Skip to main content

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

From bench to clinic with apoptosis-based therapeutic agents

Abstract

A retrospective look at the basis of human disease pathogenesis almost always reveals an apoptotic component that either contributes to disease progression or accounts for it. What makes this field particularly exciting is the breadth of therapeutic opportunities that are on offer. The pace of apoptosis research has raised expectations that therapeutics will follow soon. But many of the organizations that are best placed to take advantage of these discoveries consider the ability to modulate the life or death of a cell for the purpose of disease treatment as perhaps being 'too good to be true'. Nevertheless, practical therapeutics that modulate apoptosis will no doubt appear in the clinic or on the shelf in the next few years.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Bcl-2.
Figure 2: TRAIL.
Figure 3: Caspases.

References

  1. Ellis, R. E., Yuan, J. Y. & Horvitz, H. R. Mechanisms and functions of cell death. Annu. Rev. Cell Biol. 7, 663–698 (1991).

    Article  CAS  Google Scholar 

  2. Wang, J. L. et al. Structure-based discovery of an organic compound that binds bcl-2 protein and induces apoptosis of tumor cells. Proc. Natl Acad. Sci. USA 97, 7124–7129 (2000).

    Article  ADS  CAS  Google Scholar 

  3. Adams, J. M. & Cory, S. The Bcl-2 protein family: arbiters of cell survival. Science 281, 1322– 1326 (1998).

    Article  CAS  Google Scholar 

  4. Reed, J. C. Bcl-2 family proteins. Oncogene 17, 3225 –3236 (1998).

    Article  Google Scholar 

  5. Veis, D. J., Sorenson, C. M., Shutter, J. R. & Korsmeyer, S. J. Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell 75, 229–240 (1993).

    Article  CAS  Google Scholar 

  6. Cory, S. Regulation of lymphocyte survival by the bcl-2 gene family. Annu. Rev. Immunol. 13, 513–543 ( 1995).

    Article  CAS  Google Scholar 

  7. Schlagbauer-Wadl, H. et al. Bcl-2 antisense oligonucleotides (G3139) inhibit Merkel cell carcinoma growth in SCID mice. J. Invest. Dermatol. 114, 725–730 (2000).

    Article  CAS  Google Scholar 

  8. Jansen, B. et al. bcl-2 antisense therapy chemosensitizes human melanoma in SCID mice. Nature Med. 4, 232– 234 (1998).

    Article  CAS  Google Scholar 

  9. Jansen, B. et al. Bcl-2 antisense plus dacarbazine therapy for malignant melanoma . Proc. Am. Assoc. Cancer Res. Conf. Programmed Cell Death Regul. A59 (2000).

  10. Waters, J. S. et al. Phase I clinical and pharmacokinetic study of bcl-2 antisense oligonucleotide therapy in patients with non-Hodgkin's lymphoma . J. Clin. Oncol. 18, 1812– 1823 (2000).

    Article  CAS  Google Scholar 

  11. Zangemeister-Wittke, U. et al. A novel bispecific antisense oligonucleotide inhibiting both bcl-2 and bcl-xL expression efficiently induces apoptosis in tumor cells. Clin. Cancer Res. 6, 2547– 2555 (2000).

    CAS  Google Scholar 

  12. Reed, J. C. Splicing and dicing apoptosis genes. Nature Biotechnol. 17, 1064–1065 (1999).

    Article  CAS  Google Scholar 

  13. Taylor, J. K., Zhang, Q. Q., Wyatt, J. R. & Dean, N. M. Induction of endogenous Bcl-xS through the control of Bcl-x pre-mRNA splicing by antisense oligonucleotides. Nature Biotechnol. 17 , 1097–1100 (1999).

    Article  CAS  Google Scholar 

  14. Que, F. G. et al. Cholangiocarcinomas express Fas ligand and disable the Fas receptor. Hepatology 30, 1398– 1404 (1999).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  16. Schneider, P. & Tschopp, J. Apoptosis induced by death receptors . Pharm. Acta Helv. 74, 281– 286 (2000).

    Article  CAS  Google Scholar 

  17. Boldin, M. P., Goncharov, T. M., Goltsev, Y. V. & Wallach, D. Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death. Cell 85, 803–815 (1996).

    Article  CAS  Google Scholar 

  18. Muzio, M. et al. FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex. Cell 85, 817–827 ( 1996).

    Article  CAS  Google Scholar 

  19. Kischkel, F. C. et al. Apo2L/TRAIL-dependent recruitment of endogenous FADD and caspase-8 to death receptors 4 and 5. Immunity 12, 611–620 (2000).

