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Evaluation of deoxyhypusine synthase inhibitors targeting BCR-ABL positive leukemias

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Summary

Effective inhibition of BCR-ABL tyrosine kinase activity with Imatinib represents a breakthrough in the treatment of patients with chronic myeloid leukemia (CML). However, more than 30 % of patients with CML in chronic phase do not respond adequately to Imatinib and the drug seems not to affect the quiescent pool of BCR-ABL positive leukemic stem and progenitor cells. Therefore, despite encouraging clinical results, Imatinib can still not be considered a curative treatment option in CML. We recently reported downregulation of eukaryotic initiation factor 5A (eIF5A) in Imatinib treated K562 cells. Furthermore, the inhibition of eIF5A by siRNA in combination with Imatinib has been shown to exert synergistic cytotoxic effects on BCR-ABL positive cell lines. Based on the structure of known deoxyhypusine synthase (DHS) inhibitors such as CNI-1493, a drug design approach was applied to develop potential compounds targeting DHS. Here we report the biological evaluation of selected novel (DHSI-15) as compared to established (CNI-1493, deoxyspergualin) DHS inhibitors. We show that upon the compounds tested, DHSI-15 and deoxyspergualin exert strongest antiproliferative effects on BCR-ABL cells including Imatinib resistant mutants. However, this effect did not seem to be restricted to BCR-ABL positive cell lines or primary cells. Both compounds are able to induce apoptosis/necrosis during long term incubation of BCR-ABL positive BA/F3 derivates. Pharmacological synergism can be observed for deoxyspergualin and Imatinib, but not for DHSI-15 and Imatinib. Finally we show that deoxyspergualin is able to inhibit proliferation of CD34+ progenitor cells from CML patients. We conclude that inhibition of deoxyhypusine synthase (DHS) can be supportive for the anti-proliferative treatment of leukemia and merits further investigation including other cancers.

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Acknowledgements

A START Grant of the Medical Faculty of RWTH Aachen University (PZ) and a network-grant of the German Federal Ministry of Education and Research (BMBF; grant No. 01GUO715-717 to THB, JH, CM and MR) supported this work.

Conflict of interest

The authors declare that they have no conflict of interest

Ethical standards

The experiments comply with the current laws of Germany

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Authors and Affiliations

  1. Klinik für Onkologie, Hämatologie und Stammzelltransplantation, Universitätsklinikum der RWTH, Aachen University, Aachen, Germany

    Patrick Ziegler, Valeska Wiehle, Susanne Ziegler, Jens Panse & Tim H. Brümmendorf

  2. Department of Oncology, Haematology and Bone marrow transplantation with section Pneumology, Hubertus Wald-Tumor Zentrum (UCCH), University Hospital Eppendorf (UKE), Hamburg, Germany

    Tuhama Chahoud, Thomas Wilhelm, Nora Pällman, Melanie Braig & Stefan Balabanov

  3. Department of Biochemistry, University Hospital Aachen (UKA) of the Rheinisch.-Westfälische Technische Hochschule Aachen, Aachen, Germany

    Thomas Wilhelm

  4. Department of Chemistry, Organic Chemistry, Faculty of Sciences, Hamburg, Germany

    Marcus Schröder & Chris Meier

  5. Center for Bioinformatics, University of Hamburg, Hamburg, Germany

    Adrian Kolodzik & Matthias Rarey

  6. Heinrich Pette Institute - Leibniz Institute for Experimental Virology, Hamburg, Germany

    Joachim Hauber

  7. Klinik für Hämatologie, Onkologie und Stammzelltransplantation (Med. Klinik IV), Pauwelsstraße 30, 52074, Aachen, Germany

    Tim H. Brümmendorf

  8. III. medizinische Klinik und Poliklinik- Nephrologie, Rheumatologie, Sektion Endokrinologie/Diabetologie, University Hospital Eppendorf (UKE), Hamburg, Germany

    Tuhama Chahoud

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  1. Patrick Ziegler
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  2. Tuhama Chahoud
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  8. Marcus Schröder
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  9. Chris Meier
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  13. Joachim Hauber
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  14. Stefan Balabanov
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  15. Tim H. Brümmendorf
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Corresponding author

Correspondence to Tim H. Brümmendorf.

Additional information

Stefan Balabanov and Tim H. Brümmendorf equal senior authorship

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Ziegler, P., Chahoud, T., Wilhelm, T. et al. Evaluation of deoxyhypusine synthase inhibitors targeting BCR-ABL positive leukemias. Invest New Drugs 30, 2274–2283 (2012). https://doi.org/10.1007/s10637-012-9810-1

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  • DOI: https://doi.org/10.1007/s10637-012-9810-1

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