Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Directing cancer cells to self-destruct with pro-apoptotic receptor agonists

Key Points

  • Apoptosis is a mechanism of cell suicide that has evolved in multicellular animals as a means of eliminating abnormal cells that pose a threat to the organism's life.

  • Apoptosis provides an important barrier against cancer. Occasionally, a tumour cell may acquire specific mutations, such as those that inactivate the p53 tumour-suppressor protein, which allow it to escape apoptotic death and progress to full malignancy.

  • Malignant cells remain 'primed' for apoptosis, because of their underlying aberrant properties. Therefore, drugs that can overcome anti-apoptotic changes in tumour cells might lead to important advances in cancer therapy.

  • Recent discoveries about apoptosis signalling pathways have inspired several strategies to harness this cell-death mechanism for therapeutic gain.

  • There are two key signalling pathways to control apoptosis: the extrinsic pathway, initiated outside the cell, and the intrinsic pathway, triggered from inside the cell.

  • Two major types of pro-apoptotic agents have been developed: protein-based pro-apoptotic receptor agonists (PARAs), which trigger apoptosis from the cell surface, and small molecule compounds, which activate apoptosis intracellularly.

  • PARAs that activate the DR4 and/or DR5 receptors include recombinant human Apo2L/TRAIL and agonistic DR4 and DR5 antibodies.

  • Based on preclinical data, PARAs that target DR4 and/or DR5 are particularly attractive because they display a broad spectrum of anti-tumour activity with remarkable selectivity for malignant versus normal cells. They act independently of p53 and cooperate with various chemotherapeutic drugs as well as with certain biological agents.

  • Several PARAs have met the rigorous safety criteria of Phase I clinical trials successfully, with early indications of anti-cancer activity. On that basis, a number of Phase II studies are ongoing.

  • Recent discoveries have uncovered specific diagnostic biomarkers that can assist in identifying individual cancer patients who may best benefit from PARA therapy. Differences and similarities between PARAs and their implications for clinical safety and efficacy are not yet fully understood.

  • Trials are underway to identify optimal treatment regimens that combine certain PARAs with other therapies to achieve maximal anti-cancer efficacy.

Abstract

Each day, the human body eliminates billions of unwanted cells by apoptotic suicide. Apoptosis provides an important barrier against cancer; however, specific mutations enable some tumour cells to escape apoptotic death and become more malignant. Two signalling pathways initiate apoptosis: one acts through intracellular Bcl-2 proteins, the other through cell-surface pro-apoptotic receptors. New molecular insights have inspired the development of pro-apoptotic receptor agonists (PARAs), including the recombinant human protein apoptosis ligand 2/TNF-related apoptosis-inducing ligand (Apo2L/TRAIL) and agonistic monoclonal antibodies to its signalling receptors. Acting alone, or in concert with other agents, PARAs may overcome key apoptosis blocks and direct cancer cells to self-destruct.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Key steps in apoptotic signalling pathways.
Figure 2: Pro-apoptotic receptor agonists.
Figure 3: Crystal structures of pro-apoptotic receptor agonists and DR5.
Figure 4: Potential modes of pro-apoptotic receptor activation by agonistic antibodies.
Figure 5: Identification of biomarkers that might predict tumour sensitivity to rhApo2L/TRAIL.

Similar content being viewed by others

References

  1. Jemal, A. et al. Cancer statistics, 2008. CA Cancer J. Clin. 58, 71–96 (2008).

    Article  PubMed  Google Scholar 

  2. Albreht, T., McKee, M., Alexe, D. M., Coleman, M. P. & Martin-Moreno, J. M. Making progress against cancer in Europe in 2008. Eur. J. Cancer 44, 1451–1456 (2008).

    Article  PubMed  Google Scholar 

  3. Chowdhury, I., Tharakan, B. & Bhat, G. K. Current concepts in apoptosis: the physiological suicide program revisited. Cell. Mol. Biol. Lett. 11, 506–525 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Elmore, S. Apoptosis: a review of programmed cell death. Toxicol. Pathol. 35, 495–516 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Gulbins, E., Jekle, A., Ferlinz, K., Grassme, H. & Lang, F. Physiology of apoptosis. Am. J. Physiol. Renal. Physiol. 279, F605–F615 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. Casella, C. R. & Finkel, T. H. Mechanisms of lymphocyte killing by HIV. Curr. Opin. Hematol. 4, 24–31 (1997).

    Article  CAS  PubMed  Google Scholar 

  7. Rohn, T. T., Head, E., Nesse, W. H., Cotman, C. W. & Cribbs, D. H. Activation of caspase-8 in the Alzheimer's disease brain. Neurobiol. Dis. 8, 1006–1016 (2001).

    Article  CAS  PubMed  Google Scholar 

  8. Sanchez Mejia, R. O. & Friedlander, R. M. Caspases in Huntington's disease. Neuroscientist 7, 480–489 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. Hayakawa, K. et al. Sensitivity to apoptosis signal, clearance rate, and ultrastructure of fas ligand-induced apoptosis in in vivo adult cardiac cells. Circulation 105, 3039–3045 (2002).

    Article  CAS  PubMed  Google Scholar 

  10. Singh, A. B., Kaushal, V., Megyesi, J. K., Shah, S. V. & Kaushal, G. P. Cloning and expression of rat caspase-6 and its localization in renal ischemia/reperfusion injury. Kidney Int. 62, 106–115 (2002).

    Article  CAS  PubMed  Google Scholar 

  11. Prasad, K. V. & Prabhakar, B. S. Apoptosis and autoimmune disorders. Autoimmunity 36, 323–330 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. Gerl, R. & Vaux, D. L. Apoptosis in the development and treatment of cancer. Carcinogenesis 26, 263–270 (2005).

    Article  CAS  PubMed  Google Scholar 

  13. Fan, T. J., Han, L. H., Cong, R. S. & Liang, J. Caspase family proteases and apoptosis. Acta Biochim. Biophys. Sin. (Shanghai) 37, 719–727 (2005).