    Article  CAS  Google Scholar 

  20. Sprick, M. R. et al. FADD/MORT1 and caspase-8 are recruited to TRAIL receptors 1 and 2 and are essential for apoptosis mediated by TRAIL receptor 2. Immunity 12, 599–609 ( 2000).

    Article  CAS  Google Scholar 

  21. Bodmer, J. L. et al. TRAIL receptor-2 signals apoptosis through FADD and caspase-8 . Nature Cell Biol. 2, 241– 243 (2000).

    Article  CAS  Google Scholar 

  22. Thome, M. et al. Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors. Nature 386, 517– 521 (1997).

    Article  ADS  CAS  Google Scholar 

  23. Rasper, D. M. et al. Cell death attenuation by 'Usurpin', a mammalian DED-caspase homologue that precludes caspase-8 recruitment and activation by the CD-95 (Fas, APO-1) receptor complex. Cell Death Differ. 5 , 271–288 (1998).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  26. Marsters, S. A., Pitti, R. A., Sheridan, J. P. & Ashkenazi, A. Control of apoptosis signaling by Apo2 ligand. Recent Prog. Horm. Res. 54, 225–234 ( 1999).

    CAS  PubMed  Google Scholar 

  27. Griffith, T. S. & Lynch, D. H. TRAIL: a molecule with multiple receptors and control mechanisms. Curr. Opin. Immunol. 10, 559–563 ( 1998).

    Article  CAS  Google Scholar 

  28. Zhang, X. D., Franco, A. V., Nguyen, T., Gray, C. P. & Hersey, P. Differential localization and regulation of death and decoy receptors for TNF-related apoptosis-inducing ligand (TRAIL) in human melanoma cells. J. Immunol. 164, 3961–3970 (2000).

    Article  CAS  Google Scholar 

  29. Kim, K., Fisher, M. J., Xu, S. Q. & el-Deiry, W. S. Molecular determinants of response to TRAIL in killing of normal and cancer cells. Clin. Cancer Res. 6, 335–346 (2000).

    CAS  PubMed  Google Scholar 

  30. Hollstein, M., Sidransky, D., Vogelstein, B. & Harris, C. C. p53 mutations in human cancers. Science 253, 49–53 (1991).

    Article  ADS  CAS  Google Scholar 

  31. Takimoto, R. & El-Deiry, W. S. Wild-type p53 transactivates the KILLER/DR5 gene through an intronic sequence-specific DNA-binding site . Oncogene 19, 1735–1743 (2000).

    Article  CAS  Google Scholar 

  32. Ashkenazi, A. The Apo2L/TRAIL system: therapeutic opportunities. Proc. Am. Assoc. Cancer Res. Conf. Programmed Cell Death Regul. (2000 ).

  33. Nagata, S. Steering anti-cancer drugs away from the TRAIL. Nature Med. 6, 502–503 (2000).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  37. Alnemri, E. S. et al. Human ICE/CED-3 protease nomenclature. Cell 87, 171 (1996).

    Article  CAS  Google Scholar 

  38. Thornberry, N. A. et al. A novel heterodimeric cysteine protease is required for interleukin-1β processing in monocytes. Nature 356, 768 –774 (1992).

    Article  ADS  CAS  Google Scholar 

  39. Cerretti, D. P. et al. Molecular cloning of the interleukin-1β converting enzyme . Science 256, 97–100 (1992).

    Article  ADS  CAS  Google Scholar 

  40. Yuan, J., Shaham, S., Ledoux, S., Ellis, H. M. & Horvitz, H. R. The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1β-converting enzyme . Cell 75, 641–652 (1993).

    Article  CAS  Google Scholar 

  41. Nicholson, D. W. et al. Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature 376, 37– 43 (1995).

    Article  ADS  CAS  Google Scholar 

  42. Kuida, K. et al. Decreased apoptosis in the brain and premature lethality in CPP32-deficient mice. Nature 384, 368–372 (1996).

    Article  ADS  CAS  Google Scholar 

  43. Nicholson, D. W. Caspase structure, proteolytic substrates, and function during apoptotic cell death. Cell Death Differ. 6, 1028– 1042 (1999).

    Article  CAS  Google Scholar 

  44. Earnshaw, W. C., Martins, L. M. & Kaufmann, S. H. Mammalian caspases: structure, activation, substrates, and functions during apoptosis. Annu. Rev. Biochem. 68, 383–424 (1999).

    Article  CAS  Google Scholar 

  45. Thornberry, N. A. et al. A combinatorial approach defines specificities of members of the caspase family and granzyme B. Functional relationships established for key mediators of apoptosis. J. Biol. Chem. 272, 17907–17911 (1997).

