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.

  • Original Manuscript
  • Published:

CDDO induces apoptosis via the intrinsic pathway in lymphoid cells

Leukemia volume 18, pages 948–952 (2004)Cite this article

Abstract

The peroxisome-proliferator-activated receptor (PPAR) γ agonist, CDDO, is under investigation for use in various malignancies. The mechanisms by which CDDO induces apoptosis are controversial. We have therefore sought to determine these mechanisms using primary chronic lymphocyte leukemic (CLL) cells and Jurkat cell lines with defined apoptotic abnormalities. In these cells, CDDO induced-apoptosis involved caspase-independent loss in mitochondrial membrane potential followed by caspase processing. The pattern of CDDO-induced caspase processing, defined by use of a caspase inhibitor, strongly suggested that caspase-9 was the apical caspase. Moreover, CDDO induced apoptosis in caspase-8 and FADD-deficient but not in Bcl-xL overexpressing Jurkat cells. In CLL cells, CDDO induced an early release of mitochondrial cytochrome c and Smac that preceded apoptosis. Thus, in both cell types, CDDO induced apoptosis primarily by the intrinsic pathway with caspase-9 as the apical caspase. This has important implications in the design of novel agents for the treatment of CLL and other malignancies.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Bratton SB, MacFarlane M, Cain K, Cohen GM . Protein complexes activate distinct caspase cascades in death receptor and stress-induced apoptosis. Exp Cell Res 2000; 256: 27–33.

    Article  CAS  Google Scholar 

  2. van Loo G, Saelens X, van Gurp M, MacFarlane M, Martin SJ, Vandenabeele P . The role of mitochondrial factors in apoptosis: a Russian roulette with more than one bullet. Cell Death Differ 2002; 9: 1031–1042.

    Article  CAS  Google Scholar 

  3. Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 1997; 91: 479–489.

    Article  CAS  Google Scholar 

  4. Cain K, Brown DG, Langlais C, Cohen GM . Caspase activation involves the formation of the aposome, a large (approximately 700 kDa) caspase-activating complex. J Biol Chem 1999; 274: 22686–22692.

    Article  CAS  Google Scholar 

  5. Bratton SB, Walker G, Srinivasula SM, Sun XM, Butterworth M, Alnemri ES et al. Recruitment, activation and retention of caspases-9 and -3 by Apaf-1 apoptosome and associated XIAP complexes. EMBO J 2001; 20: 998–1009.

    Article  CAS  Google Scholar 

  6. Ashkenazi A, Dixit VM . Death receptors: signaling and modulation. Science 1998; 281: 1305–1308.

    Article  CAS  Google Scholar 

  7. Kersten S, Desvergne B, Wahli W . Roles of PPARs in health and disease. Nature 2000; 405: 421–424.

    Article  CAS  Google Scholar 

  8. Murphy GJ, Holder JC . PPAR-gamma agonists: therapeutic role in diabetes, inflammation and cancer. Trends Pharmacol Sci 2000; 21: 469–474.

    Article  CAS  Google Scholar 

  9. Willson TM, Lambert MH, Kliewer SA . Peroxisome proliferator-activated receptor gamma and metabolic disease. Annu Rev Biochem 2001; 70: 341–367.

    Article  CAS  Google Scholar 

  10. Suh N, Wang Y, Honda T, Gribble GW, Dmitrovsky E, Hickey WF et al. A novel synthetic oleanane triterpenoid, 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid, with potent differentiating, antiproliferative, and anti-inflammatory activity. Cancer Res 1999; 59: 336–341.

    CAS  PubMed  Google Scholar 

  11. Ito Y, Pandey P, Place A, Sporn MB, Gribble GW, Honda T et al. The novel triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid induces apoptosis of human myeloid leukemia cells by a caspase-8-dependent mechanism. Cell Growth Differ 2000; 11: 261–267.

    CAS  PubMed  Google Scholar 

  12. Ito Y, Pandey P, Sporn MB, Datta R, Kharbanda S, Kufe D . The novel triterpenoid CDDO induces apoptosis and differentiation of human osteosarcoma cells by a caspase-8 dependent mechanism. Mol Pharmacol 2001; 59: 1094–1099.

    Article  CAS  Google Scholar 

  13. Pedersen IM, Kitada S, Schimmer A, Kim Y, Zapata JM, Charboneau L et al. The triterpenoid CDDO induces apoptosis in refractory CLL B cells. Blood 2002; 100: 2965–2972.

    Article  CAS  Google Scholar 

  14. Kim KB, Lotan R, Yue P, Sporn MB, Suh N, Gribble GW et al. Identification of a novel synthetic triterpenoid, methyl-2-cyano-3,12-dioxooleana-1,9-dien-28-oate, that potently induces caspase-mediated apoptosis in human lung cancer cells. Mol Cancer Ther 2002; 1: 177–184.