    Article  CAS  PubMed  Google Scholar 

  14. Lavrik, I. N., Golks, A. & Krammer, P. H. Caspases: pharmacological manipulation of cell death. J. Clin. Invest. 115, 2665–2672 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Thornberry, N. A. Caspases: a decade of death research. Cell Death Differ. 6, 1023–1027 (1999).

    Article  CAS  PubMed  Google Scholar 

  16. Boatright, K. M. et al. A unified model for apical caspase activation. Mol. Cell 11, 529–541 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Nagata, S. Apoptotic DNA fragmentation. Exp. Cell Res. 256, 12–18 (2000).

    Article  CAS  PubMed  Google Scholar 

  18. Coultas, L. & Strasser, A. The role of the Bcl-2 protein family in cancer. Semin. Cancer Biol. 13, 115–123 (2003).

    Article  CAS  PubMed  Google Scholar 

  19. Letai, A. Pharmacological manipulation of Bcl-2 family members to control cell death. J. Clin. Invest. 115, 2648–2655 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chinnaiyan, A. M. The apoptosome: heart and soul of the cell death machine. Neoplasia 1, 5–15 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. van Loo, G. et al. The role of mitochondrial factors in apoptosis: a Russian roulette with more than one bullet. Cell Death Differ. 9, 1031–1042 (2002).

    Article  CAS  PubMed  Google Scholar 

  22. Ashkenazi, A. & Dixit, V. M. Death receptors: signaling and modulation. Science 281, 1305–1308 (1998).

    Article  CAS  PubMed  Google Scholar 

  23. Nagata, S. Apoptosis by death factor. Cell 88, 355–365 (1997).

    Article  CAS  PubMed  Google Scholar 

  24. Peter, M. E. & Krammer, P. H. The CD95(APO-1/Fas) DISC and beyond. Cell Death Differ. 10, 26–35 (2003).

    Article  CAS  PubMed  Google Scholar 

  25. Ashkenazi, A. Targeting death and decoy receptors of the tumour-necrosis factor superfamily. Nature Rev. Cancer 2, 420–430 (2002).

    Article  CAS  Google Scholar 

  26. Pitti, R. M. et al. Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer. Nature 396, 699–703 (1998).

    Article  CAS  PubMed  Google Scholar 

  27. Clancy, L. et al. Preligand assembly domain-mediated ligand-independent association between TRAIL receptor 4 (TR4) and TR2 regulates TRAIL-induced apoptosis. Proc. Natl Acad. Sci. USA 102, 18099–18104 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wagner, K. W. et al. Death-receptor O-glycosylation controls tumor-cell sensitivity to the proapoptotic ligand Apo2L/TRAIL. Nature Med. 13, 1070–1077 (2007). This study identifies specific biomarkers that robustly predict sensitivity to rhApo2L/TRAIL across numerous and diverse cancer cell lines.

    Article  CAS  PubMed  Google Scholar 

  29. Feig, C., Tchikov, V., Schutze, S. & Peter, M. E. Palmitoylation of CD95 facilitates formation of SDS-stable receptor aggregates that initiate apoptosis signaling. EMBO J. 26, 221–231 (2007).

    Article  CAS  PubMed  Google Scholar 

  30. Muppidi, J. R. & Siegel, R. M. Ligand-independent redistribution of Fas (CD95) into lipid rafts mediates clonotypic T cell death. Nature Immunol. 5, 182–189 (2004).

    Article  CAS  Google Scholar 

  31. Lee, K. H. et al. The role of receptor internalization in CD95 signaling. EMBO J. 25, 1009–1023 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Austin, C. D. et al. Death-receptor activation halts clathrin-dependent endocytosis. Proc. Natl Acad. Sci. USA 103, 10283–10288 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kohlhaas, S. L., Craxton, A., Sun, X. M., Pinkoski, M. J. & Cohen, G. M. Receptor-mediated endocytosis is not required for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. J. Biol. Chem. 282, 12831–12841 (2007).

    Article  CAS  PubMed  Google Scholar 

  34. Karin, M. & Lin, A. NF-kB at the crossroads of life and death. Nature Immunol. 3, 221–227 (2002).

    Article  CAS  Google Scholar 

  35. Micheau, O. & Tschopp, J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell 114, 181–190 (2003).

    Article  CAS  PubMed  Google Scholar 

  36. Varfolomeev, E. E. & Ashkenazi, A. Tumor necrosis factor: an apoptosis JuNKie? Cell 116, 491–497 (2004).

    Article  CAS  PubMed  Google Scholar 

  37. Letai, A. G. Diagnosing and exploiting cancer's addiction to blocks in apoptosis. Nature Rev. Cancer 8, 121–132 (2008).

    Article  CAS  Google Scholar 

  38. Nieminen, A. I., Partanen, J. I., Hau, A. & Klefstrom, J. c-Myc primed mitochondria determine cellular sensitivity to TRAIL-induced apoptosis. EMBO J. 26, 1055–1067 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Igney, F. H. & Krammer, P. H. Death and anti-death: tumour resistance to apoptosis. Nature Rev. Cancer 2, 277–288 (2002).

    Article  CAS  Google Scholar 

  40. Hollstein, M., et al. Database of p53 gene somatic mutations in human tumors and cell lines. Nucleic Acids Res. 22, 3551–3555 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Levine, A. J. p53, the cellular gatekeeper for growth and division. Cell 88, 323–331 (1997).

    Article  CAS  PubMed  Google Scholar 

  42. Ghobrial, I. M., Witzig, T. E. & Adjei, A. A. Targeting apoptosis pathways in cancer therapy. CA Cancer J. Clin. 55, 178–194 (2005).

    Article  PubMed  Google Scholar 

  43. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).

    Article  CAS  PubMed  Google Scholar 

  44. Kaufmann, S. H. & Vaux, D. L. Alterations in the apoptotic machinery and their potential role in anticancer drug resistance. Oncogene 22, 7414–7430 (2003).

