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The potential of TRAIL for cancer chemotherapy

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Abstract

Innate and acquired resistance to chemotherapy and radiation therapy has been a major obstacle for clinical oncology. One potential adjunct to such conventional treatments is direct induction of cell death by activation of death receptor-mediated apoptosis. TRAIL (tumor necrosis factor (TNF)-related apoptosis inducing ligand), a recently identified member of the growing TNF superfamily, binds to its cognate “death” receptors DR4 and DR5 as well as “decoy” receptors DcR1 and DcR2. Upon binding, rapid apoptosis is enacted in a variety of human cancer cell lines independent of p53 status, but not in normal cell lines. TRAIL treatment results in significant growth suppression of TRAIL-sensitive human cancer xenografts in mice. Furthermore, combination treatment of TRAIL with genotoxic chemotherapeutic agents synergistically suppresses growth of tumor xenografts which are otherwise resistant to treatment with TRAIL or chemotherapy alone. Unlike the other death ligands TNF-α or FasL, systemic administration of soluble human TRAIL does not cause toxicity in mice and non-human primates. While further studies are needed to evaluate the possible cytotoxicity of TRAIL especially for human hepatocytes, indications are increasing that TRAIL may be a novel therapeutic agent for human cancer.

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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.

    Google Scholar 

  2. Thornberry NA, Lazebnik Y. Caspases: Enemies within. Science 1998; 281: 1312-1316.

    Google Scholar 

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

    Google Scholar 

  4. Ashkenazi A, Dixit VM. Death receptors: Signaling and modulation. Science 1998; 281: 1305-1308.

    Google Scholar 

  5. Guchelaar HJ, Vermes A, Vermes I, et al. Apoptosis: Molecular mechanisms and implications for cancer chemotherapy. Pharm World Sci 1997; 19: 119-125.

    Google Scholar 

  6. Houghton JA. Apoptosis and drug response. Curr Opin Oncol 1999; 11: 475-481.

    Google Scholar 

  7. Reed JC. Mechanisms of apoptosis avoidance in cancer. Curr Opin Oncol 1999; 11: 68-75.

    Google Scholar 

  8. Kaufmann SH, Earnshaw WC. Induction of apoptosis by cancer chemotherapy. Exp Cell Res 2000; 256: 42-49.

    Google Scholar 

  9. Schneider P, Tschopp J. Apoptosis induced by death receptors. Pharm Acta Helv 2000; 74: 281-286.

    Google Scholar 

  10. Bonavida B, Ng CP, Jazirehi A, et al. Selectivity of TRAIL-mediated apoptosis of cancer cells and synergy with drugs: The trail to non-toxic cancer therapeutics (review). Int J Oncol 1999; 15: 793-802.

    Google Scholar 

  11. Peter ME, Scaffidi C, Medema JP, et al. The death receptors. Results Probl Cell Differ 1999; 23: 25-63.

    Google Scholar 

  12. Schulze-Osthoff K, Ferrari D, Los M, et al. Apoptosis signaling by death receptors. Eur J Biochem 1998; 254: 439-459.

    Google Scholar 

  13. Nagata S. Apoptosis by death factor. Cell 1997; 88: 355-365.

    Google Scholar 

  14. Yang X, Khosravi-Far R, Chang HY, et al. Daxx, a novel Fas-binding protein that activates JNK and apoptosis. Cell 1997; 89: 1067-1076.

    Google Scholar 

  15. Chang HY, Nishitoh H, Yang X, et al. Activation of apoptosis signal-regulating kinase 1 (ASK1) by the adapter protein Daxx. Science 1998; 281: 1860-1863.

    Google Scholar 

  16. Marsters SA, Sheridan JP, Pitti RM, et al. Identification of a ligand for the death-domain-containing receptor Apo3. Curr Biol 1998; 8: 525-528.

    Google Scholar 

  17. Chinnaiyan AM, O'Rourke K, Yu GL, et al. Signal transduction by DR3, a death domain-containing receptor related to TNFR-1 and CD95. Science 1996; 274: 990-992.

    Google Scholar 

  18. Tanaka M, Suda T, Haze K, et al. Fas ligand in human serum. Nat Med 1996; 2: 317-322.

    Google Scholar 

  19. McGeehan GM, Becherer JD, Bast RC, Jr., et al. Regulation of tumour necrosis factor-alpha processing by a metalloproteinase inhibitor. Nature 1994; 370: 558-561.

    Google Scholar 

  20. Schneider P, Holler N, Bodmer JL, et al. Conversion of membrane-bound Fas(CD95) ligand to its soluble form is associated with downregulation of its proapoptotic activity and loss of liver toxicity. J Exp Med 1998; 187: 1205-1213.

    Google Scholar 

  21. 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.

    Google Scholar 

  22. Pitti RM, Marsters SA, Ruppert S, et al. Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family. J Biol Chem 1996; 271: 12687-12690.

