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Journal of Molecular Medicine

, Volume 90, Issue 2, pp 149–161 | Cite as

Modulation of anthracycline-induced cytotoxicity by targeting the prenylated proteome in myeloid leukemia cells

  • Michael A. Morgan
  • Fredrick O. Onono
  • H. Peter Spielmann
  • Thangaiah Subramanian
  • Michaela Scherr
  • Letizia Venturini
  • Iris Dallmann
  • Arnold Ganser
  • Christoph W. M. Reuter
Original Article

Abstract

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.

Keywords

ERK signaling Topoisomerase Leukemia 

Notes

Acknowledgements

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.

Disclosure

The authors declare no conflict of interests related to this study.

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Michael A. Morgan
    • 1
  • Fredrick O. Onono
    • 1
  • H. Peter Spielmann
    • 2
    • 3
    • 4
  • Thangaiah Subramanian
    • 2
  • Michaela Scherr
    • 1
  • Letizia Venturini
    • 1
  • Iris Dallmann
    • 1
  • Arnold Ganser
    • 1
  • Christoph W. M. Reuter
    • 1
  1. 1.Department of Hematology, Hemostasis, Oncology and Stem Cell TransplantationHannover Medical SchoolHannoverGermany
  2. 2.Department of Molecular and Cellular BiochemistryUniversity of KentuckyLexingtonUSA
  3. 3.Department of ChemistryUniversity of KentuckyLexingtonUSA
  4. 4.Kentucky Center for Structural BiologyUniversity of KentuckyLexingtonUSA

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