    Article  CAS  PubMed  Google Scholar 

  45. Lowe, S. W., Cepero, E. & Evan, G. Intrinsic tumour suppression. Nature 432, 307–315 (2004).

    Article  CAS  PubMed  Google Scholar 

  46. Bin, L. et al. Tumor-derived mutations in the TRAIL receptor DR5 inhibit TRAIL signaling through the DR4 receptor by competing for ligand binding. J. Biol. Chem. 282, 28189–28194 (2007).

    Article  CAS  PubMed  Google Scholar 

  47. Harada, K. et al. Deregulation of caspase 8 and 10 expression in pediatric tumors and cell lines. Cancer Res. 62, 5897–5901 (2002).

    CAS  PubMed  Google Scholar 

  48. Russo, A., Terrasi, M., Agnese, V., Santini, D. & Bazan, V. Apoptosis: a relevant tool for anticancer therapy. Ann. Oncol. 17 (Suppl. 7), 115–123 (2006).

    Article  Google Scholar 

  49. Viardot, A., Barth, T. F., Moller, P., Dohner, H. & Bentz, M. Cytogenetic evolution of follicular lymphoma. Semin. Cancer Biol. 13, 183–190 (2003).

    Article  PubMed  Google Scholar 

  50. Kim, M. S., Jeong, E. G., Yoo, N. J. & Lee, S. H. Mutational analysis of oncogenic AKT E17K mutation in common solid cancers and acute leukaemias. Br. J. Cancer 98, 1533–1535 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Rampino, N. et al. Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. Science 275, 967–969 (1997).

    Article  CAS  PubMed  Google Scholar 

  52. Wang, Y., Quon, K. C., Knee, D. A., Nesterov, A. & Kraft, A. S. RAS, MYC, and sensitivity to tumor necrosis factor-a-related apoptosis-inducing ligand-induced apoptosis. Cancer Res. 65, 1615–1616 (2005). This paper provides direct evidence that oncogenes can sensitize cells to apoptosis stimulation by a PARA.

    Article  CAS  PubMed  Google Scholar 

  53. Lee, J. M. & Bernstein, A. Apoptosis, cancer and the p53 tumour suppressor gene. Cancer Metastasis Rev. 14, 149–161 (1995).

    Article  CAS  PubMed  Google Scholar 

  54. Cuello, M. et al. Down-regulation of the erbB-2 receptor by trastuzumab (herceptin) enhances tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in breast and ovarian cancer cell lines that overexpress erbB-2. Cancer Res. 61, 4892–4900 (2001).

    CAS  PubMed  Google Scholar 

  55. Kim, S. H., Ricci, M. S. & El Deiry, W. S. Mcl-1: a gateway to TRAIL sensitization. Cancer Res. 68, 2062–2064 (2008).

    Article  CAS  PubMed  Google Scholar 

  56. Panner, A., Parsa, A. T. & Pieper, R. O. Use of APO2L/TRAIL with mTOR inhibitors in the treatment of glioblastoma multiforme. Expert Rev. Anticancer Ther. 6, 1313–1322 (2006).

    Article  CAS  PubMed  Google Scholar 

  57. Poh, T. W., Huang, S., Hirpara, J. L. & Pervaiz, S. LY303511 amplifies TRAIL-induced apoptosis in tumor cells by enhancing DR5 oligomerization, DISC assembly, and mitochondrial permeabilization. Cell Death Differ. 14, 1813–1825 (2007).

    Article  CAS  PubMed  Google Scholar 

  58. Guo, F. et al. Ectopic overexpression of second mitochondria-derived activator of caspases (Smac/DIABLO) or cotreatment with N-terminus of Smac/DIABLO peptide potentiates epothilone B derivative-(BMS 247550) and Apo-2L/TRAIL-induced apoptosis. Blood 99, 3419–3426 (2002).

    Article  CAS  PubMed  Google Scholar 

  59. Li, L. et al. A small molecule Smac mimic potentiates T. Science 305, 1471–1474 (2004).

    Article  CAS  PubMed  Google Scholar 

  60. Ou, D. et al. Synergistic inhibition of tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in human pancreatic beta cells by Bcl-2 and X-linked inhibitor of apoptosis. Hum. Immunol. 66, 274–284 (2005).

    Article  CAS  PubMed  Google Scholar 

  61. Ray, S., Bucur, O. & Almasan, A. Sensitization of prostate carcinoma cells to Apo2L/TRAIL by a Bcl-2 family protein inhibitor. Apoptosis 10, 1411–1418 (2005).

    Article  CAS  PubMed  Google Scholar 

  62. Hersh, E. M. et al. Phase II studies of recombinant human tumor necrosis factor-a in patients with malignant disease: a summary of the Southwest Oncology Group experience. J. Immunother. 10, 426–431 (1991).

    Article  CAS  PubMed  Google Scholar 

  63. Grunhagen, D. J., De Wilt, J. H., Graveland, W. J., van Geel, A. N. & Eggermont, A. M. The palliative value of tumor necrosis factor-a-based isolated limb perfusion in patients with metastatic sarcoma and melanoma. Cancer 106, 156–162 (2006).

    Article  PubMed  Google Scholar 

  64. Ogasawara, J. et al. Lethal effect of the anti-Fas antibody in mice. Nature 364, 806–809 (1993).

    Article  CAS  PubMed  Google Scholar 

  65. Walczak, H. et al. Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nature Med. 5, 157–163 (1999).

    Article  CAS  PubMed  Google Scholar 

  66. Bouralexis, S., Findlay, D. M. & Evdokiou, A. Death to the bad guys: targeting cancer via Apo2L/TRAIL. Apoptosis 10, 35–51 (2005).

    Article  CAS  PubMed  Google Scholar 

  67. Kelley, S. K. & Ashkenazi, A. Targeting death receptors in cancer with Apo2L/TRAIL. Curr. Opin. Pharmacol. 4, 333–339 (2004).

