell lines. Cancer Res 1999;59:734–741.

    PubMed  CAS  Google Scholar 

  59. Mizutani Y, Nakao M, Ogawa O, Yoshida O, Bonavida B, Miki T. Enhanced sensitivity of bladder cancer cells to tumor necrosis factor related apoptosis inducing ligand mediated apoptosis by cisplatin and carboplatin. J Urol 2001;165:263–270.

    PubMed  CAS  Google Scholar 

  60. Mitsiades N, Poulaki V, Mitsiades C, Tsokos M. Ewing’s sarcoma family tumors are sensitive to tumor necrosis factor-related apoptosis-inducing ligand and express death receptor 4 and death receptor 5. Cancer Res 2001;61:2704–2712.

    PubMed  CAS  Google Scholar 

  61. Yu R, Mandlekar S, Ruben S, Ni J, Kong AN. Tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in androgen-independent prostate cancer cells. Cancer Res 2000;60:2384–2389.

    PubMed  CAS  Google Scholar 

  62. Gazitt Y. TRAIL is a potent inducer of apoptosis in myeloma cells derived from multiple myeloma patients and is not cytotoxic to hematopoietic stem cells. Leukemia 1999;13:1817–1824.

    PubMed  CAS  Google Scholar 

  63. Kelley SK, Harris LA, Xie D, et al. Preclinical studies to predict the disposition of Apo2L/tumor necrosis factor-related apoptosis-inducing ligand in humans: characterization of in vivo efficacy, pharmacokinetics, and safety. J Pharmacol Exp Ther 2001;299:31–38.

    PubMed  CAS  Google Scholar 

  64. Mitsiades CS, Treon SP, Mitsiades N, et al. TRAIL/Apo2L ligand selectively induces apoptosis and overcomes drug resistance in multiple myeloma: therapeutic applications. Blood 2001;98:795–804.

    PubMed  CAS  Google Scholar 

  65. Roth W, Isenmann S, Naumann U, et al. Locoregional Apo2L/TRAIL eradicates intracranial human malignant glioma xenografts in athymic mice in the absence of neurotoxicity. Biochem Biophys Res Commun 1999;265:479–483.

    PubMed  CAS  Google Scholar 

  66. Pollack IF, Erff M, Ashkenazi A. Direct stimulation of apoptotic signaling by soluble Apo2l/tumor necrosis factor-related apoptosis-inducing ligand leads to selective killing of glioma cells. Clin Cancer Res 2001;7:1362–1369.

    PubMed  CAS  Google Scholar 

  67. Ichikawa K, Liu W, Zhao L, et al. Tumoricidal activity of a novel anti-human DR5 monoclonal antibody without hepatocyte cytotoxicity. Nat Med 2001;7:954–960.

    PubMed  CAS  Google Scholar 

  68. Choi C, Kutsch O, Park J, Zhou T, Seol DW, Benveniste EN. Tumor necrosis factor-related apoptosis-inducing ligand induces caspase-dependent interleukin-8 expression and apoptosis in human astroglioma cells. Mol Cell Biol 2002;22:724–736.

    PubMed  CAS  Google Scholar 

  69. Griffith TS, Anderson RD, Davidson BL, Williams RD, Ratliff TL. Adenoviral-mediated transfer of the TNF-related apoptosis-inducing ligand/Apo-2 ligand gene induces tumor cell apoptosis. J Immunol 2000;165:2886–2894.

    PubMed  CAS  Google Scholar 

  70. Kagawa S, He C, Gu J, et al. Antitumor activity and bystander effects of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene. Cancer Res 2001;61:3330–3338.

    PubMed  CAS  Google Scholar 

  71. Griffith TS, Broghammer EL. Suppression of tumor growth following intralesional therapy with TRAIL recombinant adenovirus. Mol Ther 2001;4:257–266.

    PubMed  CAS  Google Scholar 

  72. Huang X, Lin T, Gu J, et al. Combined TRAIL and Bax gene therapy prolonged survival in mice with ovarian cancer xenograft. Gene Ther 2002;9:1379–1386.

    PubMed  CAS  Google Scholar 

  73. Norris JS, Hyer ML, Voelkel-Johnson C, Lowe SL, Rubinchik S, Dong JY. The use of Fas Ligand, TRAIL and Bax in gene therapy of prostate cancer. Curr Gene Ther 2001;1:123–136.

    PubMed  CAS  Google Scholar 

  74. Lee J, Hampl M, Albert P, Fine HA. Antitumor activity and prolonged expression from a TRAIL-expressing adenoviral vector. Neoplasia 2002;4:312–323.

