The MEK inhibitor PD184352 enhances BMS-214662-induced apoptosis in CD34+ CML stem/progenitor cells
| Autor: | Steven Grant, Francesca Pellicano, Tessa L. Holyoake, Mhairi Copland, Amy Sinclair, Pavel Šimara, Gudmundur V Helgason |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
MAPK/ERK pathway
Cancer Research medicine.drug_class Recombinant Fusion Proteins MAP Kinase Kinase 1 Antigens CD34 Apoptosis Oncogene Protein p21(ras) Biology Article Tyrosine-kinase inhibitor Benzodiazepines 03 medical and health sciences 0302 clinical medicine Leukemia Myelogenous Chronic BCR-ABL Positive hemic and lymphatic diseases Tumor Cells Cultured medicine Farnesyltranstransferase Humans Enzyme Inhibitors Progenitor cell Genes Dominant 030304 developmental biology 0303 health sciences Kinase MEK inhibitor Imidazoles Drug Synergism Hematology Hematopoietic Stem Cells MAP Kinase Kinase Kinases Neoplasm Proteins 3. Good health Haematopoiesis Genes ras Oncology 030220 oncology & carcinogenesis Benzamides Leukemia Myeloid Chronic-Phase Neoplastic Stem Cells Cancer research Drug Screening Assays Antitumor Stem cell Blast Crisis K562 Cells K562 cells |
| Zdroj: | Leukemia. 25:1159-1167 |
| ISSN: | 1476-5551 0887-6924 |
| DOI: | 10.1038/leu.2011.67 |
| Popis: | The cytotoxic farnesyl transferase inhibitor BMS-214662 has been shown to potently induce mitochondrial apoptosis in primitive CD34+ chronic myeloid leukaemia (CML) stem/progenitor cells. Here, to enhance the BMS-214662 apoptotic effect, we further targeted the extracellular signal-regulated kinase (ERK) pathway, downstream of BCR-ABL, by treating CD34+ CML stem/progenitor cells with a highly selective adenosine triphosphate (ATP) non-competitive MEK inhibitor, PD184352. PD184352 increased the apoptotic effect of BMS-214662 in a CML blast crisis cell line, K562, and in primary chronic phase CD34+ CML cells. Compared with BMS-214662, after combination treatment we observed inhibition of ERK phosphorylation, increased Annexin-V levels, caspase-3, -8 and -9 activation and potentiated mitochondrial damage, associated with decreased levels of anti-apoptotic BCL-2 family protein MCL-1. Inhibition of K-RAS function by a dominant-negative mutant resulted in CML cell death and this process was further enhanced by the addition of BMS-214662 and PD184352. Together, these findings suggest that the addition of a MEK inhibitor improves the ability of BMS-214662 to selectively target CML stem/progenitor cells, notoriously insensitive to tyrosine kinase inhibitor treatment and presumed to be responsible for the persistence and relapse of the disease. |
| Databáze: | OpenAIRE |
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