    Article  CAS  PubMed  Google Scholar 

  68. Rowinsky, E. K. Curtailing the high rate of late-stage attrition of investigational therapeutics against unprecedented targets in patients with lung and other malignancies. Clin. Cancer Res. 10, 4220s–4226s (2004).

    Article  CAS  PubMed  Google Scholar 

  69. Pitti, R. M. et al. Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family. J. Biol. Chem. 271, 12687–12690 (1996).

    Article  CAS  PubMed  Google Scholar 

  70. Wiley, S. R. et al. Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 3, 673–682 (1995).

    Article  CAS  PubMed  Google Scholar 

  71. Sedger, L. M. et al. IFNg mediates a novel antiviral activity through dynamic modulation of TRAIL and TRAIL receptor expression. J. Immunol. 163, 920–926 (1999).

    CAS  PubMed  Google Scholar 

  72. Takeda, K. et al. Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells. Nature Med. 7, 94–100 (2001).

    Article  CAS  PubMed  Google Scholar 

  73. Wang, S. & El Deiry, W. S. TRAIL and apoptosis induction by TNF-family death receptors. Oncogene 22, 8628–8633 (2003).

    Article  CAS  PubMed  Google Scholar 

  74. Hamilton, S. E., Wolkers, M. C., Schoenberger, S. P. & Jameson, S. C. The generation of protective memory-like CD8+ T cells during homeostatic proliferation requires CD4+ T cells. Nature Immunol. 7, 475–481 (2006).

    Article  CAS  Google Scholar 

  75. Huntington, N. D. et al. Interleukin 15-mediated survival of natural killer cells is determined by interactions among Bim, Noxa and Mcl-1. Nature Immunol. 8, 856–863 (2007).

    Article  CAS  Google Scholar 

  76. Janssen, E. M. et al. CD4+ T-cell help controls CD8+ T-cell memory via TRAIL-mediated activation-induced cell death. Nature 434, 88–93 (2005).

    Article  CAS  PubMed  Google Scholar 

  77. Finnberg, N., Klein-Szanto, A. J. & El Deiry, W. S. TRAIL-R deficiency in mice promotes susceptibility to chronic inflammation and tumorigenesis. J. Clin. Invest. 118, 111–123 (2008).

    Article  CAS  PubMed  Google Scholar 

  78. Grosse-Wilde, A. et al. TRAIL-R deficiency in mice enhances lymph node metastasis without affecting primary tumor development. J. Clin. Invest. 118, 100–110 (2008).

    Article  CAS  PubMed  Google Scholar 

  79. Laguinge, L. M. et al. DR5 receptor mediates anoikis in human colorectal carcinoma cell lines. Cancer Res. 68, 909–917 (2008).

    Article  CAS  PubMed  Google Scholar 

  80. Diehl, G. E. et al. TRAIL-R as a negative regulator of innate immune cell responses. Immunity 21, 877–889 (2004).

    Article  CAS  PubMed  Google Scholar 

  81. Wang, S. & El Deiry, W. S. Inducible silencing of KILLER/DR5 in vivo promotes bioluminescent colon tumor xenograft growth and confers resistance to chemotherapeutic agent 5-fluorouracil. Cancer Res. 64, 6666–6672 (2004).

    Article  CAS  PubMed  Google Scholar 

  82. Almasan, A. & Ashkenazi, A. Apo2L/TRAIL: apoptosis signaling, biology, and potential for cancer therapy. Cytokine Growth Factor Rev. 14, 337–348 (2003).

    Article  CAS  PubMed  Google Scholar 

  83. Smyth, M. J. et al. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) contributes to interferon g-dependent natural killer cell protection from tumor metastasis. J. Exp. Med. 193, 661–670 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Wu, G. S. et al. KILLER/DR5 is a DNA damage-inducible p53-regulated death receptor gene. Nature Genet. 17, 141–143 (1997).

    Article  CAS  PubMed  Google Scholar 

  85. Ashkenazi, A. et al. Safety and antitumor activity of recombinant soluble Apo2 ligand. J. Clin. Invest. 104, 155–162 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Ashkenazi, A., Holland, P. & Eckhardt, S. G. Ligand-based targeting of apoptosis in cancer: the potential of recombinant human apoptosis ligand 2/Tumor necrosis factor-related apoptosis-inducing ligand (rhApo2L/TRAIL). J. Clin. Oncol. 26, 3621–3630 (2008).

    Article  CAS  PubMed  Google Scholar 

  87. Georgakis, G. V. 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. 130, 501–510 (2005).

    Article  CAS  PubMed  Google Scholar 

  88. Guo, Y. et al. A novel anti-human DR5 monoclonal antibody with tumoricidal activity induces caspase-dependent and caspase-independent cell death. J. Biol. Chem. 280, 41940–41952 (2005).

    Article  CAS  PubMed  Google Scholar 

  89. Ichikawa, K. et al. Tumoricidal activity of a novel anti-human DR5 monoclonal antibody without hepatocyte cytotoxicity. Nature Med. 7, 954–960 (2001).

    Article  CAS  PubMed  Google Scholar 

  90. Motoki, K. et al. Enhanced apoptosis and tumor regression induced by a direct agonist antibody to tumor necrosis factor-related apoptosis-inducing ligand receptor 2. Clin. Cancer. Res. 11, 3126–3135 (2005). Refs. 87–90 demonstrate in vivo anti-tumour activity of agonist antibodies to DR4 or DR5 in xenograft models.

    Article  CAS  PubMed  Google Scholar 

  91. Plummer, R. et al. Phase 1 and pharmacokinetic study of lexatumumab in patients with advanced cancers. Clin. Cancer. Res. 13, 6187–6194 (2007).