    PubMed  CAS  Google Scholar 

  75. Voelkel-Johnson C, King DL, Norris JS. Resistance of prostate cancer cells to soluble TNF-related apoptosis-inducing ligand (TRAIL/Apo2L) can be overcome by doxorubicin or adenoviral delivery of full-length TRAIL. Cancer Gene Ther 2002;9:164–172.

    PubMed  CAS  Google Scholar 

  76. Yamashita Y, Shimada M, Tanaka S, Okamamoto M, Miyazaki J, Sugimachi K. Electroporation-mediated tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo2L gene therapy for hepatocellular carcinoma. Hum Gene Ther 2002;13:275–286.

    PubMed  CAS  Google Scholar 

  77. Nitsch R, Bechmann I, Deisz RA, et al. Human brain-cell death induced by tumour-necrosis-factor-related apoptosis-inducing ligand (TRAIL). Lancet 2000;356:827–828.

    PubMed  CAS  Google Scholar 

  78. Jo M, Kim TH, Seol DW, et al. Apoptosis induced in normal human hepatocytes by tumor necrosis factor-related apoptosis-inducing ligand. Nat Med 2000;6:564–567.

    PubMed  CAS  Google Scholar 

  79. Leverkus M, Neumann M, Mengling T, et al. Regulation of tumor necrosis factor-related apoptosis-inducing ligand sensitivity in primary and transformed human keratinocytes. Cancer Res 2000;60:553–559.

    PubMed  CAS  Google Scholar 

  80. Lawrence D, Shahrokh Z, Marsters S, et al. Differential hepatocyte toxicity of recombinant Apo2L/TRAIL versions. Nat Med 2001;7:383–385.

    PubMed  CAS  Google Scholar 

  81. Qin J, Chaturvedi V, Bonish B, Nickoloff BJ. Avoiding premature apoptosis of normal epidermal cells. Nat Med 2001;7:385–386.

    PubMed  CAS  Google Scholar 

  82. Wuchter C, Krappmann D, Cai Z, et al. In vitro susceptibility to TRAIL-induced apoptosis of acute leukemia cells in the context of TRAIL receptor gene expression and constitutive NF-kappa B activity. Leukemia 2001;15:921–928.

    PubMed  CAS  Google Scholar 

  83. Zhang XD, Franco A, Myers K, Gray C, Nguyen T, Hersey P. Relation of TNF-related apoptosis-inducing ligand (TRAIL) receptor and FLICE-inhibitory protein expression to TRAIL-induced apoptosis of melanoma. Cancer Res 1999; 59:2747–2753.

    PubMed  CAS  Google Scholar 

  84. Griffith TS, Rauch CT, Smolak PJ, et al. Functional analysis of TRAIL receptors using monoclonal antibodies. J Immunol 1999;162:2597–2605.

    PubMed  CAS  Google Scholar 

  85. Wen J, Ramadevi N, Nguyen D, Perkins C, Worthington E, Bhalla K. Antileukemic drugs increase death receptor 5 levels and enhance Apo-2L-induced apoptosis of human acute leukemia cells. Blood 2000;96:3900–3906.

    PubMed  CAS  Google Scholar 

  86. Zhang XD, Nguyen T, Thomas WD, Sanders JE, Hersey P. Mechanisms of resistance of normal cells to TRAIL induced apoptosis vary between different cell types. FEBS Lett 2000;482:193–199.

    PubMed  CAS  Google Scholar 

  87. Zhang XD, Franco AV, Nguyen T, Gray CP, Hersey P. Differential localization and regulation of death and decoy receptors for TNF-related apoptosis-inducing ligand (TRAIL) in human melanoma cells. J Immunol 2000;164:3961–3970.

    PubMed  CAS  Google Scholar 

  88. Irmler M, Thome M, Hahne M, et al. Inhibition of death receptor signals by cellular FLIP. Nature 1997;388:190–195.

    PubMed  CAS  Google Scholar 

  89. Xiao C, Yang BF, Asadi N, Beguinot F, Hao C. Tumor necrosis factor-related apoptosis-inducing ligand-induced death-inducing signaling complex and its modulation by c-FLIP and PED/PEA-15 in glioma cells. J Biol Chem 2002;277:25,020–25,025.

    PubMed  CAS  Google Scholar 

  90. Bin L, Li X, Xu LG, Shu HB. The short splice form of Casper/c-FLIP is a major cellular inhibitor of TRAIL-induced apoptosis. FEBS Lett 2002;510:37–40.

