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.

  • Letter to the Editor
  • Published:

Noxa upregulation is associated with apoptosis of chronic lymphocytic leukemia cells induced by hyperforin but not flavopiridol

Leukemia volume 23, pages 594–596 (2009)Cite this article

Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of a CD5+ B-lymphocyte clone resulting mainly from apoptosis deficiency. On account of the low response rate of the patients to chemotherapy, new therapeutic strategies based on apoptosis inducers including plant-derived compounds are under investigation (see Kolb et al.1 for review). Flavopiridol, a semisynthetic flavonoid, is a potent inducer of CLL cell apoptosis in vitro, and a promising phase II clinical trial was recently reported.2 The effect of flavopiridol is p53-independent and involves caspase-3 activation through the mitochondrial pathway and the downregulation of antiapoptotic proteins, notably Mcl-1. This member of the Bcl-2 family seems to be crucial in CLL, because its high expression levels are related to apoptosis resistance in vitro and to chemoresistance in vivo.3 Hyperforin, a natural phloroglucinol, is another inducer of CLL cell apoptosis4 that exhibits antiangiogenic properties and impairs transporter activities involved in multidrug resistance (see Quiney et al.5 for review). Like flavopiridol, hyperforin acts through the mitochondrial caspase-dependent pathway of apoptosis, but decreases moderately Mcl-1 expression. However, the exact mechanisms whereby hyperforin and flavopiridol lead to the release of apoptogenic factors from mitochondria are not fully understood.

Noxa is a proapoptotic BH3-only member of the Bcl-2 family, which binds specifically Mcl-1 (see Willis and Adam6 for review). When its BH3 domain inserts within the hydrophobic groove of Mcl-1, this displaces Mcl-1/Bak interaction, resulting in Bak freeing that leads to mitochondrial membrane permeabilization and finally to caspase activation. Recently, it was reported that Noxa expression levels are inversely related to CLL cell survival capacity.7

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

Relevant articles

Open Access articles citing this article.

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

References

  1. Kolb JP, Kern C, Quiney C, Roman V, Billard C . Re-establishment of a normal apoptotic process as a therapeutic approach in B-CLL. Curr Drug Targets Cardiovasc Hematol Disord 2003; 3: 261–286.

    Article  CAS  Google Scholar 

  2. Byrd JC, Lin TS, Dalton JT, Wu D, Phelps MA, Fischer B et al. Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia. Blood 2007; 109: 399–404.

    Article  CAS  Google Scholar 

  3. Kitada S, Andersen J, Akar S, Zapata JM, Takayama S, Krajewski S et al. Expression of apoptosis-regulating proteins in chronic lymphocytic leukemia: correlations with in vitro and in vivo chemoresponses. Blood 1998; 91: 3379–3389.

    CAS  PubMed  Google Scholar 

  4. Quiney C, Billard C, Faussat AM, Salanoubat C, Ensaf A, Naït-Si Y et al. Pro-apoptotic properties of hyperforin in leukemic cells from patients with B-cell chronic lymphocytic leukemia. Leukemia 2006; 20: 491–497.

    Article  CAS  Google Scholar 

  5. Quiney C, Billard C, Salanoubat C, Fourneron JD, Kolb JP . Hyperforin, a new lead compound against the progression of cancer and leukemia? Leukemia 2006; 20: 1519–1525.

    Article  CAS  Google Scholar 

  6. Willis SN, Adams JM . Life in the balance: how BH3-only proteins induce apoptosis. Curr Opin Cell Biol 2005; 17: 617–625.

    Article  CAS  Google Scholar 

  7. Smit L, Hallaert DYH, Spijker R, de Goeij B, Jaspers A, Kater AP et al. Differential Noxa/Mcl-1 balance in peripheral versus lymph node chronic lymphocytic leukemia cells correlate with survival capacity. Blood 2007; 109: 1660–1668.

    Article  CAS  Google Scholar 

  8. Billard C, Kern C, Tang R, Ajchenbaum-Cymbalista F, Kolb JP . Flavopiridol downregulates the expression of both the inducible NO synthase and p27kip1 in malignant cells from B-cell chronic lymphocytic leukemia. Leukemia 2003; 17: 2345–2443.

    Article  Google Scholar 

  9. Qin JZ, Ziffra J, Stennett L, Bodner B, Bonish BK, Chaturvedi V et al. Proteasome inhibitors trigger NOXA-mediated apoptosis in melanoma and myeloma cells. Cancer Res 2005; 65: 6282–6293.

    Article  CAS  Google Scholar 

  10. Pérez-Galan P, Roué G, Villamor N, Montserrat E, Campo E, Colomer D . The proteasome inhibitor bortezomid induces apoptosis in mantle-cell lymphome through generation of ROS and Noxa induction activation independent of p53 status. Blood 2006; 107: 257–264.

    Article  Google Scholar 

  11. Inoue S, Riley J, Gant TW, Dyer MJ, Cohen GM . Apoptosis induced by histone deacetylase inhibitors in leukemic cells is mediated by Bim and Noxa. Leukemia 2007; 21: 1773–1782.

    Article  CAS  Google Scholar 

  12. Pérez-Galan P, Roué G, Lopez-Guerra M, Nguyen M, Villamor N, Montserrat E et al. BCL-2 phosphorylation modulates sensitivity to the BH3 mimetic GX15-070 (Obatoclax) and reduces its synergistic interaction with bortezomib in chronic lymphocytic leukemia cells. Leukemia, e-pub ahead of print 3 July 2008; doi: 10.1038/leu.2008.175.

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by INSERM, Université Pierre et Marie Curie-Paris 6 and by a grant from Canceropole Ile-de-France. We are indebted to Dr JD Fourneron for his gift of hyperforin and to Professor JP Marie and colleagues for providing the blood samples of patients.

Author information

Authors and Affiliations

  1. Centre de Recherches des Cordeliers, Equipe 18, UMRS 872 INSERM,

    M Zaher, I Akrout, M Mirshahi, J-P Kolb & C Billard

  2. Université Paris-Descartes,

    M Zaher, I Akrout, M Mirshahi, J-P Kolb & C Billard

  3. Université Pierre et Marie Curie-Paris 6, Paris, France

    M Zaher, I Akrout, M Mirshahi, J-P Kolb & C Billard

Authors
  1. M Zaher
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. I Akrout
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Mirshahi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J-P Kolb
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C Billard
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C Billard.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zaher, M., Akrout, I., Mirshahi, M. et al. Noxa upregulation is associated with apoptosis of chronic lymphocytic leukemia cells induced by hyperforin but not flavopiridol. Leukemia 23, 594–596 (2009). https://doi.org/10.1038/leu.2008.239

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2008.239

This article is cited by

Search

Advanced search

Quick links