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Cell Death Associated with Abnormal Mitosis Observed by Confocal Imaging in Live Cancer Cells
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Role of poly(ADP-ribose) polymerase activity in imatinib mesylate-induced cell death

A Moehring1, L Wohlbold, W E Aulitzky

  • 1Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstr. 112, Stuttgart, Germany.

Cell Death and Differentiation
|April 9, 2005
PubMed

Insights

Imatinib induces cell death in chronic myelogenous leukemia (CML) cells through both caspase and poly(ADP-ribose) polymerase (PARP) pathways. Blocking PARP activity partially prevents imatinib-induced cell death, revealing a parallel mechanism.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Imatinib is a targeted therapy for chronic myelogenous leukemia (CML) by inhibiting Bcr-Abl.
  • The precise mechanisms of imatinib-induced cell death remain incompletely understood.

Purpose of the Study:

  • To investigate the role of poly(ADP-ribose) polymerase (PARP) activity in imatinib-induced cell death.
  • To elucidate the involvement of the phosphatidylinositol 3-kinase (PI3-K) pathway in Bcr-Abl-mediated PAR regulation.

Main Methods:

  • Assessed poly(ADP-ribosyl)ation (PAR) levels following imatinib treatment in Bcr-Abl-positive cells.
  • Investigated the impact of PAR inhibition on imatinib-induced cell death.
  • Examined the effects of combined caspase and PAR inhibition on cell viability.

Main Results:

  • Imatinib treatment caused a rapid increase in PAR preceding mitochondrial membrane damage and DNA fragmentation.
  • Inhibition of phosphatidylinositol 3-kinase (PI3-K) mimicked imatinib's effect on PAR, suggesting PI3-K pathway involvement.
  • Inhibiting PAR partially rescued cells from imatinib-induced death, similar to caspase inhibition.
  • Simultaneous blockade of caspases and PAR demonstrated additive cytoprotective effects.

Conclusions:

  • Imatinib induces cell death via a PARP-mediated pathway, acting in parallel to the known caspase-dependent pathway.
  • The PI3-K pathway plays a crucial role in regulating PAR levels in the context of Bcr-Abl signaling.

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