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In vitro effects of perifosine, bortezomib and lenalidomide against hematopoietic progenitor cells from healthy donors

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Summary

The novel AKT inhibitor perifosine possesses myelopoiesis-stimulating effects in rodents. We studied the in vitro effects of the novel agents perifosine, bortezomib and lenalidomide in addition to adriamycin against normal human hematopoietic progenitor cells (HPC) using different clonogenic and non-clonogenic assays. All agents inhibited colony-forming unit (CFU) formation, perifosine inhibiting mainly CFU-granulocyte/macrophage formation and the other agents burst-forming unit-erythroid formation. Perifosine combined with lenalidomide or adriamycin tended to act antagonistically in suppressing CFU formation. Despite their inhibition of CFU formation, perifosine, bortezomib and lenalidomide induced only slight or moderate cytotoxicity in CD34+ selected HPC, as assessed using different assays such as flow cytometry-based detection of activated caspases and immunohistochemistry studies (e.g., Ki-67 staining). In contrast to its myelopoiesis-stimulating effects in rodents, perifosine - like bortezomib and lenalidomide - suppresses the clonogenic potential of HPC from healthy donors in vitro and thus probably plays no role in preventing neutropenia or in shorting its duration after intensive chemotherapy. However, all these novel agents typically induce only slight or moderate suppression of the clonogenic potential or loss of viability of normal HPC at clinically achievable plasma concentrations, assuming that hematoxicity is manageable and functional HPC can be collected after treatment with these compounds.

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Acknowledgements

The authors would like to thank the Dr. Werner Jackstädt Foundation for a grant supporting the work of M. Schmidt-Hieber. The authors also thank Dr. J. Weirowski for providing valuable editorial assistance.

Conflict of interest disclosure statement

B. Aicher is employed at Æterna Zentaris GmbH (Frankfurt/Main, Germany), and has stock/stock options at this company. The other authors have declared no conflicts of interest.

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Authors and Affiliations

  1. Department of Medicine III (Hematology, Oncology and Transfusion Medicine), Charité Campus Benjamin Franklin, Hindenburgdamm 30, 12200, Berlin, Germany

    Martin Schmidt-Hieber, Robert Dabrowski, Antonia Busse, Carola Tietze-Buerger, Birgit Reufi, Eckhard Thiel & Igor Wolfgang Blau

  2. Æterna Zentaris GmbH, Weismuellerstrasse 50, 60314, Frankfurt/Main, Germany

    Babette Aicher

  3. Institute for Pathology, Charité Campus Mitte, Charitéplatz 1, 10117, Berlin, Germany

    Philipp Lohneis

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  1. Martin Schmidt-Hieber
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  2. Robert Dabrowski
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  9. Igor Wolfgang Blau
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Correspondence to Martin Schmidt-Hieber.

Additional information

MSH, ET and IWB designed the study. MSH, RD, BA, PL, AB, CTB and BR performed the experiments and/or analyzed data. MSH wrote the manuscript. All authors approved the final version of the manuscript.

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Supplemental Figure 1

Depiction of exemplary Ki-67 and caspase-3 staining of CD34+ selected PB HPC after 24 h incubation with lenalidomide (1 µM). Percentages refer to positive cells. Tonsilar tissue with follicular hyperplasia was used as a positive control with a high Ki-67 proliferative index and numerous cleaved caspase-3+ apoptotic cells within the germinal centers. (DOC 683 kb)

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Schmidt-Hieber, M., Dabrowski, R., Aicher, B. et al. In vitro effects of perifosine, bortezomib and lenalidomide against hematopoietic progenitor cells from healthy donors. Invest New Drugs 30, 1396–1403 (2012). https://doi.org/10.1007/s10637-011-9705-6

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  • DOI: https://doi.org/10.1007/s10637-011-9705-6

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