    Article  CAS  PubMed  Google Scholar 

  92. Pukac, L. et al. HGS-ETR1, a fully human TRAIL-receptor 1 monoclonal antibody, induces cell death in multiple tumour types in vitro and in vivo. Br. J. Cancer 92, 1430–1441 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Tolcher, A. W. et al. Phase I pharmacokinetic and biologic correlative study of mapatumumab, a fully human monoclonal antibody with agonist activity to tumor necrosis factor-related apoptosis-inducing ligand receptor-1. J. Clin. Oncol. 25, 1390–1395 (2007).

    Article  CAS  PubMed  Google Scholar 

  94. Zhang, L., Zhang, X., Barrisford, G. W. & Olumi, A. F. Lexatumumab (TRAIL-receptor 2 mAb) induces expression of DR5 and promotes apoptosis in primary and metastatic renal cell carcinoma in a mouse orthotopic model. Cancer Lett. 251, 146–157 (2007).

    Article  CAS  PubMed  Google Scholar 

  95. Krammer, P. H., Behrmann, I., Daniel, P., Dhein, J. & Debatin, K. M. Regulation of apoptosis in the immune system. Curr. Opin. Immunol. 6, 279–289 (1994).

    Article  CAS  PubMed  Google Scholar 

  96. Bodmer, J. L., Meier, P., Tschopp, J. & Schneider, P. Cysteine 230 is essential for the structure and activity of the cytotoxic ligand TRAIL. J. Biol. Chem. 275, 20632–20637 (2000).

    Article  CAS  PubMed  Google Scholar 

  97. Keane, M. M., Ettenberg, S. A., Nau, M. M., Russell, E. K. & Lipkowitz, S. Chemotherapy augments TRAIL-induced apoptosis in breast cell lines. Cancer Res. 59, 734–741 (1999).

    CAS  PubMed  Google Scholar 

  98. Ashkenazi, A., Herbst, R. S. To kill a tumor cell: the potential of proapoptotic receptor agonists. J. Clin. Invest. 118, 1979–1990 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Hymowitz, S. G. et al. Triggering cell death: the crystal structure of Apo2L/TRAIL in a complex with death receptor 5. Mol. Cell 4, 563–571 (1999).

    Article  CAS  PubMed  Google Scholar 

  100. Lawrence, D. et al. Differential hepatocyte toxicity of recombinant Apo2L/TRAIL versions. Nature Med. 7, 383–385 (2001).

    Article  CAS  PubMed  Google Scholar 

  101. LoRusso, P. et al. First-in-human study of AMG 655, a pro-apoptotic TRAIL receptor-2 agonist, in adult patients with advanced solid tumors. J. Clin. Oncol. Abstr. 25, 3534 (2007).

    Article  Google Scholar 

  102. Jo, M. et al. Apoptosis induced in normal human hepatocytes by tumor necrosis factor-related apoptosis-inducing ligand. Nature Med. 6, 564–567 (2000).

    Article  CAS  PubMed  Google Scholar 

  103. Ganten, T. M. et al. Preclinical differentiation between apparently safe and potentially hepatotoxic applications of TRAIL either alone or in combination with chemotherapeutic drugs. Clin. Cancer. Res. 12, 2640–2646 (2006).

    Article  CAS  PubMed  Google Scholar 

  104. Hao, C., et al. TRAIL inhibits tumor growth but is nontoxic to human hepatocytes in chimeric mice. Cancer Res. 64, 8502–8506 (2004).

    Article  CAS  PubMed  Google Scholar 

  105. Adams, C. et al. Structural and functional analysis of the interaction between the agonistic monoclonal antibody Apomab and the proapoptotic receptor DR5. Cell Death Differ. 15, 751–761 (2008). This paper reports the X-ray crystal structure of an agonist antibody in complex with a pro-apoptotic receptor, providing insights into the potential mechanisms of apoptosis activation.

    Article  CAS  PubMed  Google Scholar 

  106. Sheridan, J. P. et al. Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science 277, 818–821 (1997).

    Article  CAS  PubMed  Google Scholar 

  107. Marini, P. Drug evaluation: lexatumumab, an intravenous human agonistic mAb targeting TRAIL receptor 2. Curr. Opin. Mol. Ther. 8, 539–546 (2006).

    CAS  PubMed  Google Scholar 

  108. Hymowitz, S. G. et al. A unique zinc-binding site revealed by a high-resolution X-ray structure of homotrimeric Apo2L/TRAIL. Biochemistry 39, 633–640 (2000).

    Article  CAS  PubMed  Google Scholar 

  109. Yu, R., Mandlekar, S., Ruben, S., Ni, J. & Kong, A. N. Tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in androgen-independent prostate cancer cells. Cancer Res. 60, 2384–2389 (2000).

    CAS  PubMed  Google Scholar 

  110. Mitsiades, N., Poulaki, V., Tseleni-Balafouta, S., Koutras, D. A. & Stamenkovic, I. Thyroid carcinoma cells are resistant to FAS-mediated apoptosis but sensitive to tumor necrosis factor-related apoptosis-inducing ligand. Cancer Res. 60, 4122–4129 (2000).

    CAS  PubMed  Google Scholar 

  111. Xia, X. X., Shen, Y. L. & Wei, D. Z. Purification and characterization of recombinant sTRAIL expressed in Escherichia coli. Acta Biochim. Biophys. Sin. (Shanghai) 36, 118–122 (2004).

    Article  CAS  PubMed  Google Scholar 

  112. Yao, G. H. et al. Induction of apoptosis by recombinant soluble human TRAIL in Jurkat cells. Biomed. Environ. Sci. 20, 470–477 (2007).

    CAS  PubMed  Google Scholar 

  113. Mitsiades, C. S. et al. TRAIL/Apo2L ligand selectively induces apoptosis and overcomes drug resistance in multiple myeloma: therapeutic applications. Blood 98, 795–804 (2001).

    Article  CAS  PubMed  Google Scholar 

  114. Daniel, D. et al. Cooperation of the proapoptotic receptor agonist rhApo2L/TRAIL with the CD20 antibody rituximab against non-Hodgkin lymphoma xenografts. Blood 110, 4037–4046 (2007). This study demonstrated in vivo synergy between rhApo2L/TRAIL and rituximab against non-Hodgkin's lymphoma xenografts and provided insight into the underlying mechanism.

