Inhibition of c-Abl with STI571 attenuates stress-activated protein kinase activation and apoptosis in the cellular response to 1-beta-D-arabinofuranosylcytosine.
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.
Raina
Deepak
D
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA. donald_kufe@dfci.harvard.edu
Mishra
Neerad
N
Kumar
Shailendra
S
Kharbanda
Surender
S
Saxena
Satya
S
Kufe
Donald
D
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis; D001549:Benzamides; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D003561:Cytarabine / Q000494:pharmacology*; D016503:Drug Delivery Systems; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D010879:Piperazines; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D003561:Cytarabine; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases