Mechanisms of apoptosis by the tyrphostin AG957 in hematopoietic cells.
AG957 (NSC 654705) is a tyrphostin tyrosine kinase inhibitor that has been demonstrated previously to induce growth arrest in chronic myelogenous leukemia cells by inhibiting p210(bcr-abl) kinase activity and by stabilizing the association of p210(bcr-abl) kinase with its signaling adaptor molecules, Shc and Grb2. In previous studies, it has been demonstrated that AG957-associated down-regulation of bcr-abl activates the cytochrome c/Apaf-1/caspase-9 pathway and induces apoptosis in chronic myelogenous leukemia blasts and progenitor cells. While AG957 has been purported to have specificity for the p210(bcr-abl) kinase, antiproliferative effects of AG957 in normal T-lymphocytes and bcr-abl negative leukemia cells suggest that other targets, such as c-CBL, may be substrates. In this study, we explored the mechanisms of AG957-mediated growth inhibition and apoptosis in the p210(bcr-abl) negative leukemia cell lines Nalm-6 and Jurkat, and demonstrate that AG957-mediated apoptosis is associated with altered phosphorylation of Akt and BAD, which destabilizes the Bcl-xL/BAD complex and releases the block to apoptosis. We, therefore, propose that AG957 induces apoptosis in bcr-abl negative hematopoietic cells by affecting the phosphorylation state of phosphatidylinositol-3 kinase/Akt.
Urbano
Alexander
A
Hematology Oncology and Experimental Therapeutics, Tufts New England Medical Center, Boston, MA 02111, USA.
Gorgun
Gullu
G
Foss
Francine
F
D017209:Apoptosis; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D019169:Jurkat Cells; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D014407:Tumor Cells, Cultured; D020032:Tyrphostins / Q000494:pharmacology*; D051025:bcl-Associated Death Protein
C494819:BAD protein, human; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D020032:Tyrphostins; D051025:bcl-Associated Death Protein; C104965:tyrphostin AG957; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt