Skip to main content
SpringerLink
Log in

Cutting-Edge Apoptosis-Based Therapeutics

A Panacea for Cancer?

  • Drug Development
  • Published:
BioDrugs Aims and scope Submit manuscript

Abstract

Defects in programmed cell death or apoptosis are major hallmarks of cancer contributing to tumorigenesis, tumor progression, and therapy resistance. In the past decade, many of the pathways leading to apoptosis, as well as the molecular mechanisms blocking the death of tumor cells, have been elucidated. This detailed knowledge of the core apoptosis machinery is now being exploited for translation into novel cancer therapies in order to restore apoptosis induction in tumor cells. Strategies include activation of proapoptotic mediators such as death receptors, tumor protein p53, and second mitochondria-derived activator of caspases (SMAC)/DIABLO as well as inhibition of endogenous apoptosis inhibitors such as IAPs (inhibitor of apoptosis proteins) and BCL-2 (B-cell chronic lymphoid leukemia/lymphoma) proteins. Several approaches employing gene therapy and antisense strategies, recombinant biologics, or classic organic and combinatorial chemistry, have advanced into clinical trials or are already approved. This review looks at recent developments in apoptosis-based cancer therapies and highlights some very promising advances in drug design.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Table I
Table II
Fig. 2
Table III
Table IV
Table V

Similar content being viewed by others

Notes

  1. A method to establish a relationship between the structure and activity of a compound by modification of its chemical structure and subsequent analysis of the effect on its activity.

References

  1. Fischer U, Schulze-Osthoff K. New approaches and therapeutics targeting apoptosis in disease. Pharmacol Rev 2005; 57: 187–215

    Article  PubMed  CAS  Google Scholar 

  2. Schulze-Osthoff K, Ferrari D, Los M, et al. Apoptosis signaling by death receptors. Eur J Biochem 1998; 254: 439–59

    Article  PubMed  CAS  Google Scholar 

  3. Stroh C, Schulze-Osthoff K. Death by a thousand cuts: an ever increasing list of caspase substrates. Cell Death Differ 1998; 5: 997–1000

    Article  PubMed  CAS  Google Scholar 

  4. Fischer U, Janicke RU, Schulze-Osthoff K. Many cuts to ruin: a comprehensive update of caspase substrates. Cell Death Differ 2003; 10: 76–100

    Article  PubMed  CAS  Google Scholar 

  5. Los M, Wesselborg S, Schulze-Osthoff K. The role of caspases in development, immunity, and apoptotic signal transduction: lessons from knockout mice. Immunity 1999; 10: 629–39

    Article  PubMed  CAS  Google Scholar 

  6. Trauth BC, Klas C, Peters AM. Monoclonal antibody-mediated tumor regression by induction of apoptosis. Science 1989; 245 (4915): 301–5

    Article  PubMed  CAS  Google Scholar 

  7. Walczak H, Miller RE, Ariail K, et al. Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nat Med 1999; 5: 157–63

    Article  PubMed  CAS  Google Scholar 

  8. Roth W, Isenmann S, Naumann U, et al. Locoregional Apo2L/TRAIL eradicates intracranial human malignant glioma xenografts in athymic mice in the absence of neurotoxicity. Biochem Biophys Res Commun 1999; 265: 479–83

    Article  PubMed  CAS  Google Scholar 

  9. Ashkenazi A, Pai RC, Fong S, et al. Safety and antitumor activity of recombinant soluble Apo2 ligand. J Clin Invest 1999; 104: 155–62

    Article  PubMed  CAS  Google Scholar 

  10. Jo M, Kim TH, Seol DW, et al. Apoptosis induced in normal human hepatocytes by tumor necrosis factor-related apoptosis-inducing ligand. Nat Med 2000; 6: 564–7

    Article  PubMed  CAS  Google Scholar 

  11. Nitsch R, Bechmann I, Deisz RA, et al. Human brain-cell death induced by tumour-necrosis-factor-related apoptosis-inducing ligand (TRAIL). Lancet 2000; 356: 827–8

    Article  PubMed  CAS  Google Scholar 

  12. Ganten TM, Koschny R, Sykora J, et al. Preclinical differentiation between apparently safe and potentially hepatotoxic applications of TRAIL either alone or in combination with chemotherapeutic drugs. Clin Cancer Res 2006; 12: 2640–6

    Article  PubMed  CAS  Google Scholar 

  13. Lawrence D, Shahrokh Z, Marsters S, et al. Differential hepatocyte toxicity of recombinant Apo2L/TRAIL versions. Nat Med 2001; 7: 383–5

    Article  PubMed  CAS  Google Scholar 

  14. Corazza N, Jakob S, Schaer C, et al. TRAIL receptor-mediated JNK activation and Bim phosphorylation critically regulate Fas-mediated liver damage and lethality. J Clin Invest 2006; 116: 2493–9

    Article  PubMed  CAS  Google Scholar 

  15. Belka C, Schmid B, Marini P, et al. Sensitization of resistant lymphoma cells to irradiation-induced apoptosis by the death ligand TRAIL. Oncogene 2001; 20: 2190–6

    Article  PubMed  CAS  Google Scholar 

  16. Held J, Schulze-Osthoff K. Potential and caveats of TRAIL in cancer therapy. Drug Resist Updat 2001; 4: 243–52

    Article  PubMed  CAS  Google Scholar 

  17. Ichikawa K, Liu W, Zhao L, et al. Tumoricidal activity of a novel anti-human DR5 monoclonal antibody without hepatocyte cytotoxicity. Nat Med 2001; 7: 954–60

    Article  PubMed  CAS  Google Scholar 

  18. Ehtesham M, Kabos P, Gutierrez MA, et al. Induction of glioblastoma apoptosis using neural stem cell-mediated delivery of tumor necrosis factor-related apoptosis-inducing ligand. Cancer Res 2002; 62: 7170–4

    PubMed  CAS  Google Scholar 

  19. Siegmund D, Hadwiger P, Pfizenmaier K, et al. Selective inhibition of FLICE-like inhibitory protein expression with small interfering RNA oligonucleotides is sufficient to sensitize tumor cells for TRAIL-induced apoptosis. Mol Med 2002; 8: 725–32

    PubMed  CAS  Google Scholar 

  20. Suh WS, Kim YS, Schimmer AD, et al. Synthetic triterpenoids activate a pathway for apoptosis in AML cells involving downregulation of FLIP and sensitization to TRAIL. Leukemia 2003; 17: 2122–9

    Article  PubMed  CAS  Google Scholar 

  21. Eggermont AM, ten Hagen TL. Isolated limb perfusion for extremity soft-tissue sarcomas, in-transit metastases, and other unresectable tumors: credits, debits, and future perspectives. Curr Oncol Rep 2001; 3: 359–67

    Article  PubMed  CAS  Google Scholar 

  22. Djerbi M, Screpanti V, Catrina AI, et al. The inhibitor of death receptor signaling, FLICE-inhibitory protein defines a new class of tumor progression factors. J Exp Med 1999; 190: 1025–32

    Article  PubMed  CAS  Google Scholar 

  23. Medema JP, de Jong J, van Hall T, et al. Immune escape of tumors in vivo by expression of cellular FLICE-inhibitory protein. J Exp Med 1999; 190: 1033–8

    Article  PubMed  CAS  Google Scholar 

  24. Couch RD, Browning RG, Honda T, et al. Studies on the reactivity of CDDO, a promising new chemopreventive and chemotherapeutic agent: implications for a molecular mechanism of action. Bioorg Med Chem Lett 2005; 15: 2215–9

    Article  PubMed  CAS  Google Scholar 

  25. Fuentes-Prior P, Salvesen GS. The protein structures that shape caspase activity, specificity, activation and inhibition. Biochem J 2004; 384: 201–32

    Article  PubMed  CAS  Google Scholar 

  26. Fischer U, Schulze-Osthoff K. Pharmacological modulation of caspase activation. Curr Med Chem Anti-Inflam Anti-Allergy Agents 2005; 4: 407–19

    Article  CAS  Google Scholar 

  27. Shariat SF, Desai S, Song W, et al. Adenovirus-mediated transfer of inducible caspases: a novel ‘death switch’ gene therapeutic approach to prostate cancer. Cancer Res 2001; 61: 2562–71

    PubMed  CAS  Google Scholar 

  28. Tse E, Rabbitts TH. Intracellular antibody-caspase-mediated cell killing: an approach for application in cancer therapy. Proc Natl Acad Sci U S A 2000; 97: 12266–71

    Article  PubMed  CAS  Google Scholar 

  29. Nor JE, Hu Y, Song W, et al. Ablation of microvessels in vivo upon dimerization of iCaspase-9. Gene Ther 2002; 9: 444–51

    Article  PubMed  CAS  Google Scholar 

  30. Chelur DS, Chalfie M. From the cover: targeted cell killing by reconstituted caspases. Proc Natl Acad Sci U S A 2007; 104: 2283–8

    Article  PubMed  CAS  Google Scholar 

  31. Komata T, Kondo Y, Kanzawa T, et al. Treatment of malignant glioma cells with the transfer of constitutively active caspase-6 using the human telomerase catalytic subunit (human telomerase reverse transcriptase) gene promoter. Cancer Res 2001; 61: 5796–802

    PubMed  CAS  Google Scholar 

  32. Jia LT, Zhang LH, Yu CJ, et al. Specific tumoricidal activity of a secreted proapoptotic protein consisting of HER2 antibody and constitutively active caspase-3. Cancer Res 2003; 63: 3257–62

    PubMed  CAS  Google Scholar 

  33. Xu YM, Wang LF, Jia LT, et al. A caspase-6 and anti-human epidermal growth factor receptor-2 (HER2) antibody chimeric molecule suppresses the growth of HER2-overexpressing tumors. J Immunol 2004; 173: 61–7