    Article  CAS  Google Scholar 

  46. Garcia-Calvo, M. et al. A. Inhibition of human caspases by peptide-based and macromolecular inhibitors. J. Biol. Chem. 273, 32608– 32613 (1998).

    Article  CAS  Google Scholar 

  47. Cursio, R. et al. A caspase inhibitor fully protects rats against lethal normothermic liver ischemia by inhibition of liver apoptosis. FASEB J. 13, 253–261 (1999).

    Article  CAS  Google Scholar 

  48. Mocanu, M. M., Baxter, G. F. & Yellon, D. M. Caspase inhibition and limitation of myocardial infarct size: protection against lethal reperfusion injury. Br. J. Pharmacol. 130, 197–200 ( 2000).

    Article  CAS  Google Scholar 

  49. Farber, A. et al. A specific inhibitor of apoptosis decreases tissue injury after intestinal ischemia–reperfusion in mice. J. Vasc. Surg. 30, 752–760 ( 1999).

    Article  CAS  Google Scholar 

  50. Daemen, M. A. et al. Inhibition of apoptosis induced by ischemia–reperfusion prevents inflammation. J. Clin. Invest. 104, 541–549 (1999).

    Article  CAS  Google Scholar 

  51. Endres, M. et al. Attenuation of delayed neuronal death after mild focal ischemia in mice by inhibition of the caspase family. J. Cereb. Blood Flow Metab. 18, 238–247 ( 1998).

    Article  CAS  Google Scholar 

  52. Yakovlev, A. G. et al. Activation of CPP32-like caspases contributes to neuronal apoptosis and neurological dysfunction after traumatic brain injury. J. Neurosci. 17, 7415–7424 (1997).

    Article  CAS  Google Scholar 

  53. Kondratyev, A. & Gale, K. Intracerebral injection of caspase-3 inhibitor prevents neuronal apoptosis after kainic acid-evoked status epilepticus. Brain Res. Mol. Brain Res. 75, 216–224 (2000).

    Article  CAS  Google Scholar 

  54. Li, M. et al. Functional role of caspase-1 and caspase-3 in an ALS transgenic mouse model. Science 288, 335– 339 (2000).

    Article  ADS  CAS  Google Scholar 

  55. Schierle, G. S. et al. Caspase inhibition reduces apoptosis and increases survival of nigral transplants. Nature Med. 5, 97 –100 (1999).

    Article  CAS  Google Scholar 

  56. Braun, J. S. et al. Neuroprotection by a caspase inhibitor in acute bacterial meningitis. Nature Med. 5, 298– 302 (1999).

    Article  CAS  Google Scholar 

  57. Grobmyer, S. R. et al. Peptidomimetic fluoromethylketone rescues mice from lethal endotoxic shock. Mol. Med. 5, 585– 594 (1999).

    Article  CAS  Google Scholar 

  58. Hotchkiss, R. S. et al. Prevention of lymphocyte cell death in sepsis improves survival in mice. Proc. Natl Acad. Sci. USA 96, 14541 –14546 (1999).

    Article  ADS  CAS  Google Scholar 

  59. Sanchez, I. et al. Caspase-8 is required for cell death induced by expanded polyglutamine repeats. Neuron 22, 623– 633 (1999).

    Article  CAS  Google Scholar 

  60. Goldberg, Y. P. et al. Cleavage of huntingtin by apopain, a proapoptotic cysteine protease, is modulated by the polyglutamine tract. Nature Genet. 13, 442–449 ( 1996).

    Article  CAS  Google Scholar 

  61. Gervais, F. G. et al. Involvement of caspases in proteolytic cleavage of Alzheimer's amyloid-beta precursor protein and amyloidogenic A beta peptide formation . Cell 97, 395–406 (1999).

    Article  CAS  Google Scholar 

  62. Vocero-Akbani, A. M., Heyden, N. V., Lissy, N. A., Ratner, L. & Dowdy, S. F. Killing HIV-infected cells by transduction with an HIV protease-activated caspase-3 protein. Nature Med. 5, 29–33 (1999).

    Article  CAS  Google Scholar 

  63. Lee, D. et al. Potent and selective nonpeptide inhibitors of caspases 3 and 7 inhibit apoptosis and maintain cell functionality. J. Biol. Chem. 275, 16007–16014 ( 2000).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

I thank S. Roy, S. Xanthoudakis, D. McKay, C. Bayly and K. Clark (Merck) and A. Ashkenasi (Genentech) for assistance with this manuscript and its figures.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Donald W. Nicholson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nicholson, D. From bench to clinic with apoptosis-based therapeutic agents. Nature 407, 810–816 (2000). https://doi.org/10.1038/35037747

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/35037747

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

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

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