Apoptosis and Cancer

  • Mei Lan Tan
  • Heng Kean Tan
  • Tengku Sifzizul Tengku Muhammad
Chapter

Abstract

Cancer is a worldwide endemic and continues to be one of the most difficult diseases to treat and manage, which may be due to the multifactorial nature of the disease. Cancer generally exhibits considerable genetic complexity and aberrant cell death and survival signaling pathways. Resistance to cell death induction has long been recognized as a hallmark of cancer. Therefore, increased understanding of the underlying molecular events regulating different cell death mechanisms such as apoptosis, necroptosis, and autophagy has provided new possibilities for targeted interference of these pathways. This chapter highlights the significant signaling pathways of apoptosis and the relevant therapeutic targets and summarizes the current state of development of specific modulators of cell death and the overall outcome of this group of novel therapeutics in various phases of clinical trials.

Keywords

Fatigue Lymphoma Leukemia Lipase Oligomerization 

Notes

Acknowledgments

The authors would like to acknowledge the Ministry of Science, Technology and Innovation Malaysia and Universiti Sains Malaysia.

References

  1. 1.
    Lecuit T, Le Goff L. Orchestrating size and shape during morphogenesis. Nature. 2007;450(7167):189–92.PubMedGoogle Scholar
  2. 2.
    Li W, Baker NE. Engulfment is required for cell competition. Cell. 2007;129(6):1215–25.PubMedGoogle Scholar
  3. 3.
    Bellamy CO, Malcomson RD, Harrison DJ, Wyllie AH. Cell death in health and disease: the biology and regulation of apoptosis. Semin Cancer Biol. 1995;6(1):3–16.PubMedGoogle Scholar
  4. 4.
    Lockshin RA, Zakeri Z. Programmed cell death and apoptosis: origins of the theory. Nat Rev Mol Cell Biol. 2001;2(7):545–50.PubMedGoogle Scholar
  5. 5.
    Meier P, Finch A, Evan G. Apoptosis in development. Nature. 2000;407(6805):796–801.PubMedGoogle Scholar
  6. 6.
    Clarke PG, Clarke S. Nineteenth century research on naturally occurring cell death and related phenomena. Anat Embryol. 1996;193(2):81–99.PubMedGoogle Scholar
  7. 7.
    Clarke PG, Clarke S. Nineteenth century research on cell death. Exp Oncol. 2012;34(3):139–45.PubMedGoogle Scholar
  8. 8.
    Lockshin RA, Williams CM. Programmed cell death–I. Cytology of degeneration in the intersegmental muscles of the pernyi silkmoth. J Insect Physiol. 1965;11:123–33.PubMedGoogle Scholar
  9. 9.
    Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972;26(4):239–57.PubMedCentralPubMedGoogle Scholar
  10. 10.
    Horvitz HR. Nobel lecture. Worms, life and death. Biosci Rep. 2003;23(5–6):239–303.PubMedGoogle Scholar
  11. 11.
    Green DR, Evan GI. A matter of life and death. Cancer Cell. 2002;1(1):19–30.PubMedGoogle Scholar
  12. 12.
    Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57–70.PubMedGoogle Scholar
  13. 13.
    Thompson CB. Apoptosis in the pathogenesis and treatment of disease. Science. 1995;267(5203):1456–62.PubMedGoogle Scholar
  14. 14.
    Vaux DL, Flavell RA. Apoptosis genes and autoimmunity. Curr Opin Immunol. 2000;12(6):719–24.PubMedGoogle Scholar
  15. 15.
    Yuan J, Yankner BA. Apoptosis in the nervous system. Nature. 2000;407(6805):802–9.PubMedGoogle Scholar
  16. 16.
    Kerr JF, Searle J. A suggested explanation for the paradoxically slow growth rate of basal-cell carcinomas that contain numerous mitotic figures. J Pathol. 1972;107(1):41–4.PubMedGoogle Scholar
  17. 17.
    Steel GG. Cell loss as a factor in the growth rate of human tumours. Eur J Cancer. 1967;3(4):381–7.PubMedGoogle Scholar
  18. 18.
    Iversen OH. Kinetics of cellular proliferation and cell loss in human carcinomas. A discussion of methods available for in vivo studies. Eur J Cancer. 1967;3(4):389–94.PubMedGoogle Scholar
  19. 19.
    Galluzzi L, Vitale I, Abrams JM, Alnemri ES, Baehrecke EH, Blagosklonny MV, et al. Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ. 2012;19(1):107–20.PubMedCentralPubMedGoogle Scholar
  20. 20.
    Kerr JF, Winterford CM, Harmon BV. Apoptosis. Its significance in cancer and cancer therapy. Cancer. 1994;73(8):2013–26.PubMedGoogle Scholar
  21. 21.
    Wyllie AH, Kerr JF, Currie AR. Cell death: the significance of apoptosis. Int Rev Cytol. 1980;68:251–306.PubMedGoogle Scholar
  22. 22.
    Martin SJ, Reutelingsperger CP, McGahon AJ, Rader JA, van Schie RC, LaFace DM, et al. Early redistribution of plasma membrane phosphatidylserine is a general feature of apoptosis regardless of the initiating stimulus: inhibition by overexpression of Bcl-2 and Abl. J Exp Med. 1995;182(5):1545–56.PubMedGoogle Scholar
  23. 23.
    Kroemer G, Galluzzi L, Vandenabeele P, Abrams J, Alnemri ES, Baehrecke EH, et al. Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death Differ. 2009;16(1):3–11.PubMedCentralPubMedGoogle Scholar
  24. 24.
    Wajant H. The Fas signaling pathway: more than a paradigm. Science. 2002;296(5573):1635–6.PubMedGoogle Scholar
  25. 25.
    Schutze S, Tchikov V, Schneider-Brachert W. Regulation of TNFR1 and CD95 signalling by receptor compartmentalization. Nat Rev Mol Cell Biol. 2008;9(8):655–62.PubMedGoogle Scholar
  26. 26.
    Schulze-Osthoff K, Ferrari D, Los M, Wesselborg S, Peter ME. Apoptosis signaling by death receptors. Eur J Biochem. 1998;254(3):439–59.PubMedGoogle Scholar
  27. 27.
    Hengartner MO. The biochemistry of apoptosis. Nature. 2000;407(6805):770–6.PubMedGoogle Scholar
  28. 28.
    Ishii N, Wadsworth WG, Stern BD, Culotti JG, Hedgecock EM. UNC-6, a laminin-related protein, guides cell and pioneer axon migrations in C. elegans. Neuron. 1992;9(5):873–81.PubMedGoogle Scholar
  29. 29.
    Rajasekharan S, Kennedy TE. The netrin protein family. Genome Biol. 2009;10(9):239.PubMedCentralPubMedGoogle Scholar
  30. 30.
    Mehlen P, Furne C. Netrin-1: when a neuronal guidance cue turns out to be a regulator of tumorigenesis. Cell Mol Life Sci CMLS. 2005;62(22):2599–616.Google Scholar
  31. 31.
    Guenebeaud C, Goldschneider D, Castets M, Guix C, Chazot G, Delloye-Bourgeois C, et al. The dependence receptor UNC5H2/B triggers apoptosis via PP2A-mediated dephosphorylation of DAP kinase. Mol Cell. 2010;40(6):863–76.PubMedGoogle Scholar
  32. 32.
    Chatfield K, Eastman A. Inhibitors of protein phosphatases 1 and 2A differentially prevent intrinsic and extrinsic apoptosis pathways. Biochem Biophys Res Commun. 2004;323(4):1313–20.PubMedGoogle Scholar
  33. 33.
    Deng X, Gao F, May WS. Protein phosphatase 2A inactivates Bcl2’s antiapoptotic function by dephosphorylation and up-regulation of Bcl2-p53 binding. Blood. 2009;113(2):422–8.PubMedCentralPubMedGoogle Scholar
  34. 34.
    Letai A, Bassik MC, Walensky LD, Sorcinelli MD, Weiler S, Korsmeyer SJ. Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell. 2002;2(3):183–92.PubMedGoogle Scholar
  35. 35.
    Scaffidi C, Schmitz I, Zha J, Korsmeyer SJ, Krammer PH, Peter ME. Differential modulation of apoptosis sensitivity in CD95 type I and type II cells. J Biol Chem. 1999;274(32):22532–8.PubMedGoogle Scholar
  36. 36.
    Cho KR, Fearon ER. DCC: linking tumor suppressor genes and altered cell surface interactions in cancer? Curr Opin Genet Dev. 1995;5(1):72–8.PubMedGoogle Scholar
  37. 37.
    Hedrick L, Cho KR, Fearon ER, Wu TC, Kinzler KW, Vogelstein B. The DCC gene product in cellular differentiation and colorectal tumorigenesis. Genes Dev. 1994;8(10):1174–83.PubMedGoogle Scholar
  38. 38.
    Forcet C, Ye X, Granger L, Corset V, Shin H, Bredesen DE, et al. The dependence receptor DCC (deleted in colorectal cancer) defines an alternative mechanism for caspase activation. Proc Natl Acad Sci U S A. 2001;98(6):3416–21.PubMedCentralPubMedGoogle Scholar
  39. 39.
    Hahn H, Wicking C, Zaphiropoulous PG, Gailani MR, Shanley S, Chidambaram A, et al. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell. 1996;85(6):841–51.PubMedGoogle Scholar
  40. 40.
    Goodrich LV, Milenkovic L, Higgins KM, Scott MP. Altered neural cell fates and medulloblastoma in mouse patched mutants. Science. 1997;277(5329):1109–13.PubMedGoogle Scholar
  41. 41.
    Mille F, Thibert C, Fombonne J, Rama N, Guix C, Hayashi H, et al. The patched dependence receptor triggers apoptosis through a DRAL-caspase-9 complex. Nat Cell Biol. 2009;11(6):739–46.PubMedCentralPubMedGoogle Scholar
  42. 42.
    Fombonne J, Bissey PA, Guix C, Sadoul R, Thibert C, Mehlen P. Patched dependence receptor triggers apoptosis through ubiquitination of caspase-9. Proc Natl Acad Sci U S A. 2012;109(26):10510–5.PubMedCentralPubMedGoogle Scholar
  43. 43.
    Stennicke HR, Salvesen GS. Biochemical characteristics of caspases-3, -6, -7, and -8. J Biol Chem. 1997;272(41):25719–23.PubMedGoogle Scholar
  44. 44.
    Slee EA, Adrain C, Martin SJ. Executioner caspase-3, -6, and -7 perform distinct, non-redundant roles during the demolition phase of apoptosis. J Biol Chem. 2001;276(10):7320–6.PubMedGoogle Scholar
  45. 45.
    Janicke RU, Ng P, Sprengart ML, Porter AG. Caspase-3 is required for alpha-fodrin cleavage but dispensable for cleavage of other death substrates in apoptosis. J Biol Chem. 1998;273(25):15540–5.PubMedGoogle Scholar
  46. 46.
    Janicke RU, Sprengart ML, Wati MR, Porter AG. Caspase-3 is required for DNA fragmentation and morphological changes associated with apoptosis. J Biol Chem. 1998;273(16):9357–60.PubMedGoogle Scholar
  47. 47.