    PubMed  CAS  Google Scholar 

  34. MacCorkle RA, Freeman KW, Spencer DM. Synthetic activation of caspases: artificial death switches. Proc Natl Acad Sci U S A 1998; 95: 3655–60

    Article  PubMed  CAS  Google Scholar 

  35. Xie X, Zhao X, Liu Y, et al. Adenovirus-mediated tissue-targeted expression of a caspase-9-based artificial death switch for the treatment of prostate cancer. Cancer Res 2001; 61: 6795–804

    PubMed  CAS  Google Scholar 

  36. Roy S, Bayly CI, Gareau Y, et al. Maintenance of caspase-3 proenzyme dormancy by an intrinsic ’safety catch’ regulatory tripeptide. Proc Natl Acad Sci U S A 2001; 98: 6132–7

    Article  PubMed  CAS  Google Scholar 

  37. Buckley CD, Pilling D, Henriquez NV, et al. RGD peptides induce apoptosis by direct caspase-3 activation. Nature 1999; 397: 534–9

    Article  PubMed  CAS  Google Scholar 

  38. Lode HN, Moehler T, Xiang R, et al. Synergy between an antiangiogenic integrin alphav antagonist and an antibody-cytokine fusion protein eradicates spontaneous tumor metastases. Proc Natl Acad Sci U S A 1999; 96: 1591–6

    Article  PubMed  CAS  Google Scholar 

  39. Arap W, Pasqualini R, Ruoslahti E. Cancer treatment by targeted drug delivery to tumor vasculature in a mouse model. Science 1998; 279: 377–80

    Article  PubMed  CAS  Google Scholar 

  40. Jiang X, Kim HE, Shu H, et al. Distinctive roles of PHAP proteins and prothymosin-alpha in a death regulatory pathway. Science 2003; 299: 223–6

    Article  PubMed  CAS  Google Scholar 

  41. Zhang HZ, Kasibhatla S, Wang Y, et al. Discovery, characterization and SAR of gambogic acid as a potent apoptosis inducer by a HTS assay. Bioorg Med Chem 2004; 12: 309–17

    Article  PubMed  CAS  Google Scholar 

  42. Nguyen JT, Wells JA. Direct activation of the apoptosis machinery as a mechanism to target cancer cells. Proc Natl Acad Sci U S A 2003; 100: 7533–8

    Article  PubMed  CAS  Google Scholar 

  43. Salvesen GS, Duckett CS. IAP proteins: blocking the road to death’s door. Nat Rev Mol Cell Biol 2002; 3: 401–10

    Article  PubMed  CAS  Google Scholar 

  44. Holcik M, Yeh C, Korneluk RG, et al. Translational upregulation of X-linked inhibitor of apoptosis (XIAP) increases resistance to radiation induced cell death. Oncogene 2000; 19: 4174–7

    Article  PubMed  CAS  Google Scholar 

  45. Sasaki H, Sheng Y, Kotsuji F, et al. Down-regulation of X-linked inhibitor of apoptosis protein induces apoptosis in chemoresistant human ovarian cancer cells. Cancer Res 2000; 60: 5659–66

    PubMed  CAS  Google Scholar 

  46. Hu Y, Cherton-Horvat G, Dragowska V, et al. Antisense oligonucleotides targeting XIAP induce apoptosis and enhance chemotherapeutic activity against human lung cancer cells in vitro and in vivo. Clin Cancer Res 2003; 9: 2826–36

    PubMed  CAS  Google Scholar 

  47. LeCasse EC, Cherton-Horvat GG, Hewitt KE, et al. Preclinical characterization of AEG35156/GEM 640, a second-generation antisense oligonucleotide targeting X-linked inhibitor of apoptosis. Clin Cancer Res 2006 Sep 1; 12 (17): 5231–41

    Article  Google Scholar 

  48. Bilim V, Kasahara T, Hara N, et al. Role of XIAP in the malignant phenotype of transitional cell cancer (TCC) and therapeutic activity of XIAP antisense oligonucleotides against multidrug-resistant TCC in vitro. Int J Cancer 2003; 103: 29–37

    Article  PubMed  CAS  Google Scholar 

  49. McManus DC, Lefebvre CA, Cherton-Horvat G, et al. Loss of XIAP protein expression by RNAi and antisense approaches sensitizes cancer cells to functionally diverse chemotherapeutics. Oncogene 2004; 23: 8105–17

    Article  PubMed  CAS  Google Scholar 

  50. Amantana A, London CA, Iversen PL, et al. X-Linked inhibitor of apoptosis protein inhibition induces apoptosis and enhances chemotherapy sensitivity in human prostate cancer cells. Mol Cancer Ther 2004; 3: 699–707

    PubMed  CAS  Google Scholar 

  51. Nikolovska-Coleska Z, Xu L, Hu Z, et al. Discovery of embelin as a cell-permeable, small-molecular weight inhibitor of XIAP through structure-based computational screening of a traditional herbal medicine three-dimensional structure database. J Med Chem 2004; 47: 2430–40

