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.
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.
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Jemal, A. et al. Cancer statistics, 2008. CA Cancer J. Clin. 58, 71–96 (2008).
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).
Chowdhury, I., Tharakan, B. & Bhat, G. K. Current concepts in apoptosis: the physiological suicide program revisited. Cell. Mol. Biol. Lett. 11, 506–525 (2006).
Elmore, S. Apoptosis: a review of programmed cell death. Toxicol. Pathol. 35, 495–516 (2007).
Gulbins, E., Jekle, A., Ferlinz, K., Grassme, H. & Lang, F. Physiology of apoptosis. Am. J. Physiol. Renal. Physiol. 279, F605–F615 (2000).
Casella, C. R. & Finkel, T. H. Mechanisms of lymphocyte killing by HIV. Curr. Opin. Hematol. 4, 24–31 (1997).
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).
Sanchez Mejia, R. O. & Friedlander, R. M. Caspases in Huntington's disease. Neuroscientist 7, 480–489 (2001).
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).
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).
Prasad, K. V. & Prabhakar, B. S. Apoptosis and autoimmune disorders. Autoimmunity 36, 323–330 (2003).
Gerl, R. & Vaux, D. L. Apoptosis in the development and treatment of cancer. Carcinogenesis 26, 263–270 (2005).
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).
Lavrik, I. N., Golks, A. & Krammer, P. H. Caspases: pharmacological manipulation of cell death. J. Clin. Invest. 115, 2665–2672 (2005).
Thornberry, N. A. Caspases: a decade of death research. Cell Death Differ. 6, 1023–1027 (1999).
Boatright, K. M. et al. A unified model for apical caspase activation. Mol. Cell 11, 529–541 (2003).
Nagata, S. Apoptotic DNA fragmentation. Exp. Cell Res. 256, 12–18 (2000).
Coultas, L. & Strasser, A. The role of the Bcl-2 protein family in cancer. Semin. Cancer Biol. 13, 115–123 (2003).
Letai, A. Pharmacological manipulation of Bcl-2 family members to control cell death. J. Clin. Invest. 115, 2648–2655 (2005).
Chinnaiyan, A. M. The apoptosome: heart and soul of the cell death machine. Neoplasia 1, 5–15 (1999).
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).
Ashkenazi, A. & Dixit, V. M. Death receptors: signaling and modulation. Science 281, 1305–1308 (1998).
Nagata, S. Apoptosis by death factor. Cell 88, 355–365 (1997).
Peter, M. E. & Krammer, P. H. The CD95(APO-1/Fas) DISC and beyond. Cell Death Differ. 10, 26–35 (2003).
Ashkenazi, A. Targeting death and decoy receptors of the tumour-necrosis factor superfamily. Nature Rev. Cancer 2, 420–430 (2002).
Pitti, R. M. et al. Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer. Nature 396, 699–703 (1998).
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).
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.
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).
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).
Lee, K. H. et al. The role of receptor internalization in CD95 signaling. EMBO J. 25, 1009–1023 (2006).
Austin, C. D. et al. Death-receptor activation halts clathrin-dependent endocytosis. Proc. Natl Acad. Sci. USA 103, 10283–10288 (2006).
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).
Karin, M. & Lin, A. NF-kB at the crossroads of life and death. Nature Immunol. 3, 221–227 (2002).
Micheau, O. & Tschopp, J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell 114, 181–190 (2003).
Varfolomeev, E. E. & Ashkenazi, A. Tumor necrosis factor: an apoptosis JuNKie? Cell 116, 491–497 (2004).
Letai, A. G. Diagnosing and exploiting cancer's addiction to blocks in apoptosis. Nature Rev. Cancer 8, 121–132 (2008).
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).
Igney, F. H. & Krammer, P. H. Death and anti-death: tumour resistance to apoptosis. Nature Rev. Cancer 2, 277–288 (2002).
Hollstein, M., et al. Database of p53 gene somatic mutations in human tumors and cell lines. Nucleic Acids Res. 22, 3551–3555 (1994).
Levine, A. J. p53, the cellular gatekeeper for growth and division. Cell 88, 323–331 (1997).
Ghobrial, I. M., Witzig, T. E. & Adjei, A. A. Targeting apoptosis pathways in cancer therapy. CA Cancer J. Clin. 55, 178–194 (2005).
Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).
Kaufmann, S. H. & Vaux, D. L. Alterations in the apoptotic machinery and their potential role in anticancer drug resistance. Oncogene 22, 7414–7430 (2003).
Lowe, S. W., Cepero, E. & Evan, G. Intrinsic tumour suppression. Nature 432, 307–315 (2004).
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).
Harada, K. et al. Deregulation of caspase 8 and 10 expression in pediatric tumors and cell lines. Cancer Res. 62, 5897–5901 (2002).
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).
Viardot, A., Barth, T. F., Moller, P., Dohner, H. & Bentz, M. Cytogenetic evolution of follicular lymphoma. Semin. Cancer Biol. 13, 183–190 (2003).
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).
Rampino, N. et al. Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. Science 275, 967–969 (1997).
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.
Lee, J. M. & Bernstein, A. Apoptosis, cancer and the p53 tumour suppressor gene. Cancer Metastasis Rev. 14, 149–161 (1995).
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).
Kim, S. H., Ricci, M. S. & El Deiry, W. S. Mcl-1: a gateway to TRAIL sensitization. Cancer Res. 68, 2062–2064 (2008).