    Ferreira KS, Kreutz C, Macnelly S, Neubert K, Haber A, Bogyo M, et al. Caspase-3 feeds back on caspase-8, Bid and XIAP in type I Fas signaling in primary mouse hepatocytes. Apoptosis Int J Programmed Cell Death. 2012;17(5):503–15.Google Scholar
  48. 48.
    Walsh JG, Cullen SP, Sheridan C, Luthi AU, Gerner C, Martin SJ. Executioner caspase-3 and caspase-7 are functionally distinct proteases. Proc Natl Acad Sci U S A. 2008;105(35):12815–9.PubMedCentralPubMedGoogle Scholar
  49. 49.
    Kothakota S, Azuma T, Reinhard C, Klippel A, Tang J, Chu K, et al. Caspase-3-generated fragment of gelsolin: effector of morphological change in apoptosis. Science. 1997;278(5336):294–8.PubMedGoogle Scholar
  50. 50.
    Cosulich SC, Horiuchi H, Zerial M, Clarke PR, Woodman PG. Cleavage of rabaptin-5 blocks endosome fusion during apoptosis. EMBO J. 1997;16(20):6182–91.PubMedCentralPubMedGoogle Scholar
  51. 51.
    Bennett V. Spectrin-based membrane skeleton: a multipotential adaptor between plasma membrane and cytoplasm. Physiol Rev. 1990;70(4):1029–65.PubMedGoogle Scholar
  52. 52.
    Martin SJ, O’Brien GA, Nishioka WK, McGahon AJ, Mahboubi A, Saido TC, et al. Proteolysis of fodrin (Non-erythroid Spectrin) during apoptosis. J Biol Chem. 1995;270(12):6425–8.PubMedGoogle Scholar
  53. 53.
    Cryns VL, Bergeron L, Zhu H, Li H, Yuan J. Specific cleavage of α-fodrin during fas- and tumor necrosis factor-induced apoptosis is mediated by an interleukin-1β-converting enzyme/ced-3 protease distinct from the poly(ADP-ribose) polymerase protease. J Biol Chem. 1996;271(49):31277–82.PubMedGoogle Scholar
  54. 54.
    Mitra SK, Hanson DA, Schlaepfer DD. Focal adhesion kinase: in command and control of cell motility. Nat Rev Mol Cell Biol. 2005;6(1):56–68.PubMedGoogle Scholar
  55. 55.
    Wen L-P, Fahrni JA, Troie S, Guan J-L, Orth K, Rosen GD. Cleavage of focal adhesion kinase by caspases during apoptosis. J Biol Chem. 1997;272(41):26056–61.PubMedGoogle Scholar
  56. 56.
    Sells MA, Knaus UG, Bagrodia S, Ambrose DM, Bokoch GM, Chernoff J. Human p21-activated kinase (Pak1) regulates actin organization in mammalian cells. Curr Biol CB. 1997;7(3):202–10.Google Scholar
  57. 57.
    Brzeska H, Knaus UG, Wang Z-Y, Bokoch GM, Korn ED. p21-activated kinase has substrate specificity similar to Acanthamoeba myosin I heavy chain kinase and activates Acanthamoeba myosin I. Proc Natl Acad Sci. 1997;94(4):1092–5.PubMedCentralPubMedGoogle Scholar
  58. 58.
    Rudel T, Bokoch GM. Membrane and morphological changes in apoptotic cells regulated by caspase-mediated activation of PAK2. Science. 1997;276(5318):1571–4.PubMedGoogle Scholar
  59. 59.
    Porter AG, Ng P, Janicke RU. Death substrates come alive. Bioessays News Rev Mol Cell Dev Biol. 1997;19(6):501–7.Google Scholar
  60. 60.
    Benchoua A, Couriaud C, Guegan C, Tartier L, Couvert P, Friocourt G, et al. Active caspase-8 translocates into the nucleus of apoptotic cells to inactivate poly(ADP-ribose) polymerase-2. J Biol Chem. 2002;277(37):34217–22.PubMedGoogle Scholar
  61. 61.
    Wolf BB, Schuler M, Echeverri F, Green DR. Caspase-3 is the primary activator of apoptotic DNA fragmentation via DNA fragmentation factor-45/inhibitor of caspase-activated DNase inactivation. J Biol Chem. 1999;274(43):30651–6.PubMedGoogle Scholar
  62. 62.
    Widlak P, Garrard WT. Discovery, regulation, and action of the major apoptotic nucleases DFF40/CAD and endonuclease G. J Cell Biochem. 2005;94(6):1078–87.PubMedGoogle Scholar
  63. 63.
    Antonsson B, Martinou JC. The Bcl-2 protein family. Exp Cell Res. 2000;256(1):50–7.PubMedGoogle Scholar
  64. 64.
    Martinez-Ruiz G, Maldonado V, Ceballos-Cancino G, Grajeda JP, Melendez-Zajgla J. Role of Smac/DIABLO in cancer progression. J Exp Clin Cancer Res. 2008;27:48.PubMedCentralPubMedGoogle Scholar
  65. 65.
    James D, Parone PA, Terradillos O, Lucken-Ardjomande S, Montessuit S, Martinou JC. Mechanisms of mitochondrial outer membrane permeabilization. Novartis Found Symp. 2007;287:170–6; discussion 6–82.PubMedGoogle Scholar
  66. 66.
    Lipton SA, Bossy-Wetzel E. Dueling activities of AIF in cell death versus survival: DNA binding and redox activity. Cell. 2002;111(2):147–50.PubMedGoogle Scholar
  67. 67.
    Low RL. Mitochondrial endonuclease G function in apoptosis and mtDNA metabolism: a historical perspective. Mitochondrion. 2003;2(4):225–36.PubMedGoogle Scholar
  68. 68.
    David KK, Sasaki M, Yu SW, Dawson TM, Dawson VL. EndoG is dispensable in embryogenesis and apoptosis. Cell Death Differ. 2006;13(7):1147–55.PubMedGoogle Scholar
  69. 69.
    Hegde R, Srinivasula SM, Zhang Z, Wassell R, Mukattash R, Cilenti L, et al. Identification of Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts inhibitor of apoptosis protein-caspase interaction. J Biol Chem. 2002;277(1):432–8.PubMedGoogle Scholar
  70. 70.
    Kroemer G, Galluzzi L, Brenner C. Mitochondrial membrane permeabilization in cell death. Physiol Rev. 2007;87(1):99–163.PubMedGoogle Scholar
  71. 71.
    Kulikov AV, Shilov ES, Mufazalov IA, Gogvadze V, Nedospasov SA, Zhivotovsky B. Cytochrome c: the Achilles’ heel in apoptosis. Cell Mol Life Sci CMLS. 2012;69(11):1787–97.Google Scholar
  72. 72.
    Ow YP, Green DR, Hao Z, Mak TW. Cytochrome c: functions beyond respiration. Nat Rev Mol Cell Biol. 2008;9(7):532–42.PubMedGoogle Scholar
  73. 73.
    Scorrano L. Opening the doors to cytochrome c: changes in mitochondrial shape and apoptosis. Int J Biochem Cell Biol. 2009;41(10):1875–83.PubMedGoogle Scholar
  74. 74.
    Tsujimoto Y. Stress-resistance conferred by high level of bcl-2 alpha protein in human B lymphoblastoid cell. Oncogene. 1989;4(11):1331–6.PubMedGoogle Scholar
  75. 75.
    Tsujimoto Y. Role of Bcl-2 family proteins in apoptosis: apoptosomes or mitochondria? Genes Cells. 1998;3(11):697–707.PubMedGoogle Scholar
  76. 76.
    Uren RT, Dewson G, Chen L, Coyne SC, Huang DC, Adams JM, et al. Mitochondrial permeabilization relies on BH3 ligands engaging multiple prosurvival Bcl-2 relatives, not Bak. J Cell Biol. 2007;177(2):277–87.PubMedCentralPubMedGoogle Scholar
  77. 77.
    Levine B, Sinha S, Kroemer G. Bcl-2 family members: dual regulators of apoptosis and autophagy. Autophagy. 2008;4(5):600–6.PubMedCentralPubMedGoogle Scholar
  78. 78.
    Tait SW, Green DR. Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol. 2010;11(9):621–32.PubMedGoogle Scholar
  79. 79.
    Brenner C, Grimm S. The permeability transition pore complex in cancer cell death. Oncogene. 2006;25(34):4744–56.PubMedGoogle Scholar
  80. 80.
    Zamzami N, Larochette N, Kroemer G. Mitochondrial permeability transition in apoptosis and necrosis. Cell Death Differ. 2005;12 Suppl 2:1478–80.PubMedGoogle Scholar
  81. 81.
    Arnoult D, Gaume B, Karbowski M, Sharpe JC, Cecconi F, Youle RJ. Mitochondrial release of AIF and EndoG requires caspase activation downstream of Bax/Bak-mediated permeabilization. EMBO J. 2003;22(17):4385–99.PubMedCentralPubMedGoogle Scholar
  82. 82.
    Kaufmann T, Strasser A, Jost PJ. Fas death receptor signalling: roles of Bid and XIAP. Cell Death Differ. 2012;19(1):42–50.PubMedCentralPubMedGoogle Scholar
  83. 83.
    Salvesen GS, Duckett CS. IAP proteins: blocking the road to death’s door. Nat Rev Mol Cell Biol. 2002;3(6):401–10.PubMedGoogle Scholar
  84. 84.
    Deveraux QL, Takahashi R, Salvesen GS, Reed JC. X-linked IAP is a direct inhibitor of cell-death proteases. Nature. 1997;388(6639):300–4.PubMedGoogle Scholar
  85. 85.
    Roy N, Deveraux QL, Takahashi R, Salvesen GS, Reed JC. The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases. EMBO J. 1997;16(23):6914–25.PubMedCentralPubMedGoogle Scholar
  86. 86.
    Deveraux QL, Roy N, Stennicke HR, Van Arsdale T, Zhou Q, Srinivasula SM, et al. IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases. EMBO J. 1998;17(8):2215–23.PubMedCentralPubMedGoogle Scholar
  87. 87.
    Chai J, Du C, Wu JW, Kyin S, Wang X, Shi Y. Structural and biochemical basis of apoptotic activation by Smac/DIABLO. Nature. 2000;406(6798):855–62.PubMedGoogle Scholar
  88. 88.
    Yang QH, Church-Hajduk R, Ren J, Newton ML, Du C. Omi/HtrA2 catalytic cleavage of inhibitor of apoptosis (IAP) irreversibly inactivates IAPs and facilitates caspase activity in apoptosis. Genes Dev. 2003;17(12):1487–96.PubMedCentralPubMedGoogle Scholar
  89. 89.
    Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE, et al. Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell. 2000;102(1):43–53.PubMedGoogle Scholar
  90. 90.
    Suzuki Y, Imai Y, Nakayama H, Takahashi K, Takio K, Takahashi R. A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death. Mol Cell. 2001;8(3):613–21.PubMedGoogle Scholar
  91. 91.