    Article  PubMed  CAS  Google Scholar 

  52. Oost TK, Sun C, Armstrong RC, et al. Discovery of potent antagonists of the antiapoptotic protein XIAP for the treatment of cancer. J Med Chem 2004; 47: 4417–26

    Article  PubMed  CAS  Google Scholar 

  53. Fulda S, Wick W, Weiler M, et al. Smac agonists sensitize for Apo2L/TRAIL- or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo. Nat Med 2002; 8: 808–15

    PubMed  CAS  Google Scholar 

  54. Yang L, Mashima T, Sato S, et al. Predominant suppression of apoptosome by inhibitor of apoptosis protein in non-small cell lung cancer H460 cells: therapeutic effect of a novel polyarginine-conjugated Smac peptide. Cancer Res 2003; 63: 831–7

    PubMed  CAS  Google Scholar 

  55. Sun H, Nikolovska-Coleska Z, Lu J, et al. Design, synthesis, and evaluation of a potent, cell-permeable, conformationally constrained second mitochondria derived activator of caspase (Smac) mimetic. J Med Chem 2006; 49: 7916–20

    Article  PubMed  CAS  Google Scholar 

  56. Li L, Thomas RM, Suzuki H, et al. A small molecule Smac mimic potentiates TRAIL- and TNFalpha-mediated cell death. Science 2004; 305: 1471–4

    Article  PubMed  CAS  Google Scholar 

  57. Glover CJ, Hite K, DeLosh R, et al. A high-throughput screen for identification of molecular mimics of Smac/DIABLO utilizing a fluorescence polarization assay. Anal Biochem 2003; 320: 157–69

    Article  PubMed  CAS  Google Scholar 

  58. Wu TY, Wagner KW, Bursulaya B, et al. Development and characterization of nonpeptidic small molecule inhibitors of the XIAP/caspase-3 interaction. Chem Biol 2003; 10: 759–67

    Article  PubMed  CAS  Google Scholar 

  59. Schimmer AD, Welsh K, Pinilla C, et al. Small-molecule antagonists of apoptosis suppressor XIAP exhibit broad antitumor activity. Cancer Cell 2004; 5: 25–35

    Article  PubMed  CAS  Google Scholar 

  60. Wang Z, Cuddy M, Samuel T, et al. Cellular, biochemical, and genetic analysis of mechanism of small-molecule IAP inhibitors. J Biol Chem 2004 Nov 12; 279 (46): 48168–76

    Article  PubMed  CAS  Google Scholar 

  61. Tolcher AW, Hao D, de Bono J, et al. Phase I, pharmacokinetic, and pharmacodynamic study of intravenously administered Ad5CMV-p53, an adenoviral vector containing the wild-type p53 gene, in patients with advanced cancer. J Clin Oncol 2006; 24: 2052–8

    Article  PubMed  CAS  Google Scholar 

  62. Mesri M, Wall NR, Li J, et al. Cancer gene therapy using a survivin mutant adenovirus. J Clin Invest 2001; 108: 981–90

    PubMed  CAS  Google Scholar 

  63. Huang Y, Park YC, Rich RL, et al. Structural basis of caspase inhibition by XIAP: differential roles of the linker versus the BIR domain. Cell 2001; 104: 781–90

    PubMed  CAS  Google Scholar 

  64. Riedl SJ, Renatus M, Schwarzenbacher R, et al. Structural basis for the inhibition of caspase-3 by XIAP. Cell 2001; 104: 791–800

    Article  PubMed  CAS  Google Scholar 

  65. Deveraux QL, Leo E, Stennicke HR, et al. Cleavage of human inhibitor of apoptosis protein XIAP results in fragments with distinct specificities for caspases. Embo J 1999; 18: 5242–51

    Article  PubMed  CAS  Google Scholar 

  66. Arnt CR, Chiorean MV, Heldebrant MP, et al. Synthetic Smac/DIABLO peptides enhance the effects of chemotherapeutic agents by binding XIAP and cIAP1 in situ. J Biol Chem 2002; 277: 44236–43

    Article  PubMed  CAS  Google Scholar 

  67. Guo F, Nimmanapalli R, Paranawithana S, 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 2002; 99: 3419–26

    Article  PubMed  CAS  Google Scholar 

  68. Tamm I, Trepel M, Cardo-Vila M, et al. Peptides targeting caspase inhibitors. J Biol Chem 2003; 278: 14401–5

    Article  PubMed  CAS  Google Scholar 

  69. Wu G, Chai J, Suber TL, et al. Structural basis of IAP recognition by Smac/ DIABLO. Nature 2000; 408: 1008–12

    Article  PubMed  CAS  Google Scholar 

  70. Imoto I, Yang ZQ, Pimkhaokham A, et al. Identification of cIAPl as a candidate target gene within an amplicon at 11q22 in esophageal squamous cell carcinomas. Cancer Res 2001; 61: 6629–34