    PubMed  CAS  Google Scholar 

  91. Poulaki V, Mitsiades CS, Kotoula V, et al. Regulation of Apo2L/tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in thyroid carcinoma cells. Am J Pathol 2002;161:643–654.

    PubMed  CAS  Google Scholar 

  92. Shin EC, Seong YR, Kim CH, et al. Human hepatocellular carcinoma cells resist to TRAIL-induced apoptosis, and the resistance is abolished by cisplatin. Exp Mol Med 2002;34:114–122.

    PubMed  CAS  Google Scholar 

  93. Elnemr A, Ohta T, Yachie A, et al. Human pancreatic cancer cells disable function of Fas receptors at several levels in Fas signal transduction pathway. Int J Oncol 2001;18:311–316.

    PubMed  CAS  Google Scholar 

  94. Tepper CG, Seldin MF. Modulation of caspase-8 and FLICE-inhibitory protein expression as a potential mechanism of Epstein-Barr virus tumorigenesis in Burkitt’s lymphoma. Blood 1999;94:1727–737.

    PubMed  CAS  Google Scholar 

  95. Djerbi M, Screpanti V, Bogen B, Catrina A, Biberfeld P, Grandien A. The inhibitor of death receptor signaling, FLICE-inhibitory protein defines a new class of tumour progression factors. J Exp Med 1999;190:1025–1032.

    PubMed  CAS  Google Scholar 

  96. Li J, Yen C, Liaw D, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 1997;275:1943–1947.

    PubMed  CAS  Google Scholar 

  97. Whang YE, Wu X, Suzuki H, et al. Inactivation of the tumor suppressor PTEN/MMAC1 in advanced human prostate cancer through loss of expression. Proc Natl Acad Sci USA 1998;95:5246–5250.

    PubMed  CAS  Google Scholar 

  98. Vlietstra RJ, van Alewijk DC, Hermans KG, van Steenbrugge GJ, Trapman J. Frequent inactivation of PTEN in prostate cancer cell lines and xenografts. Cancer Res 1998;58:2720–2723.

    PubMed  CAS  Google Scholar 

  99. Nesterov A, Lu X, Johnson M, Miller GJ, Ivashchenko Y, Kraft AS. Elevated AKT activity protects the prostate cancer cell line LNCaP from TRAIL-induced apoptosis. J Biol Chem 2001;276:10,767–10,774.

    PubMed  CAS  Google Scholar 

  100. Chen X, Thakkar H, Tyan F, et al. Constitutively active Akt is an important regulator of TRAIL sensitivity in prostate cancer. Oncogene 2001;20:6073–6083.

    PubMed  CAS  Google Scholar 

  101. Thakkar H, Chen X, Tyan F, et al. Pro-survival function of Akt/protein kinase B in prostate cancer cells: relationship with trail resistance. J Biol Chem 2001;276:38,361–38,369.

    PubMed  CAS  Google Scholar 

  102. Mitsiades CS, Mitsiades N, Poulaki V, et al. Activation of NF-kappaB and upregulation of intracellular anti-apoptotic proteins via the IGF-1/Akt signaling in human multiple myeloma cells: therapeutic implications. Oncogene 2002;21:5673–5683.

    PubMed  CAS  Google Scholar 

  103. Wang Q, Wang X, Hernandez A, Hellmich MR, Gatalica Z, Evers BM. Regulation of trail expression by the PI3-KINASE/Akt/GSK-3 pathway in human colon cancer cells. J Biol Chem 2002;277:36,602–36,610.

    PubMed  CAS  Google Scholar 

  104. Kandasamy K, Srivastava RK. Role of the phosphatidylinositol 3′-kinase/PTEN/Akt kinase pathway in tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in non-small cell lung cancer cells. Cancer Res 2002;62:4929–4937.

    PubMed  CAS  Google Scholar 

  105. Wang J, Zheng L, Lobito A, et al. Inherited human caspase 10 mutations underlie defective lymphocyte and dendritic cell apoptosis in autoimmune lymphoproliferative syndrome type II. Cell 1999;98:47–58.

    PubMed  CAS  Google Scholar 

  106. Sprick MR, Rieser E, Stahl H, Grosse-Wilde A, Weigand MA, Walczak H. Caspase-10 is recruited to and activated at the native TRAIL and CD95 death-inducing signalling complexes in a FADD-dependent manner but can not functionally substitute caspase-8. Embo J 2002;21:4520–4530.

