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Akt inhibitors induce apoptosis in chronic lymphocytic leukemia cells

Mercè de Frias1, Daniel Iglesias-Serret, Ana M Cosialls

  • 1Departament de Ciències Fisiològiques II, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.

Haematologica
|October 10, 2009
PubMed
Abstract

Insights

Selective Akt inhibitors induce apoptosis in chronic lymphocytic leukemia (CLL) cells, offering a potential new therapy. These Akt inhibitors effectively kill CLL cells, regardless of TP53 mutation status, and are more potent against B cells.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Immunology

Background:

  • The phosphatidylinositol-3-kinase/Akt pathway is crucial for chronic lymphocytic leukemia (CLL) cell survival.
  • Targeting this pathway presents a potential therapeutic strategy for CLL.

Purpose of the Study:

  • To investigate the efficacy of two selective Akt inhibitors, Akti-1/2 and A-443654, against CLL cells.
  • To analyze the impact of these inhibitors on CLL cell survival and apoptosis.

Main Methods:

  • Cytometry was used to assess the cytotoxic effects of Akt inhibitors on peripheral B and T lymphocytes from CLL patients and healthy donors.
  • mRNA expression profiling (RT-MLPA) and Western blotting were employed to study molecular changes induced by the inhibitors, including BCL-2 family members.
  • The efficacy of Akt inhibitors was evaluated in CLL cells with deleted/mutated TP53.

Main Results:

  • Both Akt inhibitors induced dose-dependent apoptosis in CLL cells, with B cells being more sensitive than T cells or cells from healthy donors.
  • Survival factors did not prevent apoptosis induced by Akt inhibitors.
  • A-443654 modulated mRNA levels of NOXA and PUMA, suggesting additional targets, while both inhibitors increased PUMA and NOXA protein levels and decreased MCL-1.
  • Apoptosis was induced irrespective of TP53 mutation status.

Conclusions:

  • Akt inhibitors effectively induce apoptosis in chronic lymphocytic leukemia cells.
  • These findings suggest that Akt inhibitors represent a promising new therapeutic option for CLL treatment.

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