    PubMed  CAS  Google Scholar 

  71. Tamm I, Richter S, Oltersdorf D, et al. High expression levels of x-linked inhibitor of apoptosis protein and survivin correlate with poor overall survival in childhood de novo acute myeloid leukemia. Clin Cancer Res 2004; 10: 3737–44

    Article  PubMed  CAS  Google Scholar 

  72. Baens M, Maes B, Steyls A, et al. The product of the t (11;18), an API2-MLT fusion, marks nearly half of gastric MALT type lymphomas without large cell proliferation. Am J Pathol 2000; 156: 1433–9

    Article  PubMed  CAS  Google Scholar 

  73. Uren AG, O’Rourke K, Aravind LA, et al. Identification of paracaspases and metacaspases: two ancient families of caspase-like proteins, one of which plays a key role in MALT lymphoma. Mol Cell 2000; 6: 961–7

    PubMed  CAS  Google Scholar 

  74. Krajewska M, Krajewski S, Banares S, et al. Elevated expression of inhibitor of apoptosis proteins in prostate cancer. Clin Cancer Res 2003; 9: 4914–25

    PubMed  CAS  Google Scholar 

  75. Yang Y, Fang S, Jensen JP, et al. Ubiquitin protein ligase activity of IAPs and their degradation in proteasomes in response to apoptotic stimuli. Science 2000; 288: 874–7

    Article  PubMed  CAS  Google Scholar 

  76. Cory S, Huang DC, Adams JM. The BCL-2 family: roles in cell survival and oncogenesis. Oncogene 2003; 22: 8590–607

    Article  PubMed  CAS  Google Scholar 

  77. Daniel PT, Schulze-Osthoff K, Belka C, et al. Guardians of cell death: the BCL-2 family proteins. Essays Biochem 2003; 39: 73–88

    PubMed  CAS  Google Scholar 

  78. Reed JC. Drug insight: cancer therapy strategies based on restoration of endogenous cell death mechanisms. Nat Clin Pract Oncol 2006; 3: 388–98

    Article  PubMed  CAS  Google Scholar 

  79. Taylor JK, Zhang QQ, Wyatt JR, et al. Induction of endogenous BCL-xS through the control of BCL-x pre-mRNA splicing by antisense oligonucleotides. Nat Biotechnol 1999; 17: 1097–100

    Article  PubMed  CAS  Google Scholar 

  80. Zangemeister-Wittke U, Leech SH, Olie RA, et al. A novel bispecific antisense oligonucleotide inhibiting both bcl-2 and bcl-xL expression efficiently induces apoptosis in tumor cells. Clin Cancer Res 2000; 6: 2547–55

    PubMed  CAS  Google Scholar 

  81. Oliver CL, Bauer JA, Wolter KG, et al. In vitro effects of the BH3 mimetic, (−)- gossypol, on head and neck squamous cell carcinoma cells. Clin Cancer Res 2004; 10: 7757–63

    Article  PubMed  CAS  Google Scholar 

  82. Becattini B, Kitada S, Leone M, et al. Rational design and real time, in-cell detection of the proapoptotic activity of a novel compound targeting BCL-X (L). Chem Biol 2004; 11: 389–95

    Article  PubMed  CAS  Google Scholar 

  83. Holinger EP, Chittenden T, Lutz RJ. Bak BH3 peptides antagonize BCL-xL function and induce apoptosis through cytochrome c-independent activation of caspases. J Biol Chem 1999; 274: 13298–304

    Article  PubMed  CAS  Google Scholar 

  84. Wang JL, Zhang ZJ, Choksi S, et al. Cell permeable BCL-2 binding peptides: a chemical approach to apoptosis induction in tumor cells. Cancer Res 2000; 60: 1498–502

    PubMed  CAS  Google Scholar 

  85. Walensky LD, Kung AL, Escher I, et al. Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix. Science 2004; 305: 1466–70

    Article  PubMed  CAS  Google Scholar 

  86. Degterev A, Lugovskoy A, Cardone M, et al. Identification of small-molecule inhibitors of interaction between the BH3 domain and BCL-xL. Nat Cell Biol 2001; 3: 173–82

    Article  PubMed  CAS  Google Scholar 

  87. Yin H, Lee GI, Sedey KA, et al. Terphenyl-based Bak BH3 alpha-helical proteomimetics as low-molecular-weight antagonists of BCL-xL. J Am Chem Soc 2005; 127: 10191–6

    Article  PubMed  CAS  Google Scholar 

  88. Chan SL, Lee MC, Tan KO, et al. Identification of chelerythrine as an inhibitor of BCLXL function. J Biol Chem 2003; 278: 20453–6

    Article  PubMed  CAS  Google Scholar 

  89. Tzung SP, Kim KM, Basanez G, et al. Antimycin A mimics a cell-death-inducing BCL-2 homology domain 3. Nat Cell Biol 2001; 3: 183–91