    Article  CAS  Google Scholar 

  15. Almond JB, Snowden RT, Hunter A, Dinsdale D, Cain K, Cohen GM . Proteasome inhibitor-induced apoptosis of B-chronic lymphocytic leukaemia cells involves cytochrome c release and caspase activation, accompanied by formation of an approximately 700 kDa Apaf-1 containing apoptosome complex. Leukemia 2001; 15: 1388–1397.

    Article  CAS  Google Scholar 

  16. MacFarlane M, Harper N, Snowden RT, Dyer MJ, Barnett GA, Pringle JH et al. Mechanisms of resistance to TRAIL-induced apoptosis in primary B cell chronic lymphocytic leukaemia. Oncogene 2002; 21: 6809–6818.

    Article  CAS  Google Scholar 

  17. Harper N, Hughes M, MacFarlane M, Cohen GM . Fas-associated death domain protein and caspase-8 are not recruited to the tumor necrosis factor receptor 1 signaling complex during tumor necrosis factor-induced apoptosis. J Biol Chem 2003; 278: 25534–25541.

    Article  CAS  Google Scholar 

  18. Sun XM, Bratton SB, Butterworth M, MacFarlane M, Cohen GM . Bcl-2 and Bcl-xL inhibit CD95-mediated apoptosis by preventing mitochondrial release of Smac/DIABLO and subsequent inactivation of X-linked inhibitor-of-apoptosis protein. J Biol Chem 2002; 277: 11345–11351.

    Article  CAS  Google Scholar 

  19. Sun XM, MacFarlane M, Zhuang J, Wolf BB, Green DR, Cohen GM . Distinct caspase cascades are initiated in receptor-mediated and chemical-induced apoptosis. J Biol Chem 1999; 274: 5053–5060.

    Article  CAS  Google Scholar 

  20. Dewson G, Snowden RT, Almond JB, Dyer MJ, Cohen GM . Conformational change and mitochondrial translocation of Bax accompany proteasome inhibitor-induced apoptosis of chronic lymphocytic leukemic cells. Oncogene 2003; 22: 2643–2654.

    Article  CAS  Google Scholar 

  21. Medema JP, Scaffidi C, Kischkel FC, Shevchenko A, Mann M, Krammer PH et al. FLICE is activated by association with the CD95 death-inducing signaling complex (DISC). EMBO J 1997; 16: 2794–2804.

    Article  CAS  Google Scholar 

  22. Slee EA, Harte MT, Kluck RM, Wolf BB, Casiano CA, Newmeyer DD et al. Ordering the cytochrome c-initiated caspase cascade: hierarchical activation of caspases-2, -3, -6, -7, -8, and -10 in a caspase-9-dependent manner. J Cell Biol 1999; 144: 281–292.

    Article  CAS  Google Scholar 

  23. Bratton SB, Lewis J, Butterworth M, Duckett CS, Cohen GM . XIAP inhibition of caspase-3 preserves its association with the Apaf-1 apoptosome and prevents CD95- and Bax-induced apoptosis. Cell Death Differ 2002; 9: 881–892.

    Article  CAS  Google Scholar 

  24. Srinivasula SM, Ahmad M, Fernandes-Alnemri T, Alnemri ES . Autoactivation of procaspase-9 by Apaf-1-mediated oligomerization. Mol Cell 1998; 1: 949–957.

    Article  CAS  Google Scholar 

  25. Suh N, Wang Y, Williams CR, Risingsong R, Gilmer T, Willson TM et al. A new ligand for the peroxisome proliferator-activated receptor-gamma (PPAR-gamma), GW7845, inhibits rat mammary carcinogenesis. Cancer Res 1999; 59: 5671–5673.

    CAS  PubMed  Google Scholar 

  26. Fehlberg S, Trautwein S, Goke A, Goke R . Bisphenol A diglycidyl ether induces apoptosis in tumour cells independently of peroxisome proliferator-activated receptor-gamma, in caspase-dependent and -independent manners. Biochem J 2002; 362: 573–578.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Dr J Blenis (Harvard Medical School, Boston, MA, USA) for supplying the FADD- and caspase-8-deficient cells. Dr Satoshi Inoue is partially supported by the Daiwa Anglo-Japanese Foundation.

Author information

Authors and Affiliations

  1. MRC Toxicology Unit, University of Leicester, Leicester, UK

    S Inoue, R T Snowden, M J S Dyer & G M Cohen

  2. Department of Hematology, University of Leicester, Leicester Royal Infirmary, Leicester, UK

    M J S Dyer

Authors
  1. S Inoue
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R T Snowden
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M J S Dyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G M Cohen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to G M Cohen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Inoue, S., Snowden, R., Dyer, M. et al. CDDO induces apoptosis via the intrinsic pathway in lymphoid cells. Leukemia 18, 948–952 (2004). https://doi.org/10.1038/sj.leu.2403328

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2403328

Keywords

This article is cited by

Search

Advanced search

Quick links