    PubMed  CAS  Google Scholar 

  107. Teitz T, Wei T, Valentine MB, et al. Caspase 8 is deleted or silenced preferentially in childhood neuroblastomas with amplification of MYCN. Nat Med 2000;6:529–535.

    PubMed  CAS  Google Scholar 

  108. Hopkins-Donaldson S, Bodmer JL, Bourloud KB, Brognara CB, Tschopp J, Gross N. Loss of caspase-8 expression in highly malignant human neuroblastoma cells correlates with resistance to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. Cancer Res 2000;60:4315–4319.

    PubMed  CAS  Google Scholar 

  109. Fulda S, Kufer MU, Meyer E, van Valen F, Dockhorn-Dworniczak B, Debatin KM. Sensitization for death receptor-or drug-induced apoptosis by re-expression of caspase-8 through demethylation or gene transfer. Oncogene 2001;20:5865–5877.

    PubMed  CAS  Google Scholar 

  110. Eggert A, Grotzer MA, Zuzak TJ, et al. Resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in neuroblastoma cells correlates with a loss of caspase-8 expression. Cancer Res 2001; 61:1314–1319.

    PubMed  CAS  Google Scholar 

  111. Zuzak TJ, Steinhoff DF, Sutton LN, Phillips PC, Eggert A, Grotzer MA. Loss of caspase-8 mRNA expression is common in childhood primitive neuroectodermal brain tumour/medulloblastoma. Eur J Cancer 2002;38:83–91.

    PubMed  CAS  Google Scholar 

  112. Gliniak B, Le T. Tumor necrosis factor-related apoptosis-inducing ligand’s antitumor activity in vivo is enhanced by the chemotherapeutic agent CPT-11. Cancer Res 1999;59:6153–6158.

    PubMed  CAS  Google Scholar 

  113. Cuello M, Ettenberg SA, Nau MM, Lipkowitz S. Synergistic induction of apoptosis by the combination of trail and chemotherapy in chemoresistant ovarian cancer cells. Gynecol Oncol 2001;81:380–390.

    PubMed  CAS  Google Scholar 

  114. Chinnaiyan AM, Prasad U, Shankar S, et al. Combined effect of tumor necrosis factor-related apoptosis-inducing ligand and ionizing radiation in breast cancer therapy. Proc Natl Acad Sci USA 2000;97:1754–1759.

    PubMed  CAS  Google Scholar 

  115. Dejosez M, Ramp U, Mahotka C, et al. Sensitivity to TRAIL/APO-2L-mediated apoptosis in human renal cell carcinomas and its enhancement by topotecan. Cell Death Differ 2000;7:1127–1136.

    PubMed  CAS  Google Scholar 

  116. 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;60:5754–5760.

    PubMed  CAS  Google Scholar 

  117. Yamanaka T, Shiraki K, Sugimoto K, et al. Chemotherapeutic agents augment TRAIL-induced apoptosis in human hepatocellular carcinoma cell lines. Hepatology 2000;32:482–490.

    PubMed  CAS  Google Scholar 

  118. Lacour S, Hammann A, Wotawa A, Corcos L, Solary E, Dimanche-Boitrel MT. Anticancer agents sensitize tumor cells to tumor necrosis factor-related apoptosis-inducing ligand-mediated caspase-8 activation and apoptosis. Cancer Res 2001;61:1645–1651.

    PubMed  CAS  Google Scholar 

  119. Liu W, Bodle E, Chen JY, Gao M, Rosen GD, Broaddus VC. Tumor necrosis factor-related apoptosis-inducing ligand and chemotherapy cooperate to induce apoptosis in mesothelioma cell lines. Am J Respir Cell Mol Biol 2001; 25:111–118.

    PubMed  CAS  Google Scholar 

  120. Rudner J, Lepple-Wienhues A, Budach W, et al. Wild-type, mitochondrial and ER-restricted Bcl-2 inhibit DNA damage-induced apoptosis but do not affect death receptor-induced apoptosis. J Cell Sci 2001;114:4161–4172.

    PubMed  CAS  Google Scholar 

  121. Sheikh MS, Burns TF, Huang Y, et al. p53-dependent and-independent regulation of the death receptor KILLER/DR5 gene expression in response to genotoxic stress and tumor necrosis factor alpha. Cancer Res 1998;58:1593–1598.