    Article  PubMed  CAS  Google Scholar 

  90. Wang JL, Liu D, Zhang ZJ, et al. Structure-based discovery of an organic compound that binds BCL-2 protein and induces apoptosis of tumor cells. Proc Natl Acad Sci U S A 2000; 97: 7124–9

    Article  PubMed  CAS  Google Scholar 

  91. Enyedy IJ, Ling Y, Nacro K, et al. Discovery of small-molecule inhibitors of BCL-2 through structure-based computer screening. J Med Chem 2001; 44: 4313–24

    Article  PubMed  CAS  Google Scholar 

  92. Zhang Z, Jin L, Qian X, et al. Novel BCL-2 Inhibitors: discovery and mechanism study of small organic apoptosis-inducing agents. Chembiochem 2007; 8: 113–21

    Article  PubMed  CAS  Google Scholar 

  93. Leone M, Zhai D, Sareth S, et al. Cancer prevention by tea polyphenols is linked to their direct inhibition of antiapoptotic BCL-2-family proteins. Cancer Res 2003; 63: 8118–21

    PubMed  CAS  Google Scholar 

  94. Schwerk C, Schulze-Osthoff K. Regulation of apoptosis by alternative pre-mRNA splicing. Mol Cell 2005; 19: 1–13

    Article  PubMed  CAS  Google Scholar 

  95. Puthalakath H, Strasser A. Keeping killers on a tight leash: transcriptional and post-translational control of the pro-apoptotic activity of BH3-only proteins. Cell Death Differ 2002; 9: 505–12

    Article  PubMed  CAS  Google Scholar 

  96. Shangary S, Johnson DE. Peptides derived from BH3 domains of BCL-2 family members: a comparative analysis of inhibition of BCL-2, BCL-x (L) and Bax oligomerization, induction of cytochrome c release, and activation of cell death. Biochemistry 2002; 41: 9485–95

    Article  PubMed  CAS  Google Scholar 

  97. Schimmer AD, Hedley DW, Chow S, et al. The BH3 domain of BAD fused to the Antennapedia peptide induces apoptosis via its alpha helical structure and independent of BCL-2. Cell Death Differ 2001; 8: 725–33

    Article  PubMed  CAS  Google Scholar 

  98. O’Brien S, Kipps TJ, Faderl S, et al. A phase 1 trial of the small molecule pan-BCL-2 family inhibitor GX15-070 administered intravenously (iv) every 3 weeks to patients with previously treated chronic lymphocytic leukemia (CLL) [abstract]. Blood 2005; 106: 446

    Google Scholar 

  99. Feng WY, Liu FT, Patwari Y, et al. BH3-domain mimetic compound BH3I-2′ induces rapid damage to the inner mitochondrial membrane prior to the cytochrome c release from mitochondria. Br J Haematol 2003; 121: 332–40

    Article  PubMed  CAS  Google Scholar 

  100. Shuker SB, Hajduk PJ, Meadows RP, et al. Discovering high-affinity ligands for proteins: SAR by NMR. Science 1996; 274: 1531–4

    Article  PubMed  CAS  Google Scholar 

  101. Oltersdorf T, Elmore SW, Shoemaker AR, et al. An inhibitor of BCL-2 family proteins induces regression of solid tumours. Nature 2005; 435: 677–81

    Article  PubMed  CAS  Google Scholar 

  102. van Delft MF, Wei AH, Mason KD, et al. The BH3 mimetic ABT-737 targets selective BCL-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell 2006; 10: 389–99

    Article  PubMed  CAS  Google Scholar 

  103. Khuri FR, Nemunaitis J, Ganly I, et al. A controlled trial of intratumoral ON-YX-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer. Nat Med 2000; 6: 879–85

    Article  PubMed  CAS  Google Scholar 

  104. Maurici D, Monti P, Campomenosi P, et al. Amifostine (WR2721) restores transcriptional activity of specific p53 mutant proteins in a yeast functional assay. Oncogene 2001; 20: 3533–40

    Article  PubMed  CAS  Google Scholar 

  105. Foster BA, Coffey HA, Morin MJ, et al. Pharmacological rescue of mutant p53 conformation and function. Science 1999; 286: 2507–10

    Article  PubMed  CAS  Google Scholar 

  106. Bykov VJ, Issaeva N, Shilov A, et al. Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound. Nat Med 2002; 8: 282–8

    Article  PubMed  CAS  Google Scholar 

  107. Friedler A, Hansson LO, Veprintsev DB, et al. A peptide that binds and stabilizes p53 core domain: chaperone strategy for rescue of oncogenic mutants. Proc Natl Acad Sci U S A 2002; 99: 937–42

    Article  PubMed  CAS  Google Scholar 

  108. Kim AL, Raffo AJ, Brandt-Rauf PW, et al. Conformational and molecular basis for induction of apoptosis by a p53 C-terminal peptide in human cancer cells. J Biol Chem 1999; 274: 34924–31

    Article  PubMed  CAS  Google Scholar 

  109. Sclivanova G, Iotsova V, Okan I, et al. Restoration of the growth suppression function of mutant p53 by a synthetic peptide derived from the p53 C-terminal domain. Nat Med 1997; 3: 632–8

