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
| Autor: | Francis J. Giles, Beverly D. Smolich, Kristina A. West, Julie M. Cherrington, Helene A. Yuen, Maher Albitar |
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| Rok vydání: | 2001 |
| Předmět: |
Indoles
Immunology Angiogenesis Inhibitors Apoptosis Stem cell factor Leukemia inhibitory factor receptor Biochemistry Receptor tyrosine kinase Growth factor receptor Tumor Cells Cultured medicine Humans Pyrroles Phosphorylation Protein kinase A Stem Cell Factor Dose-Response Relationship Drug biology Caspase 3 Kinase Myeloid leukemia Cell Biology Hematology Protein-Tyrosine Kinases medicine.disease Oxindoles Proto-Oncogene Proteins c-kit Leukemia Leukemia Myeloid Caspases biology.protein Cancer research Mitogen-Activated Protein Kinases Propionates Cell Division |
| Zdroj: | Blood. 97:1413-1421 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood.v97.5.1413 |
| Popis: | 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% [IC(50)] 0.1-1 microM). Inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, a signaling event downstream of c-kit activation, was also inhibited in a dose-dependent manner. Both compounds also inhibited SCF-induced proliferation of MO7E cells (IC(50) 0.1 microM for SU5416; 0.29 microM 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. |
| Databáze: | OpenAIRE |
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