    PubMed  CAS  Google Scholar 

  122. Wu GS, Burns TF, McDonald ER, 3rd, et al. KILLER/DR5 is a DNA damage-inducible p53-regulated death receptor gene. Nat Genet 1997;17:141–143.

    PubMed  CAS  Google Scholar 

  123. Nagane M, Pan G, Weddle JJ, Dixit VM, Cavenee WK, Huang HJ. Increased death receptor 5 expression by chemotherapeutic agents in human gliomas causes synergistic cytotoxicity with tumor necrosis factor-related apoptosis-inducing ligand in vitro and in vivo. Cancer Res 2000;60:847–853.

    PubMed  CAS  Google Scholar 

  124. Munshi A, McDonnell TJ, Meyn RE. Chemotherapeutic agents enhance TRAIL-induced apoptosis in prostate cancer cells. Cancer Chemother Pharmacol 2002;50:46–52.

    PubMed  CAS  Google Scholar 

  125. Wu GS, Kim K, el-Deiry WS. KILLER/DR5, a novel DNA-damage inducible death receptor gene, links the p53-tumor suppressor to caspase activation and apoptotic death. Adv Exp Med Biol 2000;465:143–151.

    PubMed  CAS  Google Scholar 

  126. Meng RD, El-Deiry WS. p53-independent upregulation of KILLER/DR5 TRAIL receptor expression by glucocorticoids and interferon-gamma. Exp Cell Res 2001;262:154–169.

    PubMed  CAS  Google Scholar 

  127. Guan B, Yue P, Clayman GL, Sun SY. Evidence that the death receptor DR4 is a DNA damage-inducible, p53-regulated gene. J Cell Physiol 2001;188:98–105.

    PubMed  CAS  Google Scholar 

  128. Rohn TA, Wagenknecht B, Roth W, et al. CCNU-dependent potentiation of TRAIL/Apo2L-induced apoptosis in human glioma cells is p53-independent but may involve enhanced cytochrome c release. Oncogene 2001;20:4128–4137.

    PubMed  CAS  Google Scholar 

  129. Gibson SB, Oyer R, Spalding AC, Anderson SM, Johnson GL. Increased expression of death receptors 4 and 5 synergizes the apoptosis response to combined treatment with etoposide and TRAIL. Mol Cell Biol 2000;20:205–212.

    PubMed  CAS  Google Scholar 

  130. Sun SY, Yue P, Hong WK, Lotan R. Augmentation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by the synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) through up-regulation of TRAIL receptors in human lung cancer cells. Cancer Res 2000;60:7149–7155.

    PubMed  CAS  Google Scholar 

  131. Di Pietro R, Secchiero P, Rana R, et al. Ionizing radiation sensitizes erythroleukemic cells but not normal erythroblasts to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated cytotoxicity by selective up-regulation of TRAIL-R1. Blood 2001;97:2596–2603.

    PubMed  Google Scholar 

  132. Jazirehi AR, Ng CP, Gan XH, Schiller G, Bonavida B. Adriamycin sensitizes the adriamycin-resistant 8226/Dox40 human multiple myeloma cells to Apo2L/tumor necrosis factor-related apoptosis-inducing ligand-mediated (TRAIL) apoptosis. Clin Cancer Res 2001;7:3874–3883.

    PubMed  CAS  Google Scholar 

  133. Evdokiou A, Bouralexis S, Atkins GJ, et al. Chemotherapeutic agents sensitize osteogenic sarcoma cells, but not normal human bone cells, to Apo2L/TRAIL-induced apoptosis. Int J Cancer 2002;99:491–504.

    PubMed  CAS  Google Scholar 

  134. Arizono Y, Yoshikawa H, Naganuma H, Hamada Y, Nakajima Y, Tasaka K. A mechanism of resistance to TRAIL/Apo2L-induced apoptosis of newly established glioma cell line and sensitisation to TRAIL by genotoxic agents. Br J Cancer 2003;88:298–306.

    PubMed  CAS  Google Scholar 

  135. Mori S, Murakami-Mori K, Jewett A, Nakamura S, Bonavida B. Resistance of AIDS-associated Kaposi’s sarcoma cells to Fas-mediated apoptosis. Cancer Res 1996;56:1874–1879.

    PubMed  CAS  Google Scholar 

  136. Hernandez A, Thomas R, Smith F, et al. Butyrate sensitizes human colon cancer cells to TRAIL-mediated apoptosis. Surgery 2001;130:265–272.

