Detailed Information on Publication Record
2011
The MEK inhibitor PD184352 enhances BMS-214662-induced apoptosis in CD34+ CML stem/progenitor cells
PELLICANO, Francesca, Pavel ŠIMARA, Amy SINCLAIR, Gudmundur Vignir HELGASON, Mhairi COPLAND et. al.Basic information
Original name
The MEK inhibitor PD184352 enhances BMS-214662-induced apoptosis in CD34+ CML stem/progenitor cells
Authors
PELLICANO, Francesca (380 Italy), Pavel ŠIMARA (203 Czech Republic, guarantor, belonging to the institution), Amy SINCLAIR (826 United Kingdom of Great Britain and Northern Ireland), Gudmundur Vignir HELGASON (826 United Kingdom of Great Britain and Northern Ireland), Mhairi COPLAND (826 United Kingdom of Great Britain and Northern Ireland), Steven GRANT (826 United Kingdom of Great Britain and Northern Ireland) and Tessa HOLYOAKE (826 United Kingdom of Great Britain and Northern Ireland)
Edition
Leukemia, London, Nature Publishing Group, 2011, 0887-6924
Other information
Language
English
Type of outcome
Článek v odborném periodiku
Field of Study
30200 3.2 Clinical medicine
Country of publisher
United Kingdom of Great Britain and Northern Ireland
Confidentiality degree
není předmětem státního či obchodního tajemství
References:
Impact factor
Impact factor: 9.561
RIV identification code
RIV/00216224:14330/11:00067303
Organization unit
Faculty of Informatics
UT WoS
000292682600012
Keywords in English
CML; BMS-214662; MEK inhibitor; PD184352; HSC; TKI
Tags
Tags
International impact
Změněno: 2/3/2018 10:21, Mgr. Pavel Šimara, Ph.D.
Abstract
V originále
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.
Links
| MSM0021622430, plan (intention) |
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| 2B06052, research and development project |
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