    Martins LM, Iaccarino I, Tenev T, Gschmeissner S, Totty NF, Lemoine NR, et al. The serine protease Omi/HtrA2 regulates apoptosis by binding XIAP through a reaper-like motif. J Biol Chem. 2002;277(1):439–44.PubMedGoogle Scholar
  92. 92.
    van Loo G, van Gurp M, Depuydt B, Srinivasula SM, Rodriguez I, Alnemri ES, et al. The serine protease Omi/HtrA2 is released from mitochondria during apoptosis. Omi interacts with caspase-inhibitor XIAP and induces enhanced caspase activity. Cell Death Differ. 2002;9(1):20–6.PubMedGoogle Scholar
  93. 93.
    Liu Z, Sun C, Olejniczak ET, Meadows RP, Betz SF, Oost T, et al. Structural basis for binding of Smac/DIABLO to the XIAP BIR3 domain. Nature. 2000;408(6815):1004–8.PubMedGoogle Scholar
  94. 94.
    Wu G, Chai J, Suber TL, Wu JW, Du C, Wang X, et al. Structural basis of IAP recognition by Smac/DIABLO. Nature. 2000;408(6815):1008–12.PubMedGoogle Scholar
  95. 95.
    Srinivasula SM, Hegde R, Saleh A, Datta P, Shiozaki E, Chai J, et al. A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis. Nature. 2001;410(6824):112–6.PubMedGoogle Scholar
  96. 96.
    Li W, Srinivasula SM, Chai J, Li P, Wu JW, Zhang Z, et al. Structural insights into the pro-apoptotic function of mitochondrial serine protease HtrA2/Omi. Nat Struct Biol. 2002;9(6):436–41.PubMedGoogle Scholar
  97. 97.
    Faccio L, Fusco C, Chen A, Martinotti S, Bonventre JV, Zervos AS. Characterization of a novel human serine protease that has extensive homology to bacterial heat shock endoprotease HtrA and is regulated by kidney ischemia. J Biol Chem. 2000;275(4):2581–8.PubMedGoogle Scholar
  98. 98.
    Gray CW, Ward RV, Karran E, Turconi S, Rowles A, Viglienghi D, et al. Characterization of human HtrA2, a novel serine protease involved in the mammalian cellular stress response. Eur J Biochem. 2000;267(18):5699–710.PubMedGoogle Scholar
  99. 99.
    Srinivasula SM, Gupta S, Datta P, Zhang Z, Hegde R, Cheong N, et al. Inhibitor of apoptosis proteins are substrates for the mitochondrial serine protease Omi/HtrA2. J Biol Chem. 2003;278(34):31469–72.PubMedGoogle Scholar
  100. 100.
    Vande Walle L, Van Damme P, Lamkanfi M, Saelens X, Vandekerckhove J, Gevaert K, et al. Proteome-wide identification of HtrA2/Omi substrates. J Proteome Res. 2007;6(3):1006–15.PubMedGoogle Scholar
  101. 101.
    Joza N, Susin SA, Daugas E, Stanford WL, Cho SK, Li CY, et al. Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death. Nature. 2001;410(6828):549–54.PubMedGoogle Scholar
  102. 102.
    Li LY, Luo X, Wang X. Endonuclease G is an apoptotic DNase when released from mitochondria. Nature. 2001;412(6842):95–9.PubMedGoogle Scholar
  103. 103.
    Gerschenson M, Houmiel KL, Low RL. Endonuclease G from mammalian nuclei is identical to the major endonuclease of mitochondria. Nucleic Acids Res. 1995;23(1):88–97.PubMedCentralPubMedGoogle Scholar
  104. 104.
    Sevrioukova IF. Apoptosis-inducing factor: structure, function, and redox regulation. Antioxid Redox Signal. 2011;14(12):2545–79.PubMedCentralPubMedGoogle Scholar
  105. 105.
    van Loo G, Schotte P, van Gurp M, Demol H, Hoorelbeke B, Gevaert K, et al. Endonuclease G: a mitochondrial protein released in apoptosis and involved in caspase-independent DNA degradation. Cell Death Differ. 2001;8(12):1136–42.PubMedGoogle Scholar
  106. 106.
    Zhang J, Ye J, Altafaj A, Cardona M, Bahi N, Llovera M, et al. EndoG links Bnip3-induced mitochondrial damage and caspase-independent DNA fragmentation in ischemic cardiomyocytes. PLoS One. 2011;6(3):e17998.PubMedCentralPubMedGoogle Scholar
  107. 107.
    Zamzami N, Susin SA, Marchetti P, Hirsch T, Gomez-Monterrey I, Castedo M, et al. Mitochondrial control of nuclear apoptosis. J Exp Med. 1996;183(4):1533–44.PubMedGoogle Scholar
  108. 108.
    Susin SA, Zamzami N, Castedo M, Daugas E, Wang HG, Geley S, et al. The central executioner of apoptosis: multiple connections between protease activation and mitochondria in Fas/APO-1/CD95- and ceramide-induced apoptosis. J Exp Med. 1997;186(1):25–37.PubMedCentralPubMedGoogle Scholar
  109. 109.
    Susin SA, Lorenzo HK, Zamzami N, Marzo I, Brenner C, Larochette N, et al. Mitochondrial release of caspase-2 and -9 during the apoptotic process. J Exp Med. 1999;189(2):381–94.PubMedCentralPubMedGoogle Scholar
  110. 110.
    Cregan SP, Fortin A, MacLaurin JG, Callaghan SM, Cecconi F, Yu SW, et al. Apoptosis-inducing factor is involved in the regulation of caspase-independent neuronal cell death. J Cell Biol. 2002;158(3):507–17.PubMedCentralPubMedGoogle Scholar
  111. 111.
    Park YC, Jeong JH, Park KJ, Choi HJ, Park YM, Jeong BK, et al. Sulindac activates nuclear translocation of AIF, DFF40 and endonuclease G but not induces oligonucleosomal DNA fragmentation in HT-29 cells. Life Sci. 2005;77(16):2059–70.PubMedGoogle Scholar
  112. 112.
    Susin SA, Daugas E, Ravagnan L, Samejima K, Zamzami N, Loeffler M, et al. Two distinct pathways leading to nuclear apoptosis. J Exp Med. 2000;192(4):571–80.PubMedCentralPubMedGoogle Scholar
  113. 113.
    Pahl HL. Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene. 1999;18(49):6853–66.PubMedGoogle Scholar
  114. 114.
    Prasad S, Ravindran J, Aggarwal BB. NF-kappaB and cancer: how intimate is this relationship. Mol Cell Biochem. 2010;336(1–2):25–37.PubMedCentralPubMedGoogle Scholar
  115. 115.
    Abbadie C, Kabrun N, Bouali F, Smardova J, Stehelin D, Vandenbunder B, et al. High levels of c-rel expression are associated with programmed cell death in the developing avian embryo and in bone marrow cells in vitro. Cell. 1993;75(5):899–912.PubMedGoogle Scholar
  116. 116.
    Dumont A, Hehner SP, Hofmann TG, Ueffing M, Droge W, Schmitz ML. Hydrogen peroxide-induced apoptosis is CD95-independent, requires the release of mitochondria-derived reactive oxygen species and the activation of NF-kappaB. Oncogene. 1999;18(3):747–57.PubMedGoogle Scholar
  117. 117.
    Kasibhatla S, Brunner T, Genestier L, Echeverri F, Mahboubi A, Green DR. DNA damaging agents induce expression of Fas ligand and subsequent apoptosis in T lymphocytes via the activation of NF-kappa B and AP-1. Mol Cell. 1998;1(4):543–51.PubMedGoogle Scholar
  118. 118.
    Schneider A, Martin-Villalba A, Weih F, Vogel J, Wirth T, Schwaninger M. NF-kappaB is activated and promotes cell death in focal cerebral ischemia. Nat Med. 1999;5(5):554–9.PubMedGoogle Scholar
  119. 119.
    Qin ZH, Chen RW, Wang Y, Nakai M, Chuang DM, Chase TN. Nuclear factor kappaB nuclear translocation upregulates c-Myc and p53 expression during NMDA receptor-mediated apoptosis in rat striatum. J Neurosci: Off J Soc Neurosci. 1999;19(10):4023–33.Google Scholar
  120. 120.
    Karin M, Ben-Neriah Y. Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annu Rev Immunol. 2000;18:621–63.PubMedGoogle Scholar
  121. 121.
    Pham LV, Tamayo AT, Yoshimura LC, Lo P, Ford RJ. Inhibition of constitutive NF-κB activation in mantle cell lymphoma B cells leads to induction of cell cycle arrest and apoptosis. J Immunol. 2003;171(1):88–95.PubMedGoogle Scholar
  122. 122.
    Wang CY, Guttridge DC, Mayo MW, Baldwin Jr AS. NF-kappaB induces expression of the Bcl-2 homologue A1/Bfl-1 to preferentially suppress chemotherapy-induced apoptosis. Mol Cell Biol. 1999;19(9):5923–9.PubMedCentralPubMedGoogle Scholar
  123. 123.
    Chu ZL, McKinsey TA, Liu L, Gentry JJ, Malim MH, Ballard DW. Suppression of tumor necrosis factor-induced cell death by inhibitor of apoptosis c-IAP2 is under NF-kappaB control. Proc Natl Acad Sci U S A. 1997;94(19):10057–62.PubMedCentralPubMedGoogle Scholar
  124. 124.
    Wang CY, Mayo MW, Korneluk RG, Goeddel DV, Baldwin Jr AS. NF-kappaB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science. 1998;281(5383):1680–3.PubMedGoogle Scholar
  125. 125.
    Deveraux QL, Reed JC. IAP family proteins–suppressors of apoptosis. Genes Dev. 1999;13(3):239–52.PubMedGoogle Scholar
  126. 126.
    Stehlik C, de Martin R, Kumabashiri I, Schmid JA, Binder BR, Lipp J. Nuclear factor (NF)-kappaB-regulated X-chromosome-linked iap gene expression protects endothelial cells from tumor necrosis factor alpha-induced apoptosis. J Exp Med. 1998;188(1):211–6.PubMedCentralPubMedGoogle Scholar
  127. 127.
    Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nat Med. 2004;10(8):789–99.PubMedGoogle Scholar
  128. 128.
    Reed JC. Apoptosis-targeted therapies for cancer. Cancer Cell. 2003;3(1):17–22.PubMedGoogle Scholar
  129. 129.
    Gronbaek K, Straten PT, Ralfkiaer E, Ahrenkiel V, Andersen MK, Hansen NE, et al. Somatic Fas mutations in non-Hodgkin’s lymphoma: association with extranodal disease and autoimmunity. Blood. 1998;92(9):3018–24.PubMedGoogle Scholar
  130. 130.
    Shin MS, Park WS, Kim SY, Kim HS, Kang SJ, Song KY, et al. Alterations of Fas (Apo-1/CD95) gene in cutaneous malignant melanoma. Am J Pathol. 1999;154(6):1785–91.PubMedCentralPubMedGoogle Scholar
  131. 131.