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).
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).
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).
Li, L. et al. A small molecule Smac mimic potentiates T. Science 305, 1471–1474 (2004).
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).
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).
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).
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).
Ogasawara, J. et al. Lethal effect of the anti-Fas antibody in mice. Nature 364, 806–809 (1993).
Walczak, H. et al. Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nature Med. 5, 157–163 (1999).
Bouralexis, S., Findlay, D. M. & Evdokiou, A. Death to the bad guys: targeting cancer via Apo2L/TRAIL. Apoptosis 10, 35–51 (2005).
Kelley, S. K. & Ashkenazi, A. Targeting death receptors in cancer with Apo2L/TRAIL. Curr. Opin. Pharmacol. 4, 333–339 (2004).
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).
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).
Wiley, S. R. et al. Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 3, 673–682 (1995).
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).
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).
Wang, S. & El Deiry, W. S. TRAIL and apoptosis induction by TNF-family death receptors. Oncogene 22, 8628–8633 (2003).
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).
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).
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).
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).
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).
Laguinge, L. M. et al. DR5 receptor mediates anoikis in human colorectal carcinoma cell lines. Cancer Res. 68, 909–917 (2008).
Diehl, G. E. et al. TRAIL-R as a negative regulator of innate immune cell responses. Immunity 21, 877–889 (2004).
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).
Almasan, A. & Ashkenazi, A. Apo2L/TRAIL: apoptosis signaling, biology, and potential for cancer therapy. Cytokine Growth Factor Rev. 14, 337–348 (2003).
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).
Wu, G. S. et al. KILLER/DR5 is a DNA damage-inducible p53-regulated death receptor gene. Nature Genet. 17, 141–143 (1997).
Ashkenazi, A. et al. Safety and antitumor activity of recombinant soluble Apo2 ligand. J. Clin. Invest. 104, 155–162 (1999).
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).
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).
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).
Ichikawa, K. et al. Tumoricidal activity of a novel anti-human DR5 monoclonal antibody without hepatocyte cytotoxicity. Nature Med. 7, 954–960 (2001).
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.
Plummer, R. et al. Phase 1 and pharmacokinetic study of lexatumumab in patients with advanced cancers. Clin. Cancer. Res. 13, 6187–6194 (2007).
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).
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).
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).
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).
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).
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).
Ashkenazi, A., Herbst, R. S. To kill a tumor cell: the potential of proapoptotic receptor agonists. J. Clin. Invest. 118, 1979–1990 (2008).
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).
Lawrence, D. et al. Differential hepatocyte toxicity of recombinant Apo2L/TRAIL versions. Nature Med. 7, 383–385 (2001).
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).
Jo, M. et al. Apoptosis induced in normal human hepatocytes by tumor necrosis factor-related apoptosis-inducing ligand. Nature Med. 6, 564–567 (2000).
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).
Hao, C., et al. TRAIL inhibits tumor growth but is nontoxic to human hepatocytes in chimeric mice. Cancer Res. 64, 8502–8506 (2004).
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.
Sheridan, J. P. et al. Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science 277, 818–821 (1997).
Marini, P. Drug evaluation: lexatumumab, an intravenous human agonistic mAb targeting TRAIL receptor 2. Curr. Opin. Mol. Ther. 8, 539–546 (2006).
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).
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).
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).
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).
Yao, G. H. et al. Induction of apoptosis by recombinant soluble human TRAIL in Jurkat cells. Biomed. Environ. Sci. 20, 470–477 (2007).
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).
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.
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Fulda, S., Wick, W., Weller, M. & Debatin, K. M. Smac agonists sensitize for Apo2L/T. Nature Med. 8, 808–815 (2002).
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).
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).
Zhu, H. et al. Proteasome inhibitors-mediated TRAIL resensitization and Bik accumulation. Cancer Biol. Ther. 4, 781–786 (2005).
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).
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).
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).
LeBlanc, H. N. & Ashkenazi, A. Apo2L/TRAIL and its death and decoy receptors. Cell Death Differ. 10, 66–75 (2003).
Fulda, S., Meyer, E. & Debatin, K. M. Inhibition of TRAIL-induced apoptosis by Bcl-2 overexpression. Oncogene 21, 2283–2294 (2002).
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).
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).
Zhang, L. & Fang, B. Mechanisms of resistance to TRAIL-induced apoptosis in cancer. Cancer Gene Ther. 12, 228–237 (2005).
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).
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).
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].
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).
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).
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).
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)
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).
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).
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).
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).
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.
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.
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).
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).
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).
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).
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).
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).
Vousden, K. H. & Lu, X. Live or let die: the cell's response to p53. Nature Rev. Cancer 2, 594–604 (2002).
Datta, S. R. et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91, 231–241 (1997).
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).
Thome, M. & Tschopp, J. Regulation of lymphocyte proliferation and death by FLIP. Nature Rev. Immunol. 1, 50–58 (2001).
El Deiry, W. S. Insights into cancer therapeutic design based on p53 and TRAIL receptor signaling. Cell Death Differ. 8, 1066–1075 (2001).
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).
Wei, M. C. et al. tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c. Genes Dev. 14, 2060–2071 (2000).
The author is an employee and stock holder of Genentech, Inc.
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.
A type of apoptosis induced by cell detachment.
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.
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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
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