    Google Scholar 

  23. Rieger J, Naumann U, Glaser T, et al. APO2 ligand: A novel lethal weapon against malignant glioma? Febs Lett 1998; 427: 124-128.

    Google Scholar 

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

    Google Scholar 

  25. 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.

    Google Scholar 

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

    Google Scholar 

  27. Pan G, Ni J, Wei YF, et al. An antagonist decoy receptor and a death domain-containing receptor for TRAIL. Science 1997; 277: 815-818.

    Google Scholar 

  28. 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.

    Google Scholar 

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

    Google Scholar 

  30. 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.

    Google Scholar 

  31. Degli-Esposti MA, Dougall WC, Smolak PJ, et al. 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.

    Google Scholar 

  32. Marsters SA, Sheridan JP, Pitti RM, et al. A novel receptor for Apo2L/TRAIL contains a truncated death domain. Curr Biol 1997; 7: 1003-1006.

    Google Scholar 

  33. Pan G, Ni J, Yu G, et al. TRUNDD, a new member of the TRAIL receptor family that antagonizes TRAIL signalling. Febs Lett 1998; 424: 41-45.

    Google Scholar 

  34. Chaudhary PM, Eby M, Jasmin A, et al. Death receptor 5, a new member of the TNFR family, and DR4 induce FADD-dependent apoptosis and activate the NF-kappaB pathway. Immunity 1997; 7: 821-830.

    Google Scholar 

  35. Schneider P, Thome M, Burns K, et al. TRAIL receptors 1 (DR4) and 2 (DR5) signal FADD-dependent apoptosis and activate NF-kappaB. Immunity 1997; 7: 831-836.

    Google Scholar 

  36. Simonet WS, Lacey DL, Dunstan CR, et al. Osteoprotegerin: A novel secreted protein involved in the regulation of bone density. Cell 1997; 89: 309-319.

    Google Scholar 

  37. Emery JG, McDonnell P, Burke MB, et al. Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J Biol Chem 1998; 273: 14363-14367.

    Google Scholar 

  38. Kischkel FC, Lawrence DA, Chuntharapai A, et al. Apo2L/TRAIL-dependent recruitment of endogenous FADD and caspase-8 to death receptors 4 and 5. Immunity 2000; 12: 611-620.

    Google Scholar 

  39. Sprick MR, Weigand MA, Rieser E, et al. FADD/MORT1 and caspase-8 are recruited to TRAIL receptors 1 and 2 and are essential for apoptosis mediated by TRAIL receptor 2. Immunity 2000; 12: 599-609.

    Google Scholar 

  40. Kuang AA, Diehl GE, Zhang J, et al. FADD is required for DR4-and DR5-mediated apoptosis. Lack of trail-induced apoptosis in FADD-deficient mouse embryonic fibroblasts. J Biol Chem 2000; 275: 25065-25068.

    Google Scholar 

  41. Bodmer JL, Holler N, Reynard S, et al. TRAIL receptor-2 signals apoptosis through FADD and caspase-8. Nat Cell Biol 2000; 2: 241-243.

    Google Scholar 

  42. Rieger J, Ohgaki H, Kleihues P, et al. Human astrocytic brain tumors express AP02L/TRAIL. Acta Neuropathol (Berl) 1999; 97: 1-4.

    Google Scholar 

  43. Griffith TS, Lynch DH. TRAIL: A molecule with multiple receptors and control mechanisms. Curr Opin Immunol 1998; 10: 559-563.

    Google Scholar 

  44. Zhang XD, Franco A, Myers K, et al. 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.

    Google Scholar 

  45. 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.

    Google Scholar 

  46. Pai SI, Wu GS, Ozoren N, et al. Rare loss-of-function mutation of a death receptor gene in head and neck cancer. Cancer Res 1998; 58: 3513-3518.

    Google Scholar 

  47. Ozoren N, Fisher MJ, Kim K, et al. Homozygous deletion of the death receptor DR4 gene in a nasopharyngeal cancer cell line is associated with TRAIL resistance. Int J Oncol 2000; 16: 917-925.

    Google Scholar 

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

    Google Scholar 

  49. Walczak H, Krammer PH. The CD95 (APO-1/Fas) and the TRAIL (APO-2L) apoptosis systems. Exp Cell Res 2000; 256: 58-66.

    Google Scholar 

  50. Griffith TS, Chin WA, Jackson GC, et al. Intracellular regulation of TRAIL-induced apoptosis in human melanoma cells. J Immunol 1998; 161: 2833-2840.

    Google Scholar 

  51. Walczak H, Bouchon A, Stahl H, et al. Tumor necrosis factor-related apoptosis-inducing ligand retains its apoptosis-inducing capacity on Bcl-2-or Bcl-xL-overexpressing chemotherapy-resistant tumor cells. Cancer Res 2000; 60: 3051-3057.