    Lee SH, Shin MS, Park WS, Kim SY, Dong SM, Pi JH, et al. Alterations of Fas (APO-1/CD95) gene in transitional cell carcinomas of urinary bladder. Cancer Res. 1999;59(13):3068–72.PubMedGoogle Scholar
  132. 132.
    Lee SH, Shin MS, Park WS, Kim SY, Kim HS, Han JY, et al. Alterations of Fas (Apo-1/CD95) gene in non-small cell lung cancer. Oncogene. 1999;18(25):3754–60.PubMedGoogle Scholar
  133. 133.
    MacFarlane M, Ahmad M, Srinivasula SM, Fernandes-Alnemri T, Cohen GM, Alnemri ES. Identification and molecular cloning of two novel receptors for the cytotoxic ligand TRAIL. J Biol Chem. 1997;272(41):25417–20.PubMedGoogle Scholar
  134. 134.
    Marsters SA, Sheridan JP, Pitti RM, Huang A, Skubatch M, Baldwin D, et al. A novel receptor for Apo2L/TRAIL contains a truncated death domain. Curr Biol CB. 1997;7(12):1003–6.Google Scholar
  135. 135.
    El-Naggar AK, Coombes MM, Batsakis JG, Hong WK, Goepfert H, Kagan J. Localization of chromosome 8p regions involved in early tumorigenesis of oral and laryngeal squamous carcinoma. Oncogene. 1998;16(23):2983–7.PubMedGoogle Scholar
  136. 136.
    Emi M, Fujiwara Y, Nakajima T, Tsuchiya E, Tsuda H, Hirohashi S, et al. Frequent loss of heterozygosity for loci on chromosome 8p in hepatocellular carcinoma, colorectal cancer, and lung cancer. Cancer Res. 1992;52(19):5368–72.PubMedGoogle Scholar
  137. 137.
    Kagan J, Stein J, Babaian RJ, Joe YS, Pisters LL, Glassman AB, et al. Homozygous deletions at 8p22 and 8p21 in prostate cancer implicate these regions as the sites for candidate tumor suppressor genes. Oncogene. 1995;11(10):2121–6.PubMedGoogle Scholar
  138. 138.
    Mitelman F, Mertens F, Johansson B. A breakpoint map of recurrent chromosomal rearrangements in human neoplasia. Nat Genet. 1997;15(Spec No):417–74.PubMedGoogle Scholar
  139. 139.
    Monni O, Joensuu H, Franssila K, Knuutila S. DNA copy number changes in diffuse large B-cell lymphoma–comparative genomic hybridization study. Blood. 1996;87(12):5269–78.PubMedGoogle Scholar
  140. 140.
    Yaremko ML, Kutza C, Lyzak J, Mick R, Recant WM, Westbrook CA. Loss of heterozygosity from the short arm of chromosome 8 is associated with invasive behavior in breast cancer. Genes Chromosomes Cancer. 1996;16(3):189–95.PubMedGoogle Scholar
  141. 141.
    Wistuba II, Behrens C, Virmani AK, Milchgrub S, Syed S, Lam S, et al. Allelic losses at chromosome 8p21-23 are early and frequent events in the pathogenesis of lung cancer. Cancer Res. 1999;59(8):1973–9.PubMedGoogle Scholar
  142. 142.
    Pai SI, Wu GS, Ozoren N, Wu L, Jen J, Sidransky D, et al. Rare loss-of-function mutation of a death receptor gene in head and neck cancer. Cancer Res. 1998;58(16):3513–8.PubMedGoogle Scholar
  143. 143.
    Lee SH, Shin MS, Kim HS, Lee HK, Park WS, Kim SY, et al. Alterations of the DR5/TRAIL receptor 2 gene in non-small cell lung cancers. Cancer Res. 1999;59(22):5683–6.PubMedGoogle Scholar
  144. 144.
    Lee SH, Shin MS, Kim HS, Lee HK, Park WS, Kim SY, et al. Somatic mutations of TRAIL-receptor 1 and TRAIL-receptor 2 genes in non-Hodgkin’s lymphoma. Oncogene. 2001;20(3):399–403.PubMedGoogle Scholar
  145. 145.
    Shin MS, Kim HS, Lee SH, Park WS, Kim SY, Park JY, et al. Mutations of tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1) and receptor 2 (TRAIL-R2) genes in metastatic breast cancers. Cancer Res. 2001;61(13):4942–6.PubMedGoogle Scholar
  146. 146.
    Gallmeier E, Bader DC, Kriegl L, Berezowska S, Seeliger H, Goke B, et al. Loss of TRAIL-receptors is a recurrent feature in pancreatic cancer and determines the prognosis of patients with no nodal metastasis after surgery. PLoS One. 2013;8(2):e56760.PubMedCentralPubMedGoogle Scholar
  147. 147.
    Lorea CF, Moreno DA, Borges KS, Martinelli Jr CE, Antonini SR, de Castro M, et al. Expression profile of apoptosis-related genes in childhood adrenocortical tumors: low level of expression of BCL2 and TNF genes suggests a poor prognosis. Eur J Endocrinol/ Eur Fed Endocr Soc. 2012;167(2):199–208.Google Scholar
  148. 148.
    Junttila MR, Puustinen P, Niemela M, Ahola R, Arnold H, Bottzauw T, et al. CIP2A inhibits PP2A in human malignancies. Cell. 2007;130(1):51–62.PubMedGoogle Scholar
  149. 149.
    Eichhorn PJ, Creyghton MP, Bernards R. Protein phosphatase 2A regulatory subunits and cancer. Biochim Biophys Acta. 2009;1795(1):1–15.PubMedGoogle Scholar
  150. 150.
    Fearon ER, Cho KR, Nigro JM, Kern SE, Simons JW, Ruppert JM, et al. Identification of a chromosome 18q gene that is altered in colorectal cancers. Science. 1990;247(4938):49–56.PubMedGoogle Scholar
  151. 151.
    Fearon ER. DCC: is there a connection between tumorigenesis and cell guidance molecules? Biochim Biophys Acta. 1996;1288(2):M17–23.PubMedGoogle Scholar
  152. 152.
    Andrews GA, Xi S, Pomerantz RG, Lin CJ, Gooding WE, Wentzel AL, et al. Mutation of p53 in head and neck squamous cell carcinoma correlates with Bcl-2 expression and increased susceptibility to cisplatin-induced apoptosis. Head Neck. 2004;26(10):870–7.PubMedGoogle Scholar
  153. 153.
    Ikegaki N, Katsumata M, Minna J, Tsujimoto Y. Expression of bcl-2 in small cell lung carcinoma cells. Cancer Res. 1994;54(1):6–8.PubMedGoogle Scholar
  154. 154.
    Monni O, Joensuu H, Franssila K, Klefstrom J, Alitalo K, Knuutila S. BCL2 overexpression associated with chromosomal amplification in diffuse large B-cell lymphoma. Blood. 1997;90(3):1168–74.PubMedGoogle Scholar
  155. 155.
    Fels C, Schafer C, Huppe B, Bahn H, Heidecke V, Kramm CM, et al. Bcl-2 expression in higher-grade human glioma: a clinical and experimental study. J Neurooncol. 2000;48(3):207–16.PubMedGoogle Scholar
  156. 156.
    Kouri FM, Jensen SA, Stegh AH. The role of Bcl-2 family proteins in therapy responses of malignant astrocytic gliomas: Bcl2L12 and beyond. Sci World J. 2012;2012:838916.Google Scholar
  157. 157.
    Schimmer AD, Munk-Pedersen I, Minden MD, Reed JC. Bcl-2 and apoptosis in chronic lymphocytic leukemia. Curr Treat Options Oncol. 2003;4(3):211–8.PubMedGoogle Scholar
  158. 158.
    Rao PH, Houldsworth J, Dyomina K, Parsa NZ, Cigudosa JC, Louie DC, et al. Chromosomal and gene amplification in diffuse large B-cell lymphoma. Blood. 1998;92(1):234–40.PubMedGoogle Scholar
  159. 159.
    Hermine O, Haioun C, Lepage E, D’Agay MF, Briere J, Lavignac C, et al. Prognostic significance of bcl-2 protein expression in aggressive non-Hodgkin’s lymphoma. Groupe d’Etude des Lymphomes de l’Adulte (GELA). Blood. 1996;87(1):265–72.PubMedGoogle Scholar
  160. 160.
    Hill ME, MacLennan KA, Cunningham DC, Vaughan Hudson B, Burke M, Clarke P, et al. Prognostic significance of BCL-2 expression and bcl-2 major breakpoint region rearrangement in diffuse large cell non-Hodgkin’s lymphoma: a British National Lymphoma Investigation Study. Blood. 1996;88(3):1046–51.PubMedGoogle Scholar
  161. 161.
    Hu S, Xu-Monette ZY, Tzankov A, Green T, Wu L, Balasubramanyam A, et al. MYC/BCL2 protein co-expression contributes to the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: a report from The International DLBCL Rituximab-CHOP Consortium Program Study. Blood. 2013;121(20):4021–31; quiz 4250.PubMedCentralPubMedGoogle Scholar
  162. 162.
    Masago K, Togashi Y, Fujita S, Nagai H, Sakamori Y, Okuda C, et al. Effect of the BCL2 gene polymorphism on survival in advanced-stage non-small cell lung cancer patients who received chemotherapy. Oncology. 2013;84(4):214–8.PubMedGoogle Scholar
  163. 163.
    Brimmell M, Mendiola R, Mangion J, Packham G. BAX frameshift mutations in cell lines derived from human haemopoietic malignancies are associated with resistance to apoptosis and microsatellite instability. Oncogene. 1998;16(14):1803–12.PubMedGoogle Scholar
  164. 164.
    Rampino N, Yamamoto H, Ionov Y, Li Y, Sawai H, Reed JC, et al. Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. Science. 1997;275(5302):967–9.PubMedGoogle Scholar
  165. 165.
    McConkey DJ, Chandra J, Wright S, Plunkett W, McDonnell TJ, Reed JC, et al. Apoptosis sensitivity in chronic lymphocytic leukemia is determined by endogenous endonuclease content and relative expression of BCL-2 and BAX. J Immunol. 1996;156(7):2624–30.PubMedGoogle Scholar
  166. 166.
    Pepper C, Bentley P, Hoy T. Regulation of clinical chemoresistance by bcl-2 and bax oncoproteins in B-cell chronic lymphocytic leukaemia. Br J Haematol. 1996;95(3):513–7.PubMedGoogle Scholar
  167. 167.
    Fadeel B, Orrenius S. Apoptosis: a basic biological phenomenon with wide-ranging implications in human disease. J Intern Med. 2005;258(6):479–517.PubMedGoogle Scholar
  168. 168.
    Son JW, Kang HK, Chae MH, Choi JE, Park JM, Lee WK, et al. Polymorphisms in the caspase-8 gene and the risk of lung cancer. Cancer Genet Cytogenet. 2006;169(2):121–7.PubMedGoogle Scholar
  169. 169.
    Bethke L, Sullivan K, Webb E, Murray A, Schoemaker M, Auvinen A, et al. The common D302H variant of CASP8 is associated with risk of glioma. Cancer Epidemiol Biomarkers Prev. 2008;17(4):987–9.PubMedGoogle Scholar
  170. 170.
