Comparison of effects of the tyrosine kinase inhibitors AG957, AG490, and STI571 on BCR-ABL-expressing cells, demonstrating synergy between AG490 and STI571

Sun, XM; Layton, JE; Elefanty, A; Lieschke, GJ

Author(s): Sun, XM; Layton, JE; Elefanty, A; Lieschke, GJ;
Details: Publication Year 2001-04-01,Volume 97,Issue #7,Page 2008-2015
Journal Title: BLOOD
Publication Type: Journal Article
Abstract: ST1571 (formerly CGP57148) and AG957 are small molecule inhibitors of the protein tyrosine kinase (PTK) p145(abl) and its oncogenic derivative p210(bcr-abl). AG490 is an inhibitor of the PTK Janus kinase 2 (JAK2). No direct comparison of these inhibitors has previously been reported, so this study compared their effects on factor-dependent FDC-P1, 32D, and MO7e cells and their p210(bcr-abl)-expressing factor-independent derivatives. ST1571 was a more potent inhibitor of H-3-thymidine incorporation in p210(bcr-abl)-expressing cells than was AG957, and it showed superior discrimination between inhibitory effects on parental cell lines and effects on their p210(bcr-abl)-expressing derivatives. Assays performed with and without growth factor demonstrated that ST1571 but not AG957 reversed the p210(bcr-abl)-driven factor independence of cell lines. p210(bcr-abl)-expressing cells were less sensitive to AG490 than to AG957 or ST1571. However, for p210(bcr-abl)-expressing clones from all 3 cell lines, synergistic inhibition was demonstrated between ST1571 and concentrations of AG490 with no independent inhibitory effect. Inhibition of nucleic acid synthesis with AG957 treatment was associated with reduced cell numbers, reduced viability, and small pyknotic apoptotic cells. At concentrations of ST1571 that reversed the p210(bcr-abl) factor-independent phenotype, ST1571 treatment and growth factor deprivation together were sufficient to induce apoptosis. This study concludes that, for the cell lines studied, (1) ST1571 is a more potent and more selective inhibitor of a p210(bcr-abl)-dependent phenotype than AG957; (2) AG490 synergizes with ST1571 to enhance its inhibitory effect on p210(bcr-abl)- driven proliferation; and (3) the combination of p210(bcr-abl)-tyrosine kinase inhibition and growth factor signal withdrawal can be sufficient to induce apoptotic death of transformed cells. (Blood. 2001;97:2008-2015) (C) 2001 by The American Society of Hematology.
Publisher: AMER SOC HEMATOLOGY
Keywords: CHRONIC MYELOGENOUS LEUKEMIA; CHRONIC MYELOCYTIC-LEUKEMIA; PHILADELPHIA-CHROMOSOME; GROWTH; LINES; RESISTANCE; APOPTOSIS; INDUCTION; K562; MICE
Publisher's Version: https://doi.org/10.1182/blood.V97.7.2008
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2001-04-01 12:00:00