    Article  CAS  PubMed  Google Scholar 

  115. Kelley, S. K. 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. 299, 31–38 (2001).

    CAS  PubMed  Google Scholar 

  116. Jin, H. et al. Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand cooperates with chemotherapy to inhibit orthotopic lung tumor growth and improve survival. Cancer Res. 64, 4900–4905 (2004).

    Article  CAS  PubMed  Google Scholar 

  117. Hylander, B. L. et al. The anti-tumor effect of Apo2L/TRAIL on patient pancreatic adenocarcinomas grown as xenografts in SCID mice. J. Transl. Med. 3, 22 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Pollack, I. F., 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. 7, 1362–1369 (2001).

    CAS  PubMed  Google Scholar 

  119. Roth, W. et al. Locoregional Apo2L/TRAIL eradicates intracranial human malignant glioma xenografts in athymic mice in the absence of neurotoxicity. Biochem. Biophys. Res. Commun. 265, 479–483 (1999).

    Article  CAS  PubMed  Google Scholar 

  120. Cuello, M., Ettenberg, S. A., Nau, M. M. & Lipkowitz, S. Synergistic induction of apoptosis by the combination of trail and chemotherapy in chemoresistant ovarian cancer cells. Gynecol. Oncol. 81, 380–390 (2001).

    Article  CAS  PubMed  Google Scholar 

  121. El Zawahry, A., McKillop, J. & Voelkel-Johnson, C. Doxorubicin increases the effectiveness of Apo2L/TRAIL for tumor growth inhibition of prostate cancer xenografts. BMC Cancer 5, 2 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Frese, S. Brunner, T., Gugger, M., Uduehi, A. & Schmid, R. A. Enhancement of Apo2L/TRAIL (tumor necrosis factor-related apoptosis-inducing ligand)-induced apoptosis in non-small cell lung cancer cell lines by chemotherapeutic agents without correlation to the expression level of cellular protease caspase-8 inhibitory protein. J. Thorac. Cardiovasc. Surg. 123, 168–174 (2002).

    Article  CAS  PubMed  Google Scholar 

  123. 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. 59, 6153–6158 (1999).

    CAS  PubMed  Google Scholar 

  124. Lacour, S. et al. Anticancer agents sensitize tumor cells to tumor necrosis factor-related apoptosis-inducing ligand-mediated caspase-8 activation and apoptosis. Cancer Res. 61, 1645–1651 (2001).

    CAS  PubMed  Google Scholar 

  125. Mizutani, Y., Yoshida, O., Miki, T. & Bonavida, B. Synergistic cytotoxicity and apoptosis by Apo-2 ligand and adriamycin against bladder cancer cells. Clin. Cancer. Res. 5, 2605–2612 (1999).

    CAS  PubMed  Google Scholar 

  126. Xiang, H. et al. Enhanced tumor killing by Apo2L/TRAIL and CPT-11 co-treatment is associated with p21 cleavage and differential regulation of Apo2L/TRAIL ligand and its receptors. Oncogene 21, 3611–3619 (2002).

    Article  CAS  PubMed  Google Scholar 

  127. Nimmanapalli, R. et al. Pretreatment with paclitaxel enhances Apo-2 ligand/tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis of prostate cancer cells by inducing death receptors 4 and 5 protein levels. Cancer Res. 61, 759–763 (2001).

    CAS  PubMed  Google Scholar 

  128. Odoux, C. & Albers, A. Additive effects of TRAIL and paclitaxel on cancer cells: implications for advances in cancer therapy. Vitam. Horm. 67, 385–407 (2004).

    Article  CAS  PubMed  Google Scholar 

  129. Ravi, R. et al. Elimination of hepatic metastases of colon cancer cells via p53-independent cross-talk between irinotecan and Apo2 ligand/TRAIL. Cancer Res. 64, 9105–9114 (2004).

    Article  CAS  PubMed  Google Scholar 

  130. Ray, S. & Almasan, A. Apoptosis induction in prostate cancer cells and xenografts by combined treatment with Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand and CPT-11. Cancer Res. 63, 4713–4723 (2003).

    CAS  PubMed  Google Scholar 

  131. Vignati, S., Codegoni, A., Polato, F. & Broggini, M. Trail activity in human ovarian cancer cells: potentiation of the action of cytotoxic drugs. Eur. J. Cancer 38, 177–183 (2002).

    Article  CAS  PubMed  Google Scholar 

  132. Ricci, M. S. et al. Reduction of TRAIL-induced Mcl-1 and cIAP2 by c-Myc or sorafenib sensitizes resistant human cancer cells to TRAIL-induced death. Cancer Cell 12, 66–80 (2007).

    Article  CAS  PubMed  Google Scholar 

  133. Hyer, M. L. et al. Synthetic triterpenoids cooperate with tumor necrosis factor related apoptosis inducing ligand to induce apoptosis of breast cancer cells. Cancer Res. 65, 4799–4808 (2005).

    Article  CAS  PubMed  Google Scholar 

  134. Naka, T. et al. Effects of tumor necrosis factor-related apoptosis-inducing ligand alone and in combination with chemotherapeutic agents on patients' colon tumors grown in SCID mice. Cancer Res. 62, 5800–5806 (2002).

    CAS  PubMed  Google Scholar 

  135. Meng, X. W. et al. Mcl-1 as a buffer for proapoptotic Bcl-2 family members during TRAIL-induced apoptosis: a mechanistic basis for sorafenib (Bay 43–9006)-induced TRAIL sensitization. J. Biol. Chem. 82, 29831–29846 (2007).

    Article  CAS  Google Scholar 

  136. Rosato, R. R., Almenara, J. A., Coe, S. & Grant, S. The multikinase inhibitor sorafenib potentiates TRAIL lethality in human leukemia cells in association with Mcl-1 and cFLIPL down-regulation. Cancer Res. 67, 9490–9500 (2007).