    Cox A, Dunning AM, Garcia-Closas M, Balasubramanian S, Reed MW, Pooley KA, et al. A common coding variant in CASP8 is associated with breast cancer risk. Nat Genet. 2007;39(3):352–8.PubMedGoogle Scholar
  171. 171.
    Sun T, Gao Y, Tan W, Ma S, Shi Y, Yao J, et al. A six-nucleotide insertion-deletion polymorphism in the CASP8 promoter is associated with susceptibility to multiple cancers. Nat Genet. 2007;39(5):605–13.PubMedGoogle Scholar
  172. 172.
    Wang M, Zhang Z, Tian Y, Shao J, Zhang Z. A six-nucleotide insertion-deletion polymorphism in the CASP8 promoter associated with risk and progression of bladder cancer. Clin Cancer Res. 2009;15(7):2567–72.PubMedGoogle Scholar
  173. 173.
    Zhang L, Ming L, Yu J. BH3 mimetics to improve cancer therapy; mechanisms and examples. Drug Resist Updat. 2007;10(6):207–17.PubMedCentralPubMedGoogle Scholar
  174. 174.
    Sarela AI, Macadam RC, Farmery SM, Markham AF, Guillou PJ. Expression of the antiapoptosis gene, survivin, predicts death from recurrent colorectal carcinoma. Gut. 2000;46(5):645–50.PubMedCentralPubMedGoogle Scholar
  175. 175.
    Krajewska M, Krajewski S, Banares S, Huang X, Turner B, Bubendorf L, et al. Elevated expression of inhibitor of apoptosis proteins in prostate cancer. Clin Cancer Res. 2003;9(13):4914–25.PubMedGoogle Scholar
  176. 176.
    Kasof GM, Gomes BC. Livin, a novel inhibitor of apoptosis protein family member. J Biol Chem. 2001;276(5):3238–46.PubMedGoogle Scholar
  177. 177.
    Vucic D, Stennicke HR, Pisabarro MT, Salvesen GS, Dixit VM. ML-IAP, a novel inhibitor of apoptosis that is preferentially expressed in human melanomas. Curr Biol CB. 2000;10(21):1359–66.Google Scholar
  178. 178.
    Lane DP. Cancer. p53, guardian of the genome. Nature. 1992;358(6381):15–6.PubMedGoogle Scholar
  179. 179.
    Lane DP, Goh AM. How p53 wields the scales of fate: arrest or death? Transcription. 2012;3(5):240–4.PubMedCentralPubMedGoogle Scholar
  180. 180.
    Miyashita T, Reed JC. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell. 1995;80(2):293–9.PubMedGoogle Scholar
  181. 181.
    Miyashita T, Harigai M, Hanada M, Reed JC. Identification of a p53-dependent negative response element in the bcl-2 gene. Cancer Res. 1994;54(12):3131–5.PubMedGoogle Scholar
  182. 182.
    Sax JK, Fei P, Murphy ME, Bernhard E, Korsmeyer SJ, El-Deiry WS. BID regulation by p53 contributes to chemosensitivity. Nat Cell Biol. 2002;4(11):842–9.PubMedGoogle Scholar
  183. 183.
    Kischkel FC, Lawrence DA, Chuntharapai A, Schow P, Kim KJ, Ashkenazi A. Apo2L/TRAIL-dependent recruitment of endogenous FADD and caspase-8 to death receptors 4 and 5. Immunity. 2000;12(6):611–20.PubMedGoogle Scholar
  184. 184.
    Deng Y, Lin Y, Wu X. TRAIL-induced apoptosis requires Bax-dependent mitochondrial release of Smac/DIABLO. Genes Dev. 2002;16(1):33–45.PubMedCentralPubMedGoogle Scholar
  185. 185.
    Ashkenazi A, Pai RC, Fong S, Leung S, Lawrence DA, Marsters SA, et al. Safety and antitumor activity of recombinant soluble Apo2 ligand. J Clin Invest. 1999;104(2):155–62.PubMedCentralPubMedGoogle Scholar
  186. 186.
    Walczak H, Miller RE, Ariail K, Gliniak B, Griffith TS, Kubin M, et al. Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nat Med. 1999;5(2):157–63.PubMedGoogle Scholar
  187. 187.
    El-Deiry WS. Insights into cancer therapeutic design based on p53 and TRAIL receptor signaling. Cell Death Differ. 2001;8(11):1066–75.PubMedGoogle Scholar
  188. 188.
    Herbst RS, Mendolson DS, Ebbinghaus S, Gordon MS, O’Dwyer P, Lieberman G, et al. A phase I safety and pharmacokinetic (PK) study of recombinant Apo2L/TRAIL, an apoptosis-inducing protein in patients with advanced cancer. ASCO Meeting Abstracts. 2006;24(18 suppl):3013.Google Scholar
  189. 189.
    Ling J, Herbst RS, Mendelson DS, Eckhardt SG, O’Dwyer P, Ebbinghaus S, et al. Apo2L/TRAIL pharmacokinetics in a phase 1a trial in advanced cancer and lymphoma. ASCO Meeting Abstracts. 2006;24(18 suppl):3047.Google Scholar
  190. 190.
    Johnstone RW, Frew AJ, Smyth MJ. The TRAIL apoptotic pathway in cancer onset, progression and therapy. Nat Rev Cancer. 2008;8(10):782–98.PubMedGoogle Scholar
  191. 191.
    Herbst RS, Eckhardt SG, Kurzrock R, Ebbinghaus S, O’Dwyer PJ, Gordon MS, et al. Phase I dose-escalation study of recombinant human Apo2L/TRAIL, a dual proapoptotic receptor agonist, in patients with advanced cancer. J Clin Oncol. 2010;28(17):2839–46.PubMedGoogle Scholar
  192. 192.
    Soria JC, Smit E, Khayat D, Besse B, Yang X, Hsu CP, et al. Phase 1b study of dulanermin (recombinant human Apo2L/TRAIL) in combination with paclitaxel, carboplatin, and bevacizumab in patients with advanced non-squamous non-small-cell lung cancer. J Clin Oncol. 2010;28(9):1527–33.PubMedGoogle Scholar
  193. 193.
    Yee L, Fanale M, Dimick K, Calvert S, Robins C, Ing J, et al. A phase IB safety and pharmacokinetic (PK) study of recombinant human Apo2L/TRAIL in combination with rituximab in patients with low-grade non-Hodgkin lymphoma. ASCO Meeting Abstracts. 2007;25(18 suppl):8078.Google Scholar
  194. 194.
    Soria JC, Mark Z, Zatloukal P, Szima B, Albert I, Juhasz E, et al. Randomized phase II study of dulanermin in combination with paclitaxel, carboplatin, and bevacizumab in advanced non-small-cell lung cancer. J Clin Oncol. 2011;29(33):4442–51.PubMedGoogle Scholar
  195. 195.
    Belada D, Mayer J, Czuczman MS, Flinn IW, Durbin-Johnson B, Bray GL. Phase II study of dulanermin plus rituximab in patients with relapsed follicular non-Hodgkin’s lymphoma (NHL). ASCO Meeting Abstracts. 2010;28(15 suppl):8104.Google Scholar
  196. 196.
    Mom CH, Verweij J, Oldenhuis CN, Gietema JA, Fox NL, Miceli R, et al. Mapatumumab, a fully human agonistic monoclonal antibody that targets TRAIL-R1, in combination with gemcitabine and cisplatin: a phase I study. Clin Cancer Res: Off J Am Assoc Cancer Res. 2009;15(17):5584–90.Google Scholar
  197. 197.
    Leong S, Cohen RB, Gustafson DL, Langer CJ, Camidge DR, Padavic K, et al. Mapatumumab, an antibody targeting TRAIL-R1, in combination with paclitaxel and carboplatin in patients with advanced solid malignancies: results of a phase I and pharmacokinetic study. J Clin Oncol. 2009;27(26):4413–21.PubMedGoogle Scholar
  198. 198.
    Sun W, Nelson D, Alberts SR, Poordad F, Leong S, Teitelbaum UR, et al. Phase Ib study of mapatumumab in combination with sorafenib in patients with advanced hepatocellular carcinoma (HCC) and chronic viral hepatitis. ASCO Meeting Abstracts. 2011;29(4 suppl):261.Google Scholar
  199. 199.
    Younes A, Vose JM, Zelenetz AD, Smith MR, Burris HA, Ansell SM, et al. A Phase 1b/2 trial of mapatumumab in patients with relapsed/refractory non-Hodgkin’s lymphoma. Br J Cancer. 2010;103(12):1783–7.PubMedCentralPubMedGoogle Scholar
  200. 200.
    Trarbach T, Moehler M, Heinemann V, Kohne CH, Przyborek M, Schulz C, et al. Phase II trial of mapatumumab, a fully human agonistic monoclonal antibody that targets and activates the tumour necrosis factor apoptosis-inducing ligand receptor-1 (TRAIL-R1), in patients with refractory colorectal cancer. Br J Cancer. 2010;102(3):506–12.PubMedCentralPubMedGoogle Scholar
  201. 201.
    Von Pawel J, Harvey JH, Spigel DR, Dediu M, Reck M, Cebotaru CL, et al. A randomized phase II trial of mapatumumab, a TRAIL-R1 agonist monoclonal antibody, in combination with carboplatin and paclitaxel in patients with advanced NSCLC. ASCO Meeting Abstracts. 2010;28(18 suppl):LBA7501.Google Scholar
  202. 202.
    Wakelee HA, Patnaik A, Sikic BI, Mita M, Fox NL, Miceli R, et al. Phase I and pharmacokinetic study of lexatumumab (HGS-ETR2) given every 2 weeks in patients with advanced solid tumors. Ann Oncol. 2010;21(2):376–81.PubMedCentralPubMedGoogle Scholar
  203. 203.
    Merchant MS, Geller JI, Baird K, Chou AJ, Galli S, Charles A, et al. Phase I trial and pharmacokinetic study of lexatumumab in pediatric patients with solid tumors. J Clin Oncol. 2012;30(33):4141–7.PubMedCentralPubMedGoogle Scholar
  204. 204.
    Camidge DR, Herbst RS, Gordon MS, Eckhardt SG, Kurzrock R, Durbin B, et al. A phase I safety and pharmacokinetic study of the death receptor 5 agonistic antibody PRO95780 in patients with advanced malignancies. Clin Cancer Res: Off J Am Assoc Cancer Res. 2010;16(4):1256–63.Google Scholar
  205. 205.
    Karapetis CS, Clingan PR, Leighl NB, Durbin-Johnson B, O’Neill V, Spigel DR. Phase II study of PRO95780 plus paclitaxel, carboplatin, and bevacizumab (PCB) in non-small cell lung cancer (NSCLC). ASCO Meeting Abstracts. 2010;28(15 suppl):7535.Google Scholar
  206. 206.
