Original Article

Cancer Chemotherapy and Pharmacology

, Volume 67, Issue 1, pp 13-25

First online:

Erucylphospho-N,N,N-trimethylpropylammonium (erufosine) is a potential antimyeloma drug devoid of myelotoxicity

  • Deyan Y. YosifovAffiliated withLaboratory for Experimental Chemotherapy, Dept. of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University of SofiaToxicology and Chemotherapy Unit, German Cancer Research Center (DKFZ) Email author 
  • , Plamen T. TodorovAffiliated withInstitute of Biology and Immunology of Reproduction, Bulgarian Academy of Sciences
  • , Maya M. ZaharievaAffiliated withLaboratory for Experimental Chemotherapy, Dept. of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University of SofiaToxicology and Chemotherapy Unit, German Cancer Research Center (DKFZ)
  • , Kaloyan D. GeorgievAffiliated withToxicology and Chemotherapy Unit, German Cancer Research Center (DKFZ)Department of Preclinical and Clinical Pharmacology and Biochemistry, Medical University of Varna
  • , Bissera A. PilichevaAffiliated withLaboratory for Experimental Chemotherapy, Dept. of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University of Sofia
  • , Spiro M. KonstantinovAffiliated withLaboratory for Experimental Chemotherapy, Dept. of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University of SofiaToxicology and Chemotherapy Unit, German Cancer Research Center (DKFZ)
  • , Martin R. BergerAffiliated withToxicology and Chemotherapy Unit, German Cancer Research Center (DKFZ)

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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.

Keywords

Erufosine Alkylphosphocholines Multiple myeloma Cytotoxicity Haematopoietic progenitors Antimigratory activity