    PubMed  CAS  Google Scholar 

  137. Lee YJ, Lee KH, Kim HR, et al. Sodium nitroprusside enhances TRAIL-induced apoptosis via a mitochondria-dependent pathway in human colorectal carcinoma CX-1 cells. Oncogene 2001;20:1476–1485.

    PubMed  CAS  Google Scholar 

  138. Matsuzaki H, Schmied BM, Ulrich A, et al. Combination of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and actinomycin D induces apoptosis even in TRAIL-resistant human pancreatic cancer cells. Clin Cancer Res 2001;7:407–414.

    PubMed  CAS  Google Scholar 

  139. Fulda S, Wick W, Weller M, Debatin KM. Smac agonists sensitize for Apo2L/TRAIL-or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo. Nat Med 2002;8:808–815.

    PubMed  CAS  Google Scholar 

  140. Mizutani Y, Nakanishi H, Yoshida O, Fukushima M, Bonavida B, Miki T. Potentiation of the sensitivity of renal cell carcinoma cells to TRAIL-mediated apoptosis by subtoxic concentrations of 5-fluorouracil. Eur J Cancer 2002;38:167–176.

    PubMed  CAS  Google Scholar 

  141. Wu XX, Kakehi Y, Mizutani Y, et al. Doxorubicin enhances TRAIL-induced apoptosis in prostate cancer. Int J Oncol 2002;20:949–954.

    PubMed  CAS  Google Scholar 

  142. Lacour S, Micheau O, Hammann A, et al. Chemotherapy enhances TNF-related apoptosis-inducing ligand DISC assembly in HT29 human colon cancer cells. Oncogene 2003;22:1807–1816.

    PubMed  CAS  Google Scholar 

  143. Belka C, Schmid B, Marini P, et al. Sensitization of resistant lymphoma cells to irradiation-induced apoptosis by the death ligand TRAIL. Oncogene 2001;20:2190–2196.

    PubMed  CAS  Google Scholar 

  144. Van Valen F, Fulda S, Truckenbrod B, et al. Apoptotic responsiveness of the Ewing’s sarcoma family of tumours to tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). Int J Cancer 2000;88:252–259.

    PubMed  Google Scholar 

  145. Wu M, Das A, Tan Y, Zhu C, Cui T, Wong MC. Induction of apoptosis in glioma cell lines by TRAIL/Apo-2l. J Neurosci Res 2000;61:464–470.

    PubMed  CAS  Google Scholar 

  146. Mlynarczuk I, Hoser G, Grzela T, et al. Augmented pro-apoptotic effects of TRAIL and proteasome inhibitor in human promonocytic leukemic U937 cells. Anticancer Res 2001;21:1237–1240.

    PubMed  CAS  Google Scholar 

  147. Zisman A, Ng CP, Pantuck AJ, Bonavida B, Belldegrun AS. Actinomycin D and gemcitabine synergistically sensitize androgen-independent prostate cancer cells to Apo2L/TRAIL-mediated apoptosis. J Immunother 2001;24:459–471.

    PubMed  CAS  Google Scholar 

  148. Ahmad M, Shi Y. TRAIL-induced apoptosis of thyroid cancer cells: potential for therapeutic intervention. Oncogene 2000;19:3363–3371.

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Center for Molecular Imaging, Department of Radiology, University of Michigan, Ann Arbor, MI

    Mahaveer Swaroop Bhojani PhD, Brian D. Ross PhD & Alnawaz Rehemtulla PhD

  2. Center for Molecular Imaging, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI

    Mahaveer Swaroop Bhojani PhD & Alnawaz Rehemtulla PhD

  3. Center for Molecular Imaging, Department of Biological Chemistry, University of Michigan, Ann Arbor, MI

    Brian D. Ross PhD

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  1. Mahaveer Swaroop Bhojani PhD
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  2. Brian D. Ross PhD
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  3. Alnawaz Rehemtulla PhD
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Editors and Affiliations

  1. Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA

    Wafik S. El-Deiry MD, PhD

  2. Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA

    Wafik S. El-Deiry MD, PhD

  3. Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA

    Wafik S. El-Deiry MD, PhD

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© 2005 Humana Press Inc., Totowa, NJ

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Bhojani, M.S., Ross, B.D., Rehemtulla, A. (2005). TRAIL in Cancer Therapy. In: El-Deiry, W.S. (eds) Death Receptors in Cancer Therapy. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1385/1-59259-851-X:263

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  • DOI: https://doi.org/10.1385/1-59259-851-X:263

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-172-1

  • Online ISBN: 978-1-59259-851-9

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