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Vol. 61, Issue 6, 1489-1495, June 2002

Inhibition of c-Abl with STI571 Attenuates Stress-Activated Protein Kinase Activation and Apoptosis in the Cellular Response to 1-beta -D-Arabinofuranosylcytosine

Deepak Raina, Neerad Mishra, Shailendra Kumar, Surender Kharbanda, Satya Saxena, and Donald Kufe

Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts (D.R., S.Ku., S.Kh., D.K.); and Lovelace Respiratory Research Institute, Albuquerque, New Mexico (N.M., S.S.)

The response of myeloid leukemia cells to treatment with 1-beta -D-arabinofuranosylcytosine (ara-C) includes activation of the c-Abl protein tyrosine kinase and the stress-activated protein kinase (SAPK). The present studies demonstrate that treatment of human U-937 leukemia cells with ara-C is associated with translocation of SAPK to mitochondria. STI571 (imatinib mesylate), an inhibitor of c-Abl, blocked both activation and mitochondrial targeting of SAPK in the ara-C response. In concert with these effects of STI571, similar findings were obtained in c-Abl-deficient cells. The results further show that STI571 inhibits ara-C-induced loss of mitochondrial transmembrane potential, caspase-3 activation, and apoptosis. These findings demonstrate that STI571 down-regulates c-Abl-mediated signals that target the mitochondria in the apoptotic response to ara-C.

Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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Copyright © 2002 by the American Society for Pharmacology and Experimental Therapeutics