Abstract
Purpose
Erufosine is an i.v. injectable alkylphosphocholine which is active against various haematological malignancies in vitro. In the present study, its effects on multiple myeloma (MM) cell lines and on murine and human hematopoietic progenitor cells (HPCs) were investigated.
Methods
The following MM cell lines were used: RPMI-8226, U-266 and OPM-2. The cytotoxicity of erufosine against these cell lines was determined by the MTT-dye reduction assay. Bcl-2, Bcl-XL and pAkt expression levels, activation of caspases, as well as cleavage of PARP, were studied by Western blotting. Migration was evaluated by a modified Boyden-chamber assay. The haematologic toxicity of erufosine was assessed using clonogenicity assays with normal HPCs of murine or human origin.
Results
Significant cytotoxic activity of erufosine against the MM cell lines was found. Comparison of the characteristics of erufosine-induced cell death in the three cell lines revealed a complex mode of action with apoptotic mechanisms prevailing in OPM-2 cells and non-apoptotic mechanisms prevailing in U-266 cells. The sensitivity of the MM cell lines to erufosine-induced apoptosis correlated inversely with the Bcl-XL expression level. Erufosine participated in synergistic interactions with various drugs. Furthermore, it showed potent migration-inhibiting activity in RPMI-8226 cells. Erufosine was not toxic to normal HPCs of murine or human origin and even stimulated progenitors from human umbilical cord blood to form granulocyte/macrophage colonies. Moreover, erufosine ameliorated the toxicity of bendamustine to murine HPCs.
Conclusions
Overall, the data presented reveal that erufosine could have potential as an antimyeloma drug and deserves further development.
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Notes
Activation of caspases and PARP cleavage in RPMI-8226 cells in response to erufosine has been published before [22].
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Acknowledgments
This work was supported by a grant from the Scientific Research Fund of the Ministry of Education and Science of the Republic of Bulgaria and by a German Academic Exchange Service (DAAD) scholarship for D. Y. Yosifov. The authors are also grateful to the Scientific Board of the German Cancer Research Center (DKFZ) for the visiting fellowship grant to S.M. Konstantinov. Finally, the authors would like to thank Dr. Lutz Edler, DKFZ for the statistical advice and Prof. Robert Owen, DKFZ for proof-reading the manuscript.
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Yosifov, D.Y., Todorov, P.T., Zaharieva, M.M. et al. Erucylphospho-N,N,N-trimethylpropylammonium (erufosine) is a potential antimyeloma drug devoid of myelotoxicity. Cancer Chemother Pharmacol 67, 13–25 (2011). https://doi.org/10.1007/s00280-010-1273-5
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DOI: https://doi.org/10.1007/s00280-010-1273-5