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Strategies targeting apoptosis proteins to improve therapy of chronic lymphocytic leukemia

Samaher Besbes1, Massoud Mirshahi1, Marc Pocard1

  • 1INSERM U965, Hôpital Lariboisière, Paris, France; Université Paris Diderot-Paris 7, UMR S965, Paris, France.

Blood Reviews
|April 19, 2015
PubMed

Insights

Chronic lymphocytic leukemia (CLL) cells resist apoptosis. This review explores strategies to restore programmed cell death by targeting Bcl-2 family proteins and inhibitors of apoptosis proteins (IAPs) for effective CLL therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Chronic lymphocytic leukemia (CLL) is characterized by leukemic cells resistant to apoptosis.
  • Restoring apoptosis in CLL cells is a key therapeutic goal.
  • The mitochondrial pathway of apoptosis and caspase activation are critical targets.

Purpose of the Study:

  • To review strategies for restoring apoptosis in CLL cells.
  • To focus on targeting proteins regulating the mitochondrial apoptosis pathway.
  • To evaluate the potential of BH3 mimetics in CLL therapy.

Main Methods:

  • Review of preclinical and clinical data on apoptosis-modulating strategies in CLL.
  • Analysis of approaches targeting prosurvival Bcl-2 and IAP proteins.
  • Investigation of strategies upregulating proapoptotic BH3-only proteins.

Main Results:

  • Inhibiting prosurvival Bcl-2 and IAP proteins shows promise.
  • BH3 mimetics, mimicking BH3-only proteins, are effective in preclinical and clinical studies.
  • Upregulating proapoptotic BH3-only members offers another therapeutic avenue.

Conclusions:

  • Targeting prosurvival proteins, particularly Bcl-2 family members, is a viable strategy for CLL treatment.
  • BH3 mimetics represent an attractive therapeutic approach for CLL.
  • Future development may include BH3 mimetics that directly activate Bax and Bak.
Keywords:
Apoptosis reactivationBH3 mimeticsBcl-2 familyCLLIAP proteinsTargeting proteins regulating apoptosis

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