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@article{949250, author = {Pellicano, Francesca and Šimara, Pavel and Sinclair, Amy and Helgason, Gudmundur Vignir and Copland, Mhairi and Grant, Steven and Holyoake, Tessa}, article_location = {London}, article_number = {7}, doi = {http://dx.doi.org/10.1038/leu.2011.67}, keywords = {CML; BMS-214662; MEK inhibitor; PD184352; HSC; TKI}, language = {eng}, issn = {0887-6924}, journal = {Leukemia}, title = {The MEK inhibitor PD184352 enhances BMS-214662-induced apoptosis in CD34+ CML stem/progenitor cells}, url = {http://www.nature.com/leu/journal/v25/n7/full/leu201167a.html}, volume = {25}, year = {2011} }
TY - JOUR ID - 949250 AU - Pellicano, Francesca - Šimara, Pavel - Sinclair, Amy - Helgason, Gudmundur Vignir - Copland, Mhairi - Grant, Steven - Holyoake, Tessa PY - 2011 TI - The MEK inhibitor PD184352 enhances BMS-214662-induced apoptosis in CD34+ CML stem/progenitor cells JF - Leukemia VL - 25 IS - 7 SP - 1159-1167 EP - 1159-1167 PB - Nature Publishing Group SN - 08876924 KW - CML KW - BMS-214662 KW - MEK inhibitor KW - PD184352 KW - HSC KW - TKI UR - http://www.nature.com/leu/journal/v25/n7/full/leu201167a.html N2 - 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. ER -
PELLICANO, Francesca, Pavel ŠIMARA, Amy SINCLAIR, Gudmundur Vignir HELGASON, Mhairi COPLAND, Steven GRANT and Tessa HOLYOAKE. The MEK inhibitor PD184352 enhances BMS-214662-induced apoptosis in CD34+ CML stem/progenitor cells. \textit{Leukemia}. London: Nature Publishing Group, 2011, vol.~25, No~7, p.~1159-1167. ISSN~0887-6924. Available from: https://dx.doi.org/10.1038/leu.2011.67.
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