The MEK inhibitor PD184352 enhances BMS-214662-induced apoptosis in CD34 + CML stem/progenitor cells
In: Leukemia, Jg. 25 (2011), Heft 7, S. 1159-1167
Online
academicJournal
- print, 31 ref
Zugriff:
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.
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The MEK inhibitor PD184352 enhances BMS-214662-induced apoptosis in CD34 + CML stem/progenitor cells
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Autor/in / Beteiligte Person: | PELLICANO, F ; SIMARA, P ; SINCLAIR, A ; HELGASON, G. V ; COPLAND, M ; GRANT, S ; HOLYOAKE, T. L |
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Zeitschrift: | Leukemia, Jg. 25 (2011), Heft 7, S. 1159-1167 |
Veröffentlichung: | Avenel, NJ: Nature Publishing Group, 2011 |
Medientyp: | academicJournal |
Umfang: | print, 31 ref |
ISSN: | 0887-6924 (print) |
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