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HSP90 inhibition results in apoptosis of Philadelphia acute lymphoblastic leukaemia cells: an attractive prospect of new targeted agents

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Abstract

Purpose

HSP90 targeting is a promising therapeutic approach in cancer. 17-AAG is an HSP90 inhibitor with completed Phase I trials in patients with advanced cancer and recently published Phase II trials. The aim of this work was to study the expression of HSP 90 and apoptotic proteins, the effects in culture of 17-AAG on cell survival and apoptosis and to compare Philadelphia-positive (Ph+) ALL to common B cell ALL, in ALL cell lines and in patients’ cells collected at ALL diagnosis.

Methods

We analysed 2 ALL cell lines and 63 leukaemic samples from patients treated in our institution (44 common B cell ALL and 19 Ph+ ALL). We performed flow cytometry analysis of bone marrow aspiration and cell lines with a combination of anti-HSP90, Bax, Bcl-2 and Bcl-xl antibodies. Apoptosis after cell culture (in presence or not of 17-AAG) was assessed using Annexin V and activated caspase-3 staining.

Results

Ph+ ALL cells appeared to be more sensitive to 17-AAG cytotoxicity with a 100 % mortality rate after exposure to 10 μM for 24 h (vs. 62 % for B-common ALL). A high percentage of HSP90-positive cells (in Ph+ ALL samples) was associated with high sensitivity to 17-AAG. 17-AAG induced apoptosis in a dose-dependent manner and was associated with down-regulation of Bcl-2 and Bcl-Xl expression and up-regulation of Bax expression.

Conclusion

Considering that Bcr-Abl constitutes HSP 90 substrates, HSP 90 inhibition could be of particular interest for Ph+ ALL disease, even in patients harbouring resistance to tyrosine kinase inhibitor therapy.

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Conflict of interest

We declare that we have no conflict of interest.

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Authors and Affiliations

  1. Département d’Hématologie, Institut de Cancérologie Lucien Neuwirth, 108 bis avenue Albert Raimond, 42270, Saint Priest en Jarez, France

    Emmanuelle Tavernier, Jérôme Cornillon, Karine Augeul-Meunier & Denis Guyotat

  2. Laboratoire d’Hématologie, CHU, Saint Etienne, France

    Pascale Flandrin-Gresta, Françoise Solly, Lauren Rigollet, Aurélie Montmartin, Annie Viallet & Lydia Campos

  3. Service d’Hématologie pédiatrique, CHU, Saint Etienne, France

    Jean-Louis Stephan

  4. Laboratoire de Biologie Moléculaire de la cellule, UMR 5239 Université de Saint Etienne, Saint Etienne, France

    Emmanuelle Tavernier, Pascale Flandrin-Gresta, Françoise Solly, Denis Guyotat & Lydia Campos

Authors
  1. Emmanuelle Tavernier
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  2. Pascale Flandrin-Gresta
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  3. Françoise Solly
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  4. Lauren Rigollet
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  5. Jérôme Cornillon
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  6. Karine Augeul-Meunier
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  7. Jean-Louis Stephan
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  8. Aurélie Montmartin
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  9. Annie Viallet
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  10. Denis Guyotat
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  11. Lydia Campos
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Correspondence to Emmanuelle Tavernier.

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Tavernier, E., Flandrin-Gresta, P., Solly, F. et al. HSP90 inhibition results in apoptosis of Philadelphia acute lymphoblastic leukaemia cells: an attractive prospect of new targeted agents. J Cancer Res Clin Oncol 138, 1753–1758 (2012). https://doi.org/10.1007/s00432-012-1247-6

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  • DOI: https://doi.org/10.1007/s00432-012-1247-6

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