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, Steven GRANT and Tessa HOLYOAKE. The MEK inhibitor PD184352 enhances BMS-214662-induced apoptosis in CD34+ CML stem/progenitor cells. 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.

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

• Original language: English
• Type of outcome: Article in a journal
• Field of Study: 30200 3.2 Clinical medicine
• Country of publisher: United Kingdom of Great Britain and Northern Ireland
• Confidentiality degree: is not subject to a state or trade secret
• WWW: URL
• Impact factor: Impact factor: 9.561
• RIV identification code: RIV/00216224:14330/11:00067303
• Organization unit: Faculty of Informatics
• Doi: http://dx.doi.org/10.1038/leu.2011.67
• UT WoS: 000292682600012
• Keywords in English: CML; BMS-214662; MEK inhibitor; PD184352; HSC; TKI
• Tags: cbia-web
• Tags: International impact

Abstract

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

Investor: Ministry of Education, Youth and Sports of the CR, Functional and molecular characteristics of cancer and normal stem cells - identification of targets for novel therapeutics and therapeutic strategies

• 2B06052, research and development project: Name: Vytipování markerů, screening a časná diagnostika nádorových onemocnění pomocí vysoce automatizovaného zpracování multidimenzionálních biomedicínských obrazů (Acronym: Biomarker)

Investor: Ministry of Education, Youth and Sports of the CR, Determination of markers, screening and early diagnostics of cancer diseases using highly automated processing of multidimensional biomedical images