Modulation of anthracycline-induced cytotoxicity by targeting the prenylated proteome in myeloid leukemia cells
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Deregulation of Ras/ERK signaling in myeloid leukemias makes this pathway an interesting target for drug development. Myeloid leukemia cell lines were screened for idarubicin-induced apoptosis, cell-cycle progression, cell-cycle-dependent MAP kinase kinase (MEK-1/2) activation, and Top2 expression. Cell-cycle-dependent activation of MEK/ERK signaling was blocked using farnesyltransferase inhibitor (FTI) BMS-214,662 and dual prenyltransferase inhibitor (DPI) L-778,123 to disrupt Ras signaling. Idarubicin caused a G2/M cell-cycle arrest characterized by elevated diphosphorylated MEK-1/2 and Top2α expression levels. The FTI/DPIs elicited distinct effects on Ras signaling, protein prenylation, cell cycling and apoptosis. Combining these FTI/DPIs with idarubicin synergistically inhibited proliferation of leukemia cell lines, but the L-778,123+idarubicin combination exhibited synergistic growth inhibition over a greater range of drug concentrations. Interestingly, combined FTI/DPI treatment synergistically inhibited cell proliferation, induced apoptosis and nearly completely blocked protein prenylation. Inhibition of K-Ras expression by RNA interference or blockade of its post-translational prenylation led to increased BMS-214,662-induced apoptosis. Our results suggest that nearly complete inhibition of protein prenylation using an FTI + DPI combination is the most effective method to induce apoptosis and to block anthracycline-induced activation of ERK signaling.
KeywordsERK signaling Topoisomerase Leukemia
This work was supported in part by grants to C.R. from the Deutsche Krebshilfe and the José Carreras Foundation (DJCLS R 05/21 and DJCLS R 07/32f). We would like to thank Tania Bunke for excellent technical support and to acknowledge the assistance of the Cell Sorting Core Facility of the Hannover Medical School, which is supported in part by Braukmann-Wittenberg-Herz-Stiftung and Deutsche Forschungsgemeinschaft.
The authors declare no conflict of interests related to this study.
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