ORIGINAL ARTICLE Erucylphospho-N,N,N-trimethylpropylammonium (erufosine) is a potential antimyeloma drug devoid of myelotoxicity Deyan Y. Yosifov • Plamen T. Todorov • Maya M. Zaharieva • Kaloyan D. Georgiev • Bissera A. Pilicheva • Spiro M. Konstantinov • Martin R. Berger Received: 16 November 2009 / Accepted: 3 February 2010 / Published online: 23 February 2010 Ó Springer-Verlag 2010 Abstract Purpose Erufosine is an i.v. injectable alkylphosphoch- oline 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-X L 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 charac- teristics 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-X L 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. Keywords Erufosine  Alkylphosphocholines  Multiple myeloma  Cytotoxicity  Haematopoietic progenitors  Antimigratory activity Introduction Multiple myeloma (MM) is a relatively frequent haema- tological malignancy accounting for 15% of all cases of lymphoproliferative diseases [1]. The disease is charac- terized by malignant plasma cells that secrete monoclonal immunoglobulins and infiltrate the bone marrow. MM cells interact extensively with the bone marrow microenviron- ment via adhesion molecules and are stimulated by D. Y. Yosifov (&)  M. M. Zaharieva  B. A. Pilicheva  S. M. Konstantinov Laboratory for Experimental Chemotherapy, Dept. of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University of Sofia, Dunav 2, 1000 Sofia, Bulgaria e-mail: deyanyosifov@abv.bg D. Y. Yosifov  M. M. Zaharieva  K. D. Georgiev  S. M. Konstantinov  M. R. Berger Toxicology and Chemotherapy Unit, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany P. T. Todorov Institute of Biology and Immunology of Reproduction, Bulgarian Academy of Sciences, Tzarigradsko shosse 73, 1113 Sofia, Bulgaria K. D. Georgiev Department of Preclinical and Clinical Pharmacology and Biochemistry, Medical University of Varna, Marin Drinov 55, 9000 Varna, Bulgaria 123 Cancer Chemother Pharmacol (2011) 67:13–25 DOI 10.1007/s00280-010-1273-5