    Google Scholar 

  52. Keogh SA, Walczak H, Bouchier-Hayes L, et al. Failure of Bcl-2 to block cytochrome c redistribution during TRAIL-induced apoptosis. FEBS Lett 2000; 471: 93-98.

    Google Scholar 

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

    Google Scholar 

  54. 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.

    Google Scholar 

  55. Levine AJ. p53, the cellular gatekeeper for growth and division. Cell 1997; 88: 323-331.

    Google Scholar 

  56. Wu GS, Burns TF, McDonald ER, 3rd, et al. Induction of the TRAIL receptor KILLER/DR5 in p53-dependent apoptosis but not growth arrest. Oncogene 1999; 18: 6411-6418.

    Google Scholar 

  57. El-Deiry WS. Regulation of p53 downstream genes. Semin Cancer Biol 1998; 8: 345-357.

    Google Scholar 

  58. Owen-Schaub LB, Zhang W, Cusack JC, et al. Wild-type human p53 and a temperature-sensitive mutant induce Fas/APO-1 expression. Mol Cell Biol 1995; 15: 3032-3040.

    Google Scholar 

  59. Muller M, Wilder S, Bannasch D, et al. p53 activates the CD95 (APO-1/Fas) gene in response to DNA damage by anticancer drugs. J Exp Med 1998; 188: 2033-2045.

    Google Scholar 

  60. Friesen C, Herr I, Krammer PH, et al. Involvement of the CD95 (APO-1/FAS) receptor/ligand system in drug-induced apoptosis in leukemia cells. Nat Med 1996; 2: 574-577.

    Google Scholar 

  61. Sheikh MS, Huang Y, Fernandez-Salas EA, et al. The antiapoptotic decoy receptor TRID/TRAIL-R3 is a p53-regulated DNA damage-inducible gene that is overexpressed in primary tumors of the gastrointestinal tract. Oncogene 1999; 18: 4153-4159.

    Google Scholar 

  62. Meng RD, McDonald ER, 3rd, Sheikh MS, et al. The TRAIL decoy receptor TRUNDD (DcR2, TRAIL-R4) is induced by adenovirus-p53 overexpression and can delay TRAIL-, p53-, and KILLER/DR5-dependent colon cancer apoptosis. Mol Ther 2000; 1: 130-144.

    Google Scholar 

  63. Ogasawara J, Watanabe-Fukunaga R, Adachi M, et al. Lethal effect of the anti-Fas antibody in mice. Nature 1993; 364: 806-809.

    Google Scholar 

  64. Havell EA, Fiers W, North RJ. The antitumor function of tumor necrosis factor (TNF), I. Therapeutic action of TNF against an established murine sarcoma is indirect, immunologically dependent, and limited by severe toxicity. J Exp Med 1988; 167: 1067-1085.

    Google Scholar 

  65. Marsters SA, Pitti RA, Sheridan JP, et al. Control of apoptosis signaling by Apo2 ligand. Recent Prog Horm Res 1999; 54: 225-234.

    Google Scholar 

  66. 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.

    Google Scholar 

  67. Nagane M, Pan G, Weddle JJ, et al. 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.

    Google Scholar 

  68. 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.

    Google Scholar 

  69. Frank S, Köhler U, Schackert G, et al. Expression of TRAIL and its receptors in human brain tumors. Biochem Biophys Res Commun 1999; 257: 454-459.

    Google Scholar 

  70. Gibson SB, Oyer R, Spalding AC, et al. 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.

    Google Scholar 

  71. Keane MM, Ettenberg SA, Nau MM, et al. Chemotherapy augments TRAIL-induced apoptosis in breast cell lines. Cancer Res 1999; 59: 734-741.

    Google Scholar 

  72. 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.

    Google Scholar 

  73. 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.

    Google Scholar 

  74. 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.

    Google Scholar 

  75. Nagata S. Steering anti-cancer drugs away from the TRAIL. Nat Med 2000; 6: 502-503.

    Google Scholar 

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

    Google Scholar 

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

    Google Scholar 

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Authors and Affiliations

  1. Department of Neurosurgery, Kyorin University School of Medicine, Mitaka, Tokyo, 181-8611, Japan

    M. Nagane

  2. Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA, 92093-0660

    M. Nagane

  3. Ludwig Institute for Cancer Research, Department of Medicine, University of California at San Diego, La Jolla, CA, 92093-0660

    H.-J. S. Huang

  4. Ludwig Institute for Cancer Research, Department of Medicine, Center for Molecular Genetics, Cancer Center, University of California at San Diego, La Jolla, CA, 92093-0660

    W. K. Cavenee

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  3. W. K. Cavenee
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Nagane, M., Huang, HJ.S. & Cavenee, W.K. The potential of TRAIL for cancer chemotherapy. Apoptosis 6, 191–197 (2001). https://doi.org/10.1023/A:1011336726649

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