    Article  Google Scholar 

  110. Chene P, Fuchs J, Bohn J, et al. A small synthetic peptide, which inhibits the p53-hdm2 interaction, stimulates the p53 pathway in tumour cell lines. J Mol Biol 2000; 299: 245–53

    Article  PubMed  CAS  Google Scholar 

  111. Duncan SJ, Gruschow S, Williams DH, et al. Isolation and structure elucidation of chlorofusin, a novel p53-MDM2 antagonist from a Fusarium sp. J Am Chem Soc 2001; 123: 554–60

    Article  PubMed  CAS  Google Scholar 

  112. Zhang R, Mayhood T, Lipari P, et al. Fluorescence polarization assay and inhibitor design for MDM2/p53 interaction. Anal Biochem 2004; 331: 138–46

    PubMed  CAS  Google Scholar 

  113. Luke RWA, Hudson K, Hayward CF, et al. Design and synthesis of small molecule inhibitors of the MDM2-p53 interaction [abstract]. Proc Am Assoc Cancer Res 1999; 40: 4099

    Google Scholar 

  114. Chen L, Yin H, Farooqi B, et al. p53 alpha-Helix mimetics antagonize p53/MDM2 interaction and activate p53. Mol Cancer Ther 2005; 4: 1019–25

    Article  PubMed  CAS  Google Scholar 

  115. Yin H, Lee GI, Park HS, et al. Terphenyl-based helical mimetics that disrupt the p53/HDM2 interaction. Angew Chem Int Ed Engl 2005; 44: 2704–7

    Article  PubMed  CAS  Google Scholar 

  116. Vassilev LT, Vu BT, Graves B, et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 2004; 303: 844–8

    Article  PubMed  CAS  Google Scholar 

  117. Issaeva N, Bozko P, Enge M, et al. Small molecule RITA binds to p53, blocks p53-HDM-2 interaction and activates p53 function in tumors. Nat Med 2004; 10: 1321–8

    Article  PubMed  CAS  Google Scholar 

  118. Zheleva D, McInnes C, Baxter C, et al. Bisarylsulfonamides -novel small molecule inhibitors of p53-Mdm2 interaction [abstract]. Proc Am Assoc Cancer Res 2004; 45: 5552

    Google Scholar 

  119. Galatin PS, Abraham DJ. A nonpeptidic sulfonamide inhibits the p53-mdm2 interaction and activates p53-dependent transcription in mdm2-overexpressing cells. J Med Chem 2004; 47: 4163–5

    Article  PubMed  CAS  Google Scholar 

  120. Parks DJ, Lafrance LV, Calvo RR, et al. 1,4-Benzodiazepine-2,5-diones as small molecule antagonists of the HDM2-p53 interaction: discovery and SAR. Bioorg Med Chem Lett 2005; 15: 765–70

    Article  PubMed  CAS  Google Scholar 

  121. Hardcastle IR, Ahmed SU, Atkins H, et al. Isoindolinone-based inhibitors of the MDM2-p53 protein-protein interaction. Bioorg Med Chem Lett 2005; 15: 1515–20

    Article  PubMed  CAS  Google Scholar 

  122. Yang Y, Ludwig RL, Jensen JP, et al. Small molecule inhibitors of HDM2 ubiquitin ligase activity stabilize and activate p53 in cells. Cancer Cell 2005; 7: 547–59

    Article  PubMed  CAS  Google Scholar 

  123. Lai Z, Yang T, Kim YB, et al. Differentiation of Hdm2-mediated p53 ubiquitination and Hdm2 autoubiquitination activity by small molecular weight inhibitors. Proc Natl Acad Sci U S A 2002; 99: 14734–9

    Article  PubMed  CAS  Google Scholar 

  124. Midgley CA, Desterro JM, Saville MK, et al. An N-terminal pl4ARF peptide blocks Mdm2-dependent ubiquitination in vitro and can activate p53 in vivo. Oncogene 2000; 19: 2312–23

    Article  PubMed  CAS  Google Scholar 

  125. Chen L, Agrawal S, Zhou W, et al. Synergistic activation of p53 by inhibition of MDM2 expression and DNA damage. Proc Natl Acad Sci U S A 1998; 95: 195–200

    Article  PubMed  CAS  Google Scholar 

  126. Zhang Z, Wang H, Li M, et al. MDM2 is a negative regulator of p21WAF1/CIP1, independent of p53. J Biol Chem 2004; 279: 16000–6

    Article  PubMed  CAS  Google Scholar 

  127. Komarov PG, Komarova EA, Kondratov RV, et al. A chemical inhibitor of p53 that protects mice from the side effects of cancer therapy. Science 1999; 285: 1733–7

    Article  PubMed  CAS  Google Scholar 

  128. Martins CP, Brown-Swigart L, Evan GI. Modeling the therapeutic efficacy of p53 restoration in tumors. Cell 2006; 127: 1323–34

