The MEK inhibitor PD184352 enhances BMS-214662-induced
apoptosis in CD34+ CML stem/progenitor cells

J 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.

Základní údaje

Originální název

The MEK inhibitor PD184352 enhances BMS-214662-induced apoptosis in CD34+ CML stem/progenitor cells

Autoři

PELLICANO, Francesca (380 Itálie), Pavel ŠIMARA (203 Česká republika, garant, domácí), Amy SINCLAIR (826 Velká Británie a Severní Irsko), Gudmundur Vignir HELGASON (826 Velká Británie a Severní Irsko), Mhairi COPLAND (826 Velká Británie a Severní Irsko), Steven GRANT (826 Velká Británie a Severní Irsko) a Tessa HOLYOAKE (826 Velká Británie a Severní Irsko)

Vydání

Leukemia, London, Nature Publishing Group, 2011, 0887-6924

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30200 3.2 Clinical medicine

Stát vydavatele

Velká Británie a Severní Irsko

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 9.561

Kód RIV

RIV/00216224:14330/11:00067303

Organizační jednotka

Fakulta informatiky

DOI

http://dx.doi.org/10.1038/leu.2011.67

UT WoS

000292682600012

Klíčová slova anglicky

CML; BMS-214662; MEK inhibitor; PD184352; HSC; TKI

Štítky

cbia-web

Příznaky

Mezinárodní význam

Změněno: 2. 3. 2018 10:21, Mgr. Pavel Šimara, Ph.D.

Anotace

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.

Návaznosti

MSM0021622430, záměr

Název: Funkční a molekulární charakteristiky nádorových a normálních kmenových buněk - identifikace cílů pro nová terapeutika a terapeutické strategie

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, Funkční a molekulární charakteristiky nádorových a normálních kmenových buněk - identifikace cílů pro nová terapeutika a terapeutické strategie

2B06052, projekt VaV

Název: Vytipování markerů, screening a časná diagnostika nádorových onemocnění pomocí vysoce automatizovaného zpracování multidimenzionálních biomedicínských obrazů (Akronym: Biomarker)

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, Vytipování markerů, screening a časná diagnostika nádorových onemocnění pomocí vysoce automatizovaného zpracování multidimenzionálních biomedicínských obrazů

Citovat

PELLICANO, Francesca, Pavel ŠIMARA, Amy SINCLAIR, Gudmundur Vignir HELGASON, Mhairi COPLAND, Steven GRANT a Tessa HOLYOAKE. The MEK inhibitor PD184352 enhances BMS-214662-induced apoptosis in CD34+ CML stem/progenitor cells. Leukemia. London: Nature Publishing Group, 2011, roč. 25, č. 7, s. 1159-1167. ISSN 0887-6924. Dostupné z: https://dx.doi.org/10.1038/leu.2011.67.

@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 a Tessa HOLYOAKE. The MEK inhibitor PD184352 enhances BMS-214662-induced apoptosis in CD34+ CML stem/progenitor cells. \textit{Leukemia}. London: Nature Publishing Group, 2011, roč.~25, č.~7, s.~1159-1167. ISSN~0887-6924. Dostupné z: https://dx.doi.org/10.1038/leu.2011.67.

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