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Rapid CommunicationAccelerated Communication

Abrogation of the Cell Death Response to Oxidative Stress by the c-Abl Tyrosine Kinase Inhibitor STI571

Shailendra Kumar, Neerad Mishra, Deepak Raina, Satya Saxena and Donald Kufe
Molecular Pharmacology February 2003, 63 (2) 276-282; DOI: https://doi.org/10.1124/mol.63.2.276
Shailendra Kumar
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Neerad Mishra
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Deepak Raina
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Satya Saxena
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Donald Kufe
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Abstract

Normal aerobic metabolism is associated with the production of reactive oxygen species (ROS) and, consequently, the induction of apoptosis and necrosis. The cell death response to oxidative stress is thought to contribute to aging, neurological degeneration, and other disorders. ROS-induced apoptosis and necrosis involves activation of the cytoplasmic c-Abl tyrosine kinase and thereby signaling to mitochondria. Herein, we show that STI571, an inhibitor of Bcr-Abl in chronic myelogenous leukemia, blocks activation of c-Abl in the response of mouse embryo fibroblasts and human U-937 myeloid leukemia cells to hydrogen peroxide (H2O2). Immunofluorescence microscopy and subcellular fractionation studies demonstrate that STI571 decreases H2O2-induced targeting of c-Abl to mitochondria in the two cell types by 59 to 85%. The results also show that STI571 attenuates H2O2-induced loss of the mitochondrial transmembrane potential. In concert with these effects, STI571 inhibits the death response to H2O2 exposure by 40 to 80% depending on the cell type. These findings indicate that inhibition of c-Abl signaling by STI571 attenuates mitochondrial dysfunction and cell death in the cellular response to oxidative stress.

Footnotes

  • This investigation was supported by National Cancer Institute grants CA42802 and CA49639.

  • Abbreviations:
    PKC
    protein kinase C
    MEF
    mouse embryonic fibroblast
    GST
    glutathione S-transferase
    DCF
    dichlorofluorescein
    ROS
    reactive oxygen species
    PBS
    phosphate-buffered saline
    PCNA
    proliferating cell nuclear antigen
    FITC
    fluorescein isothiocyanate
    Δψm
    mitochondrial transmembrane potential
    • Received July 30, 2002.
    • Accepted October 21, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 63 (2)
Molecular Pharmacology
Vol. 63, Issue 2
1 Feb 2003
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Rapid CommunicationAccelerated Communication

Abrogation of the Cell Death Response to Oxidative Stress by the c-Abl Tyrosine Kinase Inhibitor STI571

Shailendra Kumar, Neerad Mishra, Deepak Raina, Satya Saxena and Donald Kufe
Molecular Pharmacology February 1, 2003, 63 (2) 276-282; DOI: https://doi.org/10.1124/mol.63.2.276

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Rapid CommunicationAccelerated Communication

Abrogation of the Cell Death Response to Oxidative Stress by the c-Abl Tyrosine Kinase Inhibitor STI571

Shailendra Kumar, Neerad Mishra, Deepak Raina, Satya Saxena and Donald Kufe
Molecular Pharmacology February 1, 2003, 63 (2) 276-282; DOI: https://doi.org/10.1124/mol.63.2.276
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