Selective induction of apoptosis in Philadelphia chromosome-positive chronic myelogenous leukemia cells by an inhibitor of BCR - ABL tyrosine kinase, CGP 57148.
The BCR - ABL tyrosine kinase has been implicated as the cause of Philadelphia chromosome (Ph1)-positive leukemias. We report herein that CGP 57148, a selective inhibitor of the ABL tyrosine kinase, caused apoptosis specifically in bcr - abl-positive chronic myelogenous leukemia (CML) cells, K562 and KYO-1. Upon treatment with CGP 57148, CRKL, a specific substrate for BCR - ABL that propagates signals via phosphatidylinositol-3' kinase (PI3K), was dephosphorylated, indicating inhibition of BCR - ABL tyrosine kinase at the cellular level. Likewise, MAPK/ERK, a downstream mediator of Ras, was also dephosphorylated. Caspase activation and cleavage of retinoblastoma protein (pRB) accompanied the development of CGP 57148-induced apoptosis. Inhibition of caspase suppressed apoptosis and the cleavage of pRB, and in turn arrested cells in the G1 phase. These results indicate that CGP 57148 shows apoptogenic and anti-proliferative effects on bcr - abl-positive cells by blocking BCR - ABL-initiated signaling pathways.
Dan
S
S
Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo.
Naito
M
M
Tsuruo
T
T
D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides; D020169:Caspases / Q000378:metabolism; D004789:Enzyme Activation; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors*; D018922:HL-60 Cells; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D010677:Philadelphia Chromosome; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology*; D016160:Retinoblastoma Protein / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D020298:U937 Cells
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D016160:Retinoblastoma Protein; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D020169:Caspases