| Abstract | The FMS-like tyrosine kinase 3 (FLT3) is a cell surface receptor tyrosine kinase. Activating mutations of this gene occur in nearly 30% of acute myelogenous leukemia (AML) patients. These mutations, in part, result in activation of mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathways. In this study, we found that AZD6244 (ARRY-142886), a novel inhibitor of MEK1/2 kinases, effectively inhibited the proliferation of acute biphenotypic leukemia MV4-11 and acute monocytic leukemia MOLM13 cells. The concentrations that inhibited 50% growth were approximately 0.3 and 1.2 microM, respectively, as measured by thymidine uptake on day 2 of culture. AZD6244 potently down-regulated the levels of phospho-ERK1/2 and its downstream effector, p-p70S6K, in the MV4-11 and MOLM13 cells as measured by Western blot analysis. Interestingly, when AZD6244 was combined with sunitinib, a FLT3 kinase inhibitor, growth inhibition and apoptosis of both MV4-11 and MOLM13 cells were synergistically enhanced in association with further down-regulation of phospho-ERK1/2 and p-p70S6K in these cells. Taken together, concomitant blockade of FLT3 and MEK signaling represents a promising treatment strategy for individuals with leukemia who possess activating mutations of FLT3. |
| Authors | Chie Nishioka, Takayuki Ikezoe, Jing Yang, Ayako Takeshita, Ayuko Taniguchi, Naoki Komatsu, Kazuto Togitani, H Phillip Koeffler, Akihito Yokoyama
(Affiliation: Department of Hematology and Respiratory Medicine, Kochi University, Kochi 783-8505, Japan.)
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| Journal | Leukemia research
(Leuk Res)
Vol. 32
Issue 6
Pg. 865-72
(Jun 2008)
ISSN: 0145-2126 England |
| PMID | 17983653
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
|
| Chemical References |
- AZD 6244
- Benzimidazoles
- Indoles
- Pyrroles
- sunitinib
- MAP Kinase Kinase 1
- MAP2K1 protein, human
- fms-Like Tyrosine Kinase 3
- Mitogen-Activated Protein Kinase 1
- Mitogen-Activated Protein Kinase 3
- Ribosomal Protein S6 Kinases, 70-kDa
- FLT3 protein, human
|
| Topics |
- Aged
- Aged, 80 and over
- Antineoplastic Combined Chemotherapy Protocols
- Apoptosis
(drug effects, physiology)
- Benzimidazoles
(therapeutic use)
- Cell Proliferation
(drug effects)
- Female
- Humans
- Indoles
(therapeutic use)
- Leukemia
(drug therapy, genetics, pathology)
- Leukemia, Megakaryoblastic, Acute
(drug therapy, genetics, pathology)
- Leukemia, Myeloid, Acute
(drug therapy, genetics, pathology)
- MAP Kinase Kinase 1
(antagonists & inhibitors, metabolism)
- Male
- Middle Aged
- Mitogen-Activated Protein Kinase 1
(antagonists & inhibitors, metabolism)
- Mitogen-Activated Protein Kinase 3
(antagonists & inhibitors, metabolism)
- Mutation
(genetics)
- Pyrroles
(therapeutic use)
- Ribosomal Protein S6 Kinases, 70-kDa
(antagonists & inhibitors, metabolism)
- Signal Transduction
(drug effects)
- Tumor Cells, Cultured
- fms-Like Tyrosine Kinase 3
(genetics)
|
