The antiangiogenic protein kinase inhibitors SU5416 and SU6668 inhibit the SCF receptor (c-kit) in a human myeloid leukemia cell line and in acute myeloid leukemia blasts
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Smolich, BD
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机构:Sugen, Preclin Therapeut, San Francisco, CA 94080 USA
Smolich, BD
Yuen, HA
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机构:Sugen, Preclin Therapeut, San Francisco, CA 94080 USA
Yuen, HA
West, KA
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机构:Sugen, Preclin Therapeut, San Francisco, CA 94080 USA
West, KA
Giles, FJ
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机构:Sugen, Preclin Therapeut, San Francisco, CA 94080 USA
Giles, FJ
Albitar, M
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机构:Sugen, Preclin Therapeut, San Francisco, CA 94080 USA
Albitar, M
Cherrington, JM
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机构:Sugen, Preclin Therapeut, San Francisco, CA 94080 USA
Cherrington, JM
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[1] Sugen, Preclin Therapeut, San Francisco, CA 94080 USA
[2] Univ Texas, MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA
[3] Univ Texas, MD Anderson Canc Ctr, Dept Lab Med, Houston, TX 77030 USA
SU5416 and SU6668 are potent antiangiogenic small-molecule inhibitors of receptor tyrosine kinases, including those of the vascular endothelial growth factor and platelet-derived growth factor receptor families. The stem cell factor (SCF) receptor, c-kit, is structurally related to these receptors and, although not expressed on mature peripheral blood cells, is expressed in leukemic blasts derived from 60% to 80% of acute myeloid leukemia (AML) patients. The c-kit kinase inhibitory activity of SU5416 and SU6668 was evaluated in MO7E cells, a human myeloid leukemia cell line. Tyrosine autophosphorylation of the receptor, induced by SCF, was inhibited in these cells by SU5416 and SU6668 in a dose-dependent manner (inhibitory concentration of 50% [IC50] 01.1 muM). Inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, a signaling event down-stream of c-kit activation, was also inhibited in a dose-dependent manner. Both compounds also inhibited SCF-induced proliferation of MO7E cells (IC50 0.1 muM for SU5416; 0.29 muM for SU6668). Furthermore, both SU5416 and SU6668 induced apoptosis in a dose- and time-dependent manner as measured by the increase in activated caspase-3 and the enhanced cleavage of its substrate poly(ADP-ribose) polymerase. These findings with MO7E cells were extended to leukemic blasts from c-kit(+) patients. In patient blasts, both SU5416 and SU6668 inhibited SCF-induced phosphorylation of c-kit and ERK1/2 and induced apoptosis. These studies indicate that SU5416 and SU6668 inhibit biologic functions of c-kit in addition to exhibiting antiangiogenic properties and suggest that the combination of these activities may provide a novel therapeutic approach for the treatment of AML. (Blood, 2001;97:1413-1421) (C) 2001 by The American Society of Hematology.