    Article  CAS  PubMed  Google Scholar 

  137. Shankar, S. 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. 24, 1133–1114 (2004).

    CAS  PubMed  Google Scholar 

  138. Shankar, S., Singh, T. R. and Srivastava, R. K. Ionizing radiation enhances the therapeutic potential of TRAIL in prostate cancer in vitro and in vivo: Intracellular mechanisms. Prostate 61, 35–49 (2004).

    Article  CAS  PubMed  Google Scholar 

  139. Fulda, S., Wick, W., Weller, M. & Debatin, K. M. Smac agonists sensitize for Apo2L/T. Nature Med. 8, 808–815 (2002).

    Article  CAS  PubMed  Google Scholar 

  140. Brooks, A. D. et al. The proteasome inhibitor bortezomib (Velcade) sensitizes some human tumor cells to Apo2L/TRAIL-mediated apoptosis. Ann. NY Acad. Sci. 1059, 160–167 (2005).

    Article  CAS  PubMed  Google Scholar 

  141. Johnson, T. R. et al. The proteasome inhibitor PS-341 overcomes TRAIL resistance in Bax and caspase 9-negative or Bcl-xL overexpressing cells. Oncogene 22, 4953–4963 (2003).

    Article  CAS  PubMed  Google Scholar 

  142. Zhu, H. et al. Proteasome inhibitors-mediated TRAIL resensitization and Bik accumulation. Cancer Biol. Ther. 4, 781–786 (2005).

    Article  CAS  PubMed  Google Scholar 

  143. Nakata, S. et al. Histone deacetylase inhibitors upregulate death receptor 5/TRAIL-R2 and sensitize apoptosis induced by TRAIL/APO2-L in human malignant tumor cells. Oncogene 23, 6261–6271 (2004).

    Article  CAS  PubMed  Google Scholar 

  144. Kelley, R. F. et al. Receptor-selective mutants of apoptosis-inducing ligand 2/tumor necrosis factor-related apoptosis-inducing ligand reveal a greater contribution of death receptor (DR) 5 than DR4 to apoptosis signaling. J. Biol. Chem. 280, 2205–2212 (2005).

    Article  CAS  PubMed  Google Scholar 

  145. Eggert, A. et al. Resistance to TRAIL-induced apoptosis in neuroblastoma cells correlates with a loss of caspase-8 expression. Med. Pediatr. Oncol. 35, 603–607 (2000).

    Article  CAS  PubMed  Google Scholar 

  146. LeBlanc, H. N. & Ashkenazi, A. Apo2L/TRAIL and its death and decoy receptors. Cell Death Differ. 10, 66–75 (2003).

    Article  CAS  PubMed  Google Scholar 

  147. Fulda, S., Meyer, E. & Debatin, K. M. Inhibition of TRAIL-induced apoptosis by Bcl-2 overexpression. Oncogene 21, 2283–2294 (2002).

    Article  CAS  PubMed  Google Scholar 

  148. Jonsson, G., Paulie, S. & Grandien, A. High level of cFLIP correlates with resistance to death receptor-induced apoptosis in bladder carcinoma cells. Anticancer Res. 23, 1213–1218 (2003).

    PubMed  Google Scholar 

  149. Ullenhag, G. J. et al. Overexpression of FLIPL is an independent marker of poor prognosis in colorectal cancer patients. Clin. Cancer. Res. 13, 5070–5075 (2007).

    Article  CAS  PubMed  Google Scholar 

  150. Zhang, L. & Fang, B. Mechanisms of resistance to TRAIL-induced apoptosis in cancer. Cancer Gene Ther. 12, 228–237 (2005).

    Article  CAS  PubMed  Google Scholar 

  151. Ricci, M. S. et al. Direct repression of FLIP expression by c-myc is a major determinant of TRAIL sensitivity. Mol. Cell Biol. 24, 8541–8555 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Baritaki, S. et al. Regulation of tumor cell sensitivity to TRAIL-induced apoptosis by the metastatic suppressor Raf kinase inhibitor protein via Yin Yang 1 inhibition and death receptor 5 up-regulation. J. Immunol. 179, 5441–5453 (2007).

    Article  CAS  PubMed  Google Scholar 

  153. Rahman, M., et al. TRAIL induces apoptosis in triple-negative breast cancer cells with a mesenchymal phenotype. Breast Cancer Res. Treat 12 Feb 2008 [Epub ahead of print].

  154. Herbst, R. S. et al. A Phase I safety and pharmacokinetic study in patients with advanced cancer treated with recombinant Apo2L/TRAIL, an apoptosis-inducing protein. J. Clin. Oncol. Abstr. 24, 3013 (2006).

    Article  CAS  Google Scholar 

  155. Fanale, M., et al. Results of a phase Ib study of recombinant human Apo2L/TRAIL with rituximab in patients with relapsed, low-grade NHL. Ann. Oncol. Abstr. 19 (Suppl 4), iv161 (2008).

    Google Scholar 

  156. Soria, J. et al. Phase Ib study of recombinant human (rh)Apo2L/TRAIL in combination with paclitaxel, carboplatin, and bevacizumab (PCB) in patients (pts) with advanced non-small cell lung cancer (NSCLC). J. Clin. Oncol. Abstr. 26 (Suppl.), 3539 (2008).

    Article  Google Scholar 

  157. Jin, H. et al. Cooperation of the agonistic DR5 antibody Apomab with chemotherapy to inhibit orthotopic lung tumor growth and improve survival. Clin. Canc. Res. (in the press)

  158. Hotte, S. J. et al. A Phase 1 study of mapatumumab (fully human monoclonal antibody to TRAIL-R1) in patients with advanced solid malignancies. Clin. Cancer. Res. 14, 3450–3455 (2008).