    Wittebol S, Ferrant A, Wickham NW, Fehrenbacher L, Durbin-Johnson B, Bray GL. Phase II study of PRO95780 plus rituximab in patients with relapsed follicular non-Hodgkin’s lymphoma (NHL). ASCO Meeting Abstracts. 2010;28(15 suppl):e18511.Google Scholar
  207. 207.
    Herbst RS, Kurzrock R, Hong DS, Valdivieso M, Hsu CP, Goyal L, et al. A first-in-human study of conatumumab in adult patients with advanced solid tumors. Clin Cancer Res: Off J Am Assoc Cancer Res. 2010;16(23):5883–91.Google Scholar
  208. 208.
    Doi T, Murakami H, Ohtsu A, Fuse N, Yoshino T, Yamamoto N, et al. Phase 1 study of conatumumab, a pro-apoptotic death receptor 5 agonist antibody, in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol. 2011;68(3):733–41.PubMedGoogle Scholar
  209. 209.
    Kindler HL, Garbo L, Stephenson J, Wiezorek J, Sabin T, Hsu M, et al. A phase Ib study to evaluate the safety and efficacy of AMG 655 in combination with gemcitabine (G) in patients (pts) with metastatic pancreatic cancer (PC). ASCO Meeting Abstracts. 2009;27(15S):4501.Google Scholar
  210. 210.
    Paz-Ares L, Sanchez Torres JM, Diaz-Padilla I, Links M, Reguart N, Boyer M, et al. Safety and efficacy of AMG 655 in combination with paclitaxel and carboplatin (PC) in patients with advanced non-small cell lung cancer (NSCLC). ASCO Meeting Abstracts. 2009;27(15S):e19048.Google Scholar
  211. 211.
    Saltz L, Infante J, Schwartzberg L, Stephenson J, Rocha-Lima C, Galimi F, et al. Safety and efficacy of AMG 655 plus modified FOLFOX6 (mFOLFOX6) and bevacizumab (B) for the first-line treatment of patients (pts) with metastatic colorectal cancer (mCRC). ASCO Meeting Abstracts. 2009;27(15S):4079.Google Scholar
  212. 212.
    Demetri GD, Le Cesne A, Chawla SP, Brodowicz T, Maki RG, Bach BA, et al. First-line treatment of metastatic or locally advanced unresectable soft tissue sarcomas with conatumumab in combination with doxorubicin or doxorubicin alone: a phase I/II open-label and double-blind study. Eur J Cancer. 2012;48(4):547–63.PubMedGoogle Scholar
  213. 213.
    Rougier P, Infante J, Van Laethem J, Stephenson JJ, Uronis H, Schwartzberg L, et al. A phase Ib/II trial of AMG 655 and panitumumab (pmab) for the treatment (tx) of metastatic colorectal cancer (mCRC): Safety results. ASCO Meeting Abstracts. 2009;27(15S):4130.Google Scholar
  214. 214.
    Kindler HL, Richards DA, Garbo LE, Garon EB, Stephenson Jr JJ, Rocha-Lima CM, et al. A randomized, placebo-controlled phase 2 study of ganitumab (AMG 479) or conatumumab (AMG 655) in combination with gemcitabine in patients with metastatic pancreatic cancer. Ann Oncol. 2012;23(11):2834–42.PubMedGoogle Scholar
  215. 215.
    Cohn AL, Tabernero J, Maurel J, Nowara E, Sastre J, Chuah BY, et al. A randomized, placebo-controlled phase 2 study of ganitumab or conatumumab in combination with FOLFIRI for second-line treatment of mutant KRAS metastatic colorectal cancer. Ann Oncol. 2013;24(7):1777–85.PubMedGoogle Scholar
  216. 216.
    Paz-Ares L, Balint B, de Boer RH, van Meerbeeck JP, Wierzbicki R, De Souza P, et al. A randomized phase 2 study of paclitaxel and carboplatin with or without conatumumab for first-line treatment of advanced non-small-cell lung cancer. J Thorac Oncol. 2013;8(3):329–37.PubMedGoogle Scholar
  217. 217.
    James DF, Castro JE, Loria O, Prada CE, Aguillon RA, Kipps TJ. AT-101, a small molecule Bcl-2 antagonist, in treatment naive CLL patients (pts) with high risk features; preliminary results from an ongoing phase I trial. J Clin Oncol (Meeting Abstracts). 2006;24(18 suppl):6605.Google Scholar
  218. 218.
    Heist RS, Fain J, Chinnasami B, Khan W, Molina JR, Sequist LV, et al. Phase I/II study of AT-101 with topotecan in relapsed and refractory small cell lung cancer. J Thorac Oncol. 2010;5(10):1637–43.PubMedGoogle Scholar
  219. 219.
    Baggstrom MQ, Qi Y, Koczywas M, Argiris A, Johnson EA, Millward MJ, et al. A phase II study of AT-101 (Gossypol) in chemotherapy-sensitive recurrent extensive-stage small cell lung cancer. J Thorac Oncol. 2011;6(10):1757–60.PubMedCentralPubMedGoogle Scholar
  220. 220.
    Ready N, Karaseva NA, Orlov SV, Luft AV, Popovych O, Holmlund JT, et al. Double-blind, placebo-controlled, randomized phase 2 study of the proapoptotic agent AT-101 plus docetaxel, in second-line non-small cell lung cancer. J Thorac Oncol. 2011;6(4):781–5.PubMedGoogle Scholar
  221. 221.
    Schimmer AD, O’Brien S, Kantarjian H, Brandwein J, Cheson BD, Minden MD, et al. A phase I study of the pan bcl-2 family inhibitor obatoclax mesylate in patients with advanced hematologic malignancies. Clin Cancer Res. 2008;14(24):8295–301.PubMedGoogle Scholar
  222. 222.
    O’Brien SM, Claxton DF, Crump M, Faderl S, Kipps T, Keating MJ, et al. Phase I study of obatoclax mesylate (GX15-070), a small molecule pan-Bcl-2 family antagonist, in patients with advanced chronic lymphocytic leukemia. Blood. 2009;113(2):299–305.PubMedGoogle Scholar
  223. 223.
    Paik PK, Rudin CM, Brown A, Rizvi NA, Takebe N, Travis W, et al. A phase I study of obatoclax mesylate, a Bcl-2 antagonist, plus topotecan in solid tumor malignancies. Cancer Chemother Pharmacol. 2010;66(6):1079–85.PubMedCentralPubMedGoogle Scholar
  224. 224.
    Hwang JJ, Kuruvilla J, Mendelson D, Pishvaian MJ, Deeken JF, Siu LL, et al. Phase I dose finding studies of obatoclax (GX15-070), a small molecule pan-BCL-2 family antagonist, in patients with advanced solid tumors or lymphoma. Clin Cancer Res. 2010;16(15):4038–45.PubMedCentralPubMedGoogle Scholar
  225. 225.
    Paik PK, Rudin CM, Pietanza MC, Brown A, Rizvi NA, Takebe N, et al. A phase II study of obatoclax mesylate, a Bcl-2 antagonist, plus topotecan in relapsed small cell lung cancer. Lung Cancer. 2011;74(3):481–5.PubMedCentralPubMedGoogle Scholar
  226. 226.
    Oki Y, Copeland A, Hagemeister F, Fayad LE, Fanale M, Romaguera J, et al. Experience with obatoclax mesylate (GX15-070), a small molecule pan–Bcl-2 family antagonist in patients with relapsed or refractory classical Hodgkin lymphoma. Blood. 2012;119(9):2171–2.PubMedGoogle Scholar
  227. 227.
    Wilson WH, O’Connor OA, Czuczman MS, LaCasce AS, Gerecitano JF, Leonard JP, et al. Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity. Lancet Oncol. 2010;11(12):1149–59.PubMedCentralPubMedGoogle Scholar
  228. 228.
    Rudin CM, Hann CL, Garon EB, Ribeiro de Oliveira M, Bonomi PD, Camidge DR, et al. Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer. Clin Cancer Res. 2012;18(11):3163–9.PubMedCentralPubMedGoogle Scholar
  229. 229.
    Ott PA, Chang J, Madden K, Kannan R, Muren C, Escano C, et al. Oblimersen in combination with temozolomide and albumin-bound paclitaxel in patients with advanced melanoma: a phase I trial. Cancer Chemother Pharmacol. 2013;71(1):183–91.PubMedGoogle Scholar
  230. 230.
    Wetzler M, Donohue KA, Odenike OM, Feldman EJ, Hurd DD, Stone RM, et al. Feasibility of administering oblimersen (G3139; Genasense) with imatinib mesylate in patients with imatinib resistant chronic myeloid leukemia–cancer and leukemia group B study 10107. Leuk Lymphoma. 2008;49(7):1274–8.PubMedCentralPubMedGoogle Scholar
  231. 231.
    Rudin CM, Salgia R, Wang X, Hodgson LD, Masters GA, Green M, et al. Randomized phase II study of carboplatin and etoposide with or without the bcl-2 antisense oligonucleotide oblimersen for extensive-stage small-cell lung cancer: CALGB 30103. J Clin Oncol. 2008;26(6):870–6.PubMedCentralPubMedGoogle Scholar
  232. 232.
    Bedikian AY, Millward M, Pehamberger H, Conry R, Gore M, Trefzer U, et al. Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: the Oblimersen Melanoma Study Group. J Clin Oncol. 2006;24(29):4738–45.PubMedGoogle Scholar
  233. 233.
    O’Brien S, Moore JO, Boyd TE, Larratt LM, Skotnicki A, Koziner B, et al. Randomized phase III trial of fludarabine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) in patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2007;25(9):1114–20.PubMedGoogle Scholar
  234. 234.
    O’Brien S, Moore JO, Boyd TE, Larratt LM, Skotnicki AB, Koziner B, et al. Five-year survival in patients with relapsed or refractory chronic lymphocytic leukemia in a randomized, phase III trial of fludarabine plus cyclophosphamide with or without oblimersen. J Clin Oncol. 2009;27(31):5208–12.PubMedGoogle Scholar
  235. 235.
    Chanan-Khan AA, Niesvizky R, Hohl RJ, Zimmerman TM, Christiansen NP, Schiller GJ, et al. Phase III randomised study of dexamethasone with or without oblimersen sodium for patients with advanced multiple myeloma. Leuk Lymphoma. 2009;50(4):559–65.PubMedGoogle Scholar
  236. 236.
    Kane RC, Farrell AT, Sridhara R, Pazdur R. United States food and drug administration approval summary: bortezomib for the treatment of progressive multiple myeloma after one prior therapy. Clin Cancer Res. 2006;12(10):2955–60.PubMedGoogle Scholar
  237. 237.
    Kane RC, Dagher R, Farrell A, Ko C-W, Sridhara R, Justice R, et al. Bortezomib for the treatment of mantle cell lymphoma. Clin Cancer Res. 2007;13(18):5291–4.PubMedGoogle Scholar
  238. 238.
    Cortes J, Thomas D, Koller C, Giles F, Estey E, Faderl S, et al. Phase I study of bortezomib in refractory or relapsed acute leukemias. Clin Cancer Res. 2004;10(10):3371–6.PubMedGoogle Scholar
  239. 239.
