MEK inhibition enhances BMS-214662-induced apoptosis in primitive CD34+ CML stem/progenitor cells.
| Authors | |
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| Year of publication | 2009 |
| Type | Conference abstract |
| MU Faculty or unit | |
| 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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