    Article  CAS  PubMed  Google Scholar 

  159. Chow, L. Q. et al. HGS-ETR1, an antibody targeting TRAIL-R1, in combination with paclitaxel and carboplatin in patients with advanced solid malignancies: Results of a phase 1 and PK study. J. Clin. Oncol. Abstr. 24 (Suppl. 18), 2515 (2006).

    Google Scholar 

  160. Oldenhuis, C., et al. A phase I study with the agonistic TRAIL-R1 antibody, mapatumumab, in combination with gemcitabine and cisplatin. J. Clin. Oncol. Abstr. 26 (Suppl.), 3540 (2008).

    Article  Google Scholar 

  161. Younes, A., Vose, J. M. & Zelenetz, A. D. Results of a Phase 2 trial of HGS-ETR1 (agonistic human monoclonal antibody to TRAIL receptor 1) in subjects with relapsed/refractory non-Hodgkin's lymphoma (ETR1-HM01). Blood Abstr. 106, 489 (2005).

    Google Scholar 

  162. Kanzler, S., Trarbach, T., Heinemann, V., Koehne, C. H. & Seeber, S. Results of a Phase 2 trial of HGS-ETR1 (agonistic human monoclonal antibody to TRAIL receptor 1) in subjects with relapsed or refractory colorectal cancer (CRC). Abstract 630. 13th European Cancer Conference, Paris, France October 30–November 3, 2005.

    Google Scholar 

  163. Bonomi, P. et al. Results of a Phase 2 trial of HGS-ETR1 (agonistic human monoclonal antibody to TRAIL receptor 1) in subjects with relapsed/recurrent non-small cell lung cancer. Abstract 1851. 11th World Conference on Lung Cancer, Barcelona, Spain July 3–6. 2005.

    Google Scholar 

  164. Patnaik, A. et al. HGS-ETR2 - A fully human monoclonal antibody to TRAIL-R2: Results of a phase I trial in patients with advanced solid tumors. J. Clin. Oncol. 24 (Suppl. 18), 3012 (2006).

    Google Scholar 

  165. Sikic, B. I. et al. A Phase Ib study to assess the safety of lexatumumab, a human monoclonal antibody that activates TRAIL-R2, in combination with gemcitabine, pemetrexed, doxorubicin or FOLFIRI. J. Clin. Oncol. 25 (Suppl. 18), 14006 (2007).

    Google Scholar 

  166. Camidge, D. R. et al. A phase I safety and pharmacokinetic study of apomab, a human DR5 agonist antibody, in patients with advanced cancer. J. Clin. Oncol. Abstr. 25 (Suppl Suppl. 18), 3582 (2008).

    Google Scholar 

  167. Sharma, S. et al. Phase I trial of LBY135, a monoclonal antibody agonist to DR5, alone and in combination with capecitabine in advanced solid tumors. J. Clin. Oncol. Abstr. 26 (Suppl.), 3538 (2008).

    Article  Google Scholar 

  168. Saleh, M. N. et al. A phase I study of CS-1008 (humanized monoclonal antibody targeting death receptor 5 or DR5), administered weekly to patients with advanced solid tumors or lymphomas. J. Clin. Oncol. Abstr. 26 (Suppl.), 3537 (2008).

    Article  Google Scholar 

  169. Levine, A. J. et al. The 1993 Walter Hubert Lecture: the role of the p53 tumour-suppressor gene in tumorigenesis. Br. J. Cancer 69, 409–416 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Vousden, K. H. & Lu, X. Live or let die: the cell's response to p53. Nature Rev. Cancer 2, 594–604 (2002).

    Article  CAS  Google Scholar 

  171. Datta, S. R. et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91, 231–241 (1997).

    Article  CAS  PubMed  Google Scholar 

  172. Sharp, D. A., Lawrence, D. A. & Ashkenazi, A. Selective knockdown of the long variant of cellular FLICE inhibitory protein augments death receptor-mediated caspase-8 activation and apoptosis. J. Biol. Chem. 280, 19401–19409 (2005).

    Article  CAS  PubMed  Google Scholar 

  173. Thome, M. & Tschopp, J. Regulation of lymphocyte proliferation and death by FLIP. Nature Rev. Immunol. 1, 50–58 (2001).

    Article  CAS  Google Scholar 

  174. El Deiry, W. S. Insights into cancer therapeutic design based on p53 and TRAIL receptor signaling. Cell Death Differ. 8, 1066–1075 (2001).

    Article  CAS  PubMed  Google Scholar 

  175. Eskes, R., Desagher, S., Antonsson, B. & Martinou, J. C. Bid induces the oligomerization and insertion of Bax into the outer mitochondrial membrane. Mol. Cell Biol. 20, 929–935 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Wei, M. C. et al. tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c. Genes Dev. 14, 2060–2071 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Ethics declarations

Competing interests

The author is an employee and stock holder of Genentech, Inc.

Related links

Related links

DATABASES

OMIM

Alzheimer's disease

Huntington's disease

FURTHER INFORMATION

Ashkenazi's homepage

The unpublished data referred to within this manuscript can be accessed at

Glossary

Apoptosis

A form of programmed cell death that serves to eliminate cells that are misplaced, no longer needed, or irreparably damaged.

Death-inducing signalling complex

(DISC). Formed upon binding of ligand to a pro-apoptotic receptor and recruitment of initiator caspases 8 and 10 through the FADD adaptor protein. The DISC activates these initiator caspases to trigger apoptosis through effector caspases 3, 6 and 7, and by engaging the intrinsic pathway via processing of the Bcl-2 family protein Bid.

Anoikis

A type of apoptosis induced by cell detachment.

Epitope

The site on a large molecule to which an antibody binds.

Antibody-dependent cell-mediated cytotoxicity

Refers to the lysis of antibody-coated target cells by immune cells.

Complement activation

Refers to the sequential activation of serum proteins, resulting in an inflammatory response.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ashkenazi, A. Directing cancer cells to self-destruct with pro-apoptotic receptor agonists. Nat Rev Drug Discov 7, 1001–1012 (2008). https://doi.org/10.1038/nrd2637

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd2637

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing