Ki11502, a novel multitargeted receptor tyrosine kinase inhibitor, induces growth arrest and apoptosis of human leukemia cells in vitro and in vivo
| Autor: | Chie Nishioka, Takayuki Ikezoe, Taizo Tasaka, Jing Yang, Akihito Yokoyama, Atsushi Miwa, H. Phillip Koeffler, Yoshio Kuwayama, Kazuto Togitani |
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| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: |
Immunology
Transplantation Heterologous Leukemia inhibitory factor receptor Antineoplastic Agents Apoptosis Mice SCID Biochemistry Receptor tyrosine kinase Mice Growth factor receptor hemic and lymphatic diseases Cell Line Tumor medicine CD135 Animals Humans Protein Kinase Inhibitors Cell Proliferation ABL Leukemia biology Neoplasia Cell growth Receptor Protein-Tyrosine Kinases Cell Biology Hematology medicine.disease Treatment Outcome biology.protein Cancer research Quinolines Platelet-derived growth factor receptor |
| Popis: | Ki11502 is a novel multitargeted receptor tyrosine kinase (RTK) inhibitor with selectivity against platelet-derived growth factor receptor alpha/beta (PDGFRα/β). Ki11502 (0.1-1 nM, 2 days) profoundly caused growth arrest, G0/G1 cell-cycle arrest, and apoptosis associated with down-regulation of Bcl-2 family proteins in the eosinophilic leukemia EOL-1 cells having the activated FIP1-like 1/PDGFRα fusion gene. Ki11502 decreased levels of p-PDGFRα and its downstream signals, including p-Akt, p-ERK, and p-STAT5, in EOL-1 cells. Of note, Ki11502 was also active against imatinib-resistant PDGFRαT674I mutant. In addition, Ki11502 inhibited proliferation of biphenotipic leukemia MV4-11 and acute myelogenous leukemia MOLM13 and freshly isolated leukemia cells having activating mutations in FMS-like tyrosine kinase 3 (FLT3). This occurred in parallel with the drug inhibiting FLT3 and its downstream signal pathways, as measured by fluorescence-activated cell sorting using the phospho-specific antibodies. In addition, Ki11502 totally inhibited proliferation of EOL-1 cells growing as tumor xenografts in SCID mice without any noticeable adverse effects. Taken together, Ki11502 has profound antiproliferative effects on select subsets of leukemia including those possessing imatinib-resistant mutation. |
| Databáze: | OpenAIRE |
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