Abstract

Abstract The response of myeloid leukemia cells to treatment with 1-β- 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.