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  • Molecular Targets For Therapy (MTT)
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Molecular Targets for Therapy (MTT)

Synergistic cytotoxic effects in myeloid leukemia cells upon cotreatment with farnesyltransferase and geranylgeranyl transferase-I inhibitors

Leukemia volume 17, pages 1508–1520 (2003)Cite this article

Abstract

As deregulation of RAS signaling is important in the pathogenesis of myeloid leukemias, molecular targeting of RAS signaling may be a promising therapeutic strategy. Farnesyl transferase inhibitors (FTIs) are the most promising class of these new cancer therapeutics. Several FTIs have entered phase II clinical trials in acute myeloid leukemia (AML). Since geranylgeranylation of K-RAS and N-RAS in the presence of FTIs may represent an important mechanism of FTI resistance, 6 geranylgeranyl transferase-I inhibitors (GGTIs) were screened alone and in combination with FTI for growth inhibition of myeloid leukemia cells. Significant growth inhibition (>70%) in myeloid cell lines was observed for GGTI-286 (9/19), GGTI-298 (14/19), GGTI-2147 (16/19) and FTI L-744,832 (17/17). GGTI treatment of NB-4 cells resulted in an accumulation of cells in G0/G1, whereas FTI L-744,832 primarily caused an increase in G2/M. FTI and GGTIs both induced apoptosis. In all cases, FTI/GGTI cotreatment led to synergistic cytotoxic effects in both myeloid cell lines (5/5) and primary AML cells (6/6). This synergy coincided with increased apoptosis. FTI/GGTI cotreatment caused an accumulation of unprocessed N-RAS and inactive N-RAS–RAF complexes. Our results suggest that alternative geranylgeranylation of N-RAS may represent an important mechanism of resistance to FTI monotherapy in myeloid leukemia cells.

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Acknowledgements

We thank Natalja Möbius for excellent technical assistance and Dr Kristine A Henningfeld and Dr Thomas Winkler for valuable discussions. We thank Dr Jürgen Krauter and Kerstin Görlich for help with the TaqMan experiments.

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  1. Department of Hematology and Oncology, Hannover Medical School, Hannover, Germany

    M A Morgan, J Wegner, E Aydilek, A Ganser & C W M Reuter

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  1. M A Morgan
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This work was supported in part by a grant to CR from the Deutsche Krebshilfe (10-18c1-ReI) and a grant to CR from Hannover Medical School (HILF-program).

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Morgan, M., Wegner, J., Aydilek, E. et al. Synergistic cytotoxic effects in myeloid leukemia cells upon cotreatment with farnesyltransferase and geranylgeranyl transferase-I inhibitors. Leukemia 17, 1508–1520 (2003). https://doi.org/10.1038/sj.leu.2403022

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