    Cresta S, Sessa C, Catapano CV, Gallerani E, Passalacqua D, Rinaldi A, et al. Phase I study of bortezomib with weekly paclitaxel in patients with advanced solid tumours. Eur J Cancer. 2008;44(13):1829–34.PubMedGoogle Scholar
  240. 240.
    Reece DE, Rodriguez GP, Chen C, Trudel S, Kukreti V, Mikhael J, et al. Phase I-II trial of bortezomib plus oral cyclophosphamide and prednisone in relapsed and refractory multiple myeloma. J Clin Oncol. 2008;26(29):4777–83.PubMedGoogle Scholar
  241. 241.
    Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003;348(26):2609–17.PubMedGoogle Scholar
  242. 242.
    Fisher RI, Bernstein SH, Kahl BS, Djulbegovic B, Robertson MJ, de Vos S, et al. Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol. 2006;24(30):4867–74.PubMedGoogle Scholar
  243. 243.
    Mendler JH, Kelly J, Voci S, Marquis D, Rich L, Rossi RM, et al. Bortezomib and gemcitabine in relapsed or refractory Hodgkin’s lymphoma. Ann Oncol. 2008;19(10):1759–64.PubMedCentralPubMedGoogle Scholar
  244. 244.
    Jatoi A, Dakhil SR, Foster NR, Ma C, Rowland Jr KM, Moore Jr DF, et al. Bortezomib, paclitaxel, and carboplatin as a first-line regimen for patients with metastatic esophageal, gastric, and gastroesophageal cancer: phase II results from the North Central Cancer Treatment Group (N044B). J Thorac Oncol. 2008;3(5):516–20.PubMedCentralPubMedGoogle Scholar
  245. 245.
    Goy A, Bernstein SH, Kahl BS, Djulbegovic B, Robertson MJ, de Vos S, et al. Bortezomib in patients with relapsed or refractory mantle cell lymphoma: updated time-to-event analyses of the multicenter phase 2 PINNACLE study. Ann Oncol. 2009;20(3):520–5.PubMedGoogle Scholar
  246. 246.
    Dispenzieri A, Jacobus S, Vesole DH, Callandar N, Fonseca R, Greipp PR. Primary therapy with single agent bortezomib as induction, maintenance and re-induction in patients with high-risk myeloma: results of the ECOG E2A02 trial. Leukemia. 2010;24(8):1406–11.PubMedCentralPubMedGoogle Scholar
  247. 247.
    Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005;352(24):2487–98.PubMedGoogle Scholar
  248. 248.
    O’Connor OA, Stewart AK, Vallone M, Molineaux CJ, Kunkel LA, Gerecitano JF, et al. A phase 1 dose escalation study of the safety and pharmacokinetics of the novel proteasome inhibitor carfilzomib (PR-171) in patients with hematologic malignancies. Clin Cancer Res. 2009;15(22):7085–91.PubMedCentralPubMedGoogle Scholar
  249. 249.
    Dean E, Jodrell D, Connolly K, Danson S, Jolivet J, Durkin J, et al. Phase I trial of AEG35156 administered as a 7-day and 3-day continuous intravenous infusion in patients with advanced refractory cancer. J Clin Oncol. 2009;27(10):1660–6.PubMedGoogle Scholar
  250. 250.
    Schimmer AD, Estey EH, Borthakur G, Carter BZ, Schiller GJ, Tallman MS, et al. Phase I/II trial of AEG35156 X-linked inhibitor of apoptosis protein antisense oligonucleotide combined with idarubicin and cytarabine in patients with relapsed or primary refractory acute myeloid leukemia. J Clin Oncol. 2009;27(28):4741–6.PubMedGoogle Scholar
  251. 251.
    Schimmer AD, Herr W, Hanel M, Borthakur G, Frankel A, Horst HA, et al. Addition of AEG35156 XIAP antisense oligonucleotide in reinduction chemotherapy does not improve remission rates in patients with primary refractory acute myeloid leukemia in a randomized phase II study. Clin Lymphoma Myeloma Leuk. 2011;11(5):433–8.PubMedGoogle Scholar
  252. 252.
    Infante JR, Dees EC, Burris HA, Zawel L, Sager JA, Stevenson C, et al. Abstract 2775: a phase I study of LCL161, an oral IAP inhibitor, in patients with advanced cancer. Cancer Res. 2011;70(8 Suppl):2775.Google Scholar
  253. 253.
    Dienstmann R, Vidal L, Dees E, Chia S, Mayer E, Porter D, et al. A phase Ib study of LCL161, an oral inhibitor of apoptosis (IAP) antagonist, in combination with weekly paclitaxel in patients with advanced solid tumors. Cancer Res. 2012;72(24 Suppl):P6-11-06.Google Scholar
  254. 254.
    Sikic BI, Eckhardt SG, Gallant G, Burris HA, Camidge DR, Colevas AD, et al. Safety, pharmacokinetics (PK), and pharmacodynamics (PD) of HGS1029, an inhibitor of apoptosis protein (IAP) inhibitor, in patients (Pts) with advanced solid tumors: results of a phase I study. ASCO Meeting Abstracts. 2011;29(15 suppl):3008.Google Scholar
  255. 255.
    Amaravadi RK, Schilder RJ, Dy GK, Ma WW, Fetterly GJ, Weng DE, et al. Abstract LB-406: phase 1 study of the smac mimetic TL32711 in adult subjects with advanced solid tumors and lymphoma to evaluate safety, pharmacokinetics, pharmacodynamics, and antitumor activity. Cancer Res. 2011;71(8 Suppl):LB-406.Google Scholar
  256. 256.
    Tolcher AW, Mita A, Lewis LD, Garrett CR, Till E, Daud AI, et al. Phase I and pharmacokinetic study of YM155, a small-molecule inhibitor of survivin. J Clin Oncol. 2008;26(32):5198–203.PubMedGoogle Scholar
  257. 257.
    Satoh T, Okamoto I, Miyazaki M, Morinaga R, Tsuya A, Hasegawa Y, et al. Phase I study of YM155, a novel survivin suppressant, in patients with advanced solid tumors. Clin Cancer Res. 2009;15(11):3872–80.PubMedGoogle Scholar
  258. 258.
    Giaccone G, Zatloukal P, Roubec J, Floor K, Musil J, Kuta M, et al. Multicenter phase II trial of YM155, a small-molecule suppressor of survivin, in patients with advanced, refractory, non-small-cell lung cancer. J Clin Oncol. 2009;27(27):4481–6.PubMedGoogle Scholar
  259. 259.
    Lewis K, Samlowski W, Ward J, Catlett J, Cranmer L, Kirkwood J, et al. A multi-center phase II evaluation of the small molecule survivin suppressor YM155 in patients with unresectable stage III or IV melanoma. Invest New Drugs. 2011;29(1):161–6.PubMedGoogle Scholar
  260. 260.
    Greco FA, Bonomi P, Crawford J, Kelly K, Oh Y, Halpern W, et al. Phase 2 study of mapatumumab, a fully human agonistic monoclonal antibody which targets and activates the TRAIL receptor-1, in patients with advanced non-small cell lung cancer. Lung Cancer. 2008;61(1):82–90.PubMedGoogle Scholar
  261. 261.
    Hotte SJ, Hirte HW, Chen EX, Siu LL, Le LH, Corey A, et al. A phase 1 study of mapatumumab (fully human monoclonal antibody to TRAIL-R1) in patients with advanced solid malignancies. Clin Cancer Res. 2008;14(11):3450–5.PubMedGoogle Scholar
  262. 262.
    Le LH, Hirte HW, Hotte SJ, Maclean M, Iacobucci A, Corey A, et al. Phase I study of a fully human monoclonal antibody to the tumor necrosis factor-related apoptosis-inducing ligand death receptor 4 (TRAIL-R1) in subjects with advanced solid malignancies or non-Hodgkin’s lymphoma (NHL). ASCO Meeting Abstracts. 2004;22(14 suppl):2533.Google Scholar
  263. 263.
    Chow LQ, Eckhardt SG, Gustafson DL, O’Bryant C, Hariharan S, Diab S, 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. ASCO Meeting Abstracts. 2006;24(18 suppl):2515.Google Scholar
  264. 264.
    Chao DT, Korsmeyer SJ. BCL-2 family: regulators of cell death. Annu Rev Immunol. 1998;16:395–419.PubMedGoogle Scholar
  265. 265.
    Reed JC. Double identity for proteins of the Bcl-2 family. Nature. 1997;387(6635):773–6.PubMedGoogle Scholar
  266. 266.
    Adams JM, Cory S. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene. 2007;26(9):1324–37.PubMedCentralPubMedGoogle Scholar
  267. 267.
    Yip KW, Reed JC. Bcl-2 family proteins and cancer. Oncogene. 2008;27(50):6398–406.PubMedGoogle Scholar
  268. 268.
    Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 2005;435(7042):677–81.PubMedGoogle Scholar
  269. 269.
    Kirkin V, Joos S, Zornig M. The role of Bcl-2 family members in tumorigenesis. Biochim Biophys Acta. 2004;1644(2–3):229–49.PubMedGoogle Scholar
  270. 270.
    Kitada S, Kress CL, Krajewska M, Jia L, Pellecchia M, Reed JC. Bcl-2 antagonist apogossypol (NSC736630) displays single-agent activity in Bcl-2-transgenic mice and has superior efficacy with less toxicity compared with gossypol (NSC19048). Blood. 2008;111(6):3211–9.PubMedCentralPubMedGoogle Scholar
  271. 271.
    Nguyen M, Marcellus RC, Roulston A, Watson M, Serfass L, Murthy Madiraju SR, et al. Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis. Proc Natl Acad Sci U S A. 2007;104(49):19512–7.PubMedCentralPubMedGoogle Scholar
  272. 272.
    Pellecchia M, Reed JC. Inhibition of anti-apoptotic Bcl-2 family proteins by natural polyphenols: new avenues for cancer chemoprevention and chemotherapy. Curr Pharm Des. 2004;10(12):1387–98.PubMedGoogle Scholar
  273. 273.
    Kitada S, Leone M, Sareth S, Zhai D, Reed JC, Pellecchia M. Discovery, characterization, and structure-activity relationships studies of proapoptotic polyphenols targeting B-cell lymphocyte/leukemia-2 proteins. J Med Chem. 2003;46(20):4259–64.PubMedGoogle Scholar
  274. 274.
    Stein RC, Joseph AE, Matlin SA, Cunningham DC, Ford HT, Coombes RC. A preliminary clinical study of gossypol in advanced human cancer. Cancer Chemother Pharmacol. 1992;30(6):480–2.PubMedGoogle Scholar
  275. 275.
    Bushunow P, Reidenberg MM, Wasenko J, Winfield J, Lorenzo B, Lemke S, et al. Gossypol treatment of recurrent adult malignant gliomas. J Neurooncol. 1999;43(1):79–86.PubMedGoogle Scholar
  276. 276.
    Van Poznak C, Seidman AD, Reidenberg MM, Moasser MM, Sklarin N, Van Zee K, et al. Oral gossypol in the treatment of patients with refractory metastatic breast cancer: a phase I/II clinical trial. Breast Cancer Res Treat. 2001;66(3):239–48.PubMedGoogle Scholar
  277. 277.