    Article  PubMed  CAS  Google Scholar 

  129. Xue W, Zender L, Miething C, et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 2007; 445: 656–60

    Article  PubMed  CAS  Google Scholar 

  130. Ventura A, Kirsch DG, McLaughlin ME, et al. Restoration of p53 function leads to tumour regression in vivo. Nature 2007; 445: 661–5

    Article  PubMed  CAS  Google Scholar 

  131. Seth P, Brinkmann U, Schwartz GN, et al. Adenovirus-mediated gene transfer to human breast tumor cells: an approach for cancer gene therapy and bone marrow purging. Cancer Res 1996; 56: 1346–51

    PubMed  CAS  Google Scholar 

  132. Rothmann T, Hengstermann A, Whitaker NJ, et al. Replication of ONYX-015, a potential anticancer adenovirus, is independent of p53 status in tumor cells. J Virol 1998; 72: 9470–8

    PubMed  CAS  Google Scholar 

  133. Sciivanova G, Ryabchenko L, Jansson E, et al. Reactivation of mutant p53 through interaction of a C-terminal peptide with the core domain. Mol Cell Biol 1999; 19: 3395–402

    Google Scholar 

  134. Garcia-Echeverria C, Furet P, Chene P. Coupling of the antennapedia third helix to a potent antagonist of the p53/hdm2 protein-protein interaction. Bioorg Med Chem Lett 2001; 11: 2161–4

    Article  PubMed  CAS  Google Scholar 

  135. Zhang Y, Xiong Y, Yarbrough WG. ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell 1998; 92: 725–34

    Article  PubMed  CAS  Google Scholar 

  136. Wang H, Zeng X, Oliver P, et al. MDM2 oncogene as a target for cancer therapy: an antisense approach. Int J Oncol 1999; 15: 653–60

    PubMed  CAS  Google Scholar 

  137. Wang H, Nan L, Yu D, et al. Anti-tumor efficacy of a novel antisense anti-MDM2 mixed-backbone oligonucleotide in human colon cancer models: p53-dependent and p53-independent mechanisms. Mol Med 2002; 8: 185–99

    PubMed  CAS  Google Scholar 

  138. Zhang Z, Wang H, Prasad G, et al. Radiosensitization by antisense anti-MDM2 mixed-backbone oligonucleotide in in vitro and in vivo human cancer models. Clin Cancer Res 2004; 10: 1263–73

    Article  PubMed  CAS  Google Scholar 

  139. Kleinberger T. Induction of apoptosis by adenovirus E4orf4 protein. Apoptosis 2000; 5: 211–5

    Article  PubMed  CAS  Google Scholar 

  140. Rohn JL, Noteborn MH. The viral death effector Apoptin reveals tumor-specific processes. Apoptosis 2004; 9: 315–22

    Article  PubMed  CAS  Google Scholar 

  141. Janssen K, Hofmann TG, Jans DA, et al. Apoptin is modified by SUMO conjugation and targeted to promyelocytic leukemia protein nuclear bodies. Oncogene 2007 Mar 8; 26 (11): 1557–66

    Article  PubMed  CAS  Google Scholar 

  142. Guelen L, Paterson H, Gaken J, et al. TAT-apoptin is efficiently delivered and induces apoptosis in cancer cells. Oncogene 2004; 23: 1153–65

    Article  PubMed  CAS  Google Scholar 

  143. Burek M, Maddika S, Burek CJ, et al. Apoptin-induced cell death is modulated by BCL-2 family members and is Apaf-1 dependent. Oncogene 2006; 25: 2213–22

    Article  PubMed  CAS  Google Scholar 

  144. van der Eb MM, Pietersen AM, Speetjens FM, et al. Gene therapy with apoptin induces regression of xenografted human hepatomas. Cancer Gene Ther 2002; 9: 53–61

    Article  PubMed  Google Scholar 

  145. Pietersen AM, van der Eb MM, Rademaker HJ, et al. Specific tumor-cell killing with adenovirus vectors containing the apoptin gene. Gene Ther 1999; 6: 882–92

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the Deutsche Krebshilfe, the Deutsche Forschungsgemeinschaft, and the Forschungskommission of the Medical Faculty of the University of Dusseldorf.

The authors have no conflicts of interest that are directly relevant to the content of this review.

Author information

Authors and Affiliations

  1. Institute of Molecular Medicine, University of Düsseldorf, Building 23.12 Universitätsstr. 1, D-40225, Düsseldorf, Germany

    Ute Fischer, Katja Janssen & Klaus Schulze-Osthoff

Authors
  1. Ute Fischer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Katja Janssen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Klaus Schulze-Osthoff
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ute Fischer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fischer, U., Janssen, K. & Schulze-Osthoff, K. Cutting-Edge Apoptosis-Based Therapeutics. BioDrugs 21, 273–297 (2007). https://doi.org/10.2165/00063030-200721050-00001

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00063030-200721050-00001

Keywords

Search

Navigation