MEK inhibition enhances BMS-214662-induced apoptosis in primitive CD34+ CML stem/progenitor cells.

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Authors

ŠIMARA Pavel GRANT Steven HOLYOAKE Tessa PELLICANO Francesca

Year of publication 2009
Type Conference abstract
MU Faculty or unit

Faculty of Informatics

Citation
Description In presented work we have used the FTI in combination with MEK inhibitor PD184352 to increase the effect of FTI BMS-214662 in both proliferating and quiescent CML stem/progenitor cells. We have shown that MEK inhibitor PD184352 increases the apoptotic effect of FTI BMS-214662 in the K562 cell line as well as in CD34+ CML cells. We observed increased Annexin V and active Caspase-3 levels. We confirmed the cleavage of Caspase-3 substrate PARP. Apoptosis acts via the intrinsic pathway, as decreased mitochondrial membrane potential and downregulation of the mitochondrial anti-apoptotic protein MCL-1 was determined. Our results suggest that the RAS-MEK pathway is involved in BMS-214662 and PD184352 induced apoptosis and Caspases play a role in apoptotic signal transduction. Our data reveal that targeting of the MEK-ERK pathway sensitises CD34+ CML stem/progenitor cells treated with FTI BMS-214662. This study suggests that combination treatment may improve the ability of BMS-214662 to selectively target quiescent leukaemia stem/progenitor cells, which are insensitive to TKI treatment and responsible for persistence and relapse of disease.
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