    Sun Y, Wu J, Aboukameel A, Banerjee S, Arnold AA, Chen J, et al. Apogossypolone, a nonpeptidic small molecule inhibitor targeting Bcl-2 family proteins, effectively inhibits growth of diffuse large cell lymphoma cells in vitro and in vivo. Cancer Biol Ther. 2008;7(9):1418–26.PubMedCentralPubMedGoogle Scholar
  278. 278.
    Moreira JN, Santos A, Simoes S. Bcl-2-targeted antisense therapy (Oblimersen sodium): towards clinical reality. Rev Recent Clin Trials. 2006;1(3):217–35.PubMedGoogle Scholar
  279. 279.
    Morris MJ, Tong WP, Cordon-Cardo C, Drobnjak M, Kelly WK, Slovin SF, et al. Phase I trial of BCL-2 antisense oligonucleotide (G3139) administered by continuous intravenous infusion in patients with advanced cancer. Clin Cancer Res. 2002;8(3):679–83.PubMedGoogle Scholar
  280. 280.
    Marshall J, Chen H, Yang D, Figueira M, Bouker KB, Ling Y, et al. A phase I trial of a Bcl-2 antisense (G3139) and weekly docetaxel in patients with advanced breast cancer and other solid tumors. Ann Oncol. 2004;15(8):1274–83.PubMedGoogle Scholar
  281. 281.
    D’Arcy P, Linder S. Proteasome deubiquitinases as novel targets for cancer therapy. Int J Biochem Cell Biol. 2012;44(11):1729–38.PubMedGoogle Scholar
  282. 282.
    Naujokat C, Hoffmann S. Role and function of the 26S proteasome in proliferation and apoptosis. Lab Inv J Tech Methods Path. 2002;82(8):965–80.Google Scholar
  283. 283.
    Wolf DH, Hilt W. The proteasome: a proteolytic nanomachine of cell regulation and waste disposal. Biochim Biophys Acta. 2004;1695(1–3):19–31.PubMedGoogle Scholar
  284. 284.
    Muratani M, Tansey WP. How the ubiquitin-proteasome system controls transcription. Nat Rev Mol Cell Biol. 2003;4(3):192–201.PubMedGoogle Scholar
  285. 285.
    Burger AM, Seth AK. The ubiquitin-mediated protein degradation pathway in cancer: therapeutic implications. Eur J Cancer. 2004;40(15):2217–29.PubMedGoogle Scholar
  286. 286.
    Hoeller D, Dikic I. Targeting the ubiquitin system in cancer therapy. Nature. 2009;458(7237):438–44.PubMedGoogle Scholar
  287. 287.
    Rolen U, Kobzeva V, Gasparjan N, Ovaa H, Winberg G, Kisseljov F, et al. Activity profiling of deubiquitinating enzymes in cervical carcinoma biopsies and cell lines. Mol Carcinog. 2006;45(4):260–9.PubMedGoogle Scholar
  288. 288.
    Gilmore TD. Multiple myeloma: lusting for NF-kappaB. Cancer Cell. 2007;12(2):95–7.PubMedGoogle Scholar
  289. 289.
    Tracey L, Perez-Rosado A, Artiga MJ, Camacho FI, Rodriguez A, Martinez N, et al. Expression of the NF-kappaB targets BCL2 and BIRC5/Survivin characterizes small B-cell and aggressive B-cell lymphomas, respectively. J Pathol. 2005;206(2):123–34.PubMedGoogle Scholar
  290. 290.
    Baldwin AS. Control of oncogenesis and cancer therapy resistance by the transcription factor NF-kappaB. J Clin Invest. 2001;107(3):241–6.PubMedCentralPubMedGoogle Scholar
  291. 291.
    Hideshima T, Richardson P, Chauhan D, Palombella VJ, Elliott PJ, Adams J, et al. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res. 2001;61(7):3071–6.PubMedGoogle Scholar
  292. 292.
    Ludwig H, Khayat D, Giaccone G, Facon T. Proteasome inhibition and its clinical prospects in the treatment of hematologic and solid malignancies. Cancer. 2005;104(9):1794–807.PubMedGoogle Scholar
  293. 293.
    Crawford LJ, Walker B, Irvine AE. Proteasome inhibitors in cancer therapy. J Cell Commun Signal. 2011;5(2):101–10.PubMedCentralPubMedGoogle Scholar
  294. 294.
    Hideshima T, Chauhan D, Richardson P, Mitsiades C, Mitsiades N, Hayashi T, et al. NF-kappa B as a therapeutic target in multiple myeloma. J Biol Chem. 2002;277(19):16639–47.PubMedGoogle Scholar
  295. 295.
    Fribley A, Zeng Q, Wang CY. Proteasome inhibitor PS-341 induces apoptosis through induction of endoplasmic reticulum stress-reactive oxygen species in head and neck squamous cell carcinoma cells. Mol Cell Biol. 2004;24(22):9695–704.PubMedCentralPubMedGoogle Scholar
  296. 296.
    Obeng EA, Carlson LM, Gutman DM, Harrington Jr WJ, Lee KP, Boise LH. Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood. 2006;107(12):4907–16.PubMedCentralPubMedGoogle Scholar
  297. 297.
    Yang DT, Young KH, Kahl BS, Markovina S, Miyamoto S. Prevalence of bortezomib-resistant constitutive NF-kappaB activity in mantle cell lymphoma. Mol Cancer. 2008;7:40.PubMedCentralPubMedGoogle Scholar
  298. 298.
    Markovina S, Callander NS, O’Connor SL, Kim J, Werndli JE, Raschko M, et al. Bortezomib-resistant nuclear factor-kappaB activity in multiple myeloma cells. Mol Cancer Res MCR. 2008;6(8):1356–64.Google Scholar
  299. 299.
    Chen S, Blank JL, Peters T, Liu XJ, Rappoli DM, Pickard MD, et al. Genome-wide siRNA screen for modulators of cell death induced by proteasome inhibitor bortezomib. Cancer Res. 2010;70(11):4318–26.PubMedGoogle Scholar
  300. 300.
    Zhu YX, Tiedemann R, Shi CX, Yin H, Schmidt JE, Bruins LA, et al. RNAi screen of the druggable genome identifies modulators of proteasome inhibitor sensitivity in myeloma including CDK5. Blood. 2011;117(14):3847–57.PubMedCentralPubMedGoogle Scholar
  301. 301.
    Nawrocki ST, Carew JS, Dunner Jr K, Boise LH, Chiao PJ, Huang P, et al. Bortezomib inhibits PKR-like endoplasmic reticulum (ER) kinase and induces apoptosis via ER stress in human pancreatic cancer cells. Cancer Res. 2005;65(24):11510–9.PubMedGoogle Scholar
  302. 302.
    Ling YH, Liebes L, Zou Y, Perez-Soler R. Reactive oxygen species generation and mitochondrial dysfunction in the apoptotic response to Bortezomib, a novel proteasome inhibitor, in human H460 non-small cell lung cancer cells. J Biol Chem. 2003;278(36):33714–23.PubMedGoogle Scholar
  303. 303.
    Yu C, Rahmani M, Dent P, Grant S. The hierarchical relationship between MAPK signaling and ROS generation in human leukemia cells undergoing apoptosis in response to the proteasome inhibitor Bortezomib. Exp Cell Res. 2004;295(2):555–66.PubMedGoogle Scholar
  304. 304.
    Wolf J, Richardson PG, Schuster M, LeBlanc A, Walters IB, Battleman DS. Utility of bortezomib retreatment in relapsed or refractory multiple myeloma patients: a multicenter case series. Clin Adv Hematol Oncol. 2008;6(10):755–60.PubMedGoogle Scholar
  305. 305.
    Laubach JP, Mitsiades CS, Roccaro AM, Ghobrial IM, Anderson KC, Richardson PG. Clinical challenges associated with bortezomib therapy in multiple myeloma and Waldenstroms Macroglobulinemia. Leuk Lymphoma. 2009;50(5):694–702.PubMedCentralPubMedGoogle Scholar
  306. 306.
    Ruschak AM, Slassi M, Kay LE, Schimmer AD. Novel proteasome inhibitors to overcome bortezomib resistance. J Natl Cancer Inst. 2011;103(13):1007–17.PubMedGoogle Scholar
  307. 307.
    Parlati F, Lee SJ, Aujay M, Suzuki E, Levitsky K, Lorens JB, et al. Carfilzomib can induce tumor cell death through selective inhibition of the chymotrypsin-like activity of the proteasome. Blood. 2009;114(16):3439–47.PubMedGoogle Scholar
  308. 308.
    Kuhn DJ, Chen Q, Voorhees PM, Strader JS, Shenk KD, Sun CM, et al. Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma. Blood. 2007;110(9):3281–90.PubMedCentralPubMedGoogle Scholar
  309. 309.
    Cossu F, Mastrangelo E, Milani M, Sorrentino G, Lecis D, Delia D, et al. Designing smac-mimetics as antagonists of XIAP, cIAP1, and cIAP2. Biochem Biophys Res Commun. 2009;378(2):162–7.PubMedGoogle Scholar
  310. 310.
    Eckelman BP, Salvesen GS, Scott FL. Human inhibitor of apoptosis proteins: why XIAP is the black sheep of the family. EMBO Rep. 2006;7(10):988–94.PubMedCentralPubMedGoogle Scholar
  311. 311.
    Imre G, Larisch S, Rajalingam K. Ripoptosome: a novel IAP-regulated cell death-signalling platform. J Mol Cell Biol. 2011;3(6):324–6.PubMedGoogle Scholar
  312. 312.
    Fandy TE, Shankar S, Srivastava RK. Smac/DIABLO enhances the therapeutic potential of chemotherapeutic drugs and irradiation, and sensitizes TRAIL-resistant breast cancer cells. Mol Cancer. 2008;7:60.PubMedCentralPubMedGoogle Scholar
  313. 313.
    Varfolomeev E, Blankenship JW, Wayson SM, Fedorova AV, Kayagaki N, Garg P, et al. IAP antagonists induce autoubiquitination of c-IAPs, NF-κB activation, and TNFα-dependent apoptosis. Cell. 2007;131(4):669–81.PubMedGoogle Scholar
  314. 314.
    Talbot DC, Davies J, Callies S, Andre V, Lahn M, Ang J, et al. First human dose study evaluating safety and pharmacokinetics of LY2181308, an antisense oligonucleotide designed to inhibit survivin. ASCO Meeting Abstracts. 2008;26(15 suppl):3518.Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Mei Lan Tan
    • 1
    • 2
  • Heng Kean Tan
    • 2
  • Tengku Sifzizul Tengku Muhammad
    • 3
  1. 1.Advanced Medical and Dental InstituteUniversiti Sains MalaysiaKepala BatasMalaysia
  2. 2.Malaysian Institute of Pharmaceuticals & Nutraceuticals, Ministry of Science, Technology & Innovation (MOSTI)MindenMalaysia
  3. 3.Institute of Marine BiotechnologyUniversiti Malaysia TerengganuKuala TerengganuMalaysia

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