Erucylphospho-N,N,N-trimethylpropylammonium (erufosine) is a potential antimyeloma drug devoid of myelotoxicity.
OBJECTIVE
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-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 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-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.
Yosifov
Deyan Y
DY
Laboratory for Experimental Chemotherapy, Dept. of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University of Sofia, Dunav 2, 1000 Sofia, Bulgaria. deyanyosifov@abv.bg
Todorov
Plamen T
PT
Zaharieva
Maya M
MM
Georgiev
Kaloyan D
KD
Pilicheva
Bissera A
BA
Konstantinov
Spiro M
SM
Berger
Martin R
MR
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D010755:Organophosphates / Q000494:pharmacology* / Q000633:toxicity; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology* / Q000633:toxicity; D051020:bcl-X Protein / Q000187:drug effects* / Q000235:genetics
D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D010755:Organophosphates; D000644:Quaternary Ammonium Compounds; D051020:bcl-X Protein; C472787:erucylphospho-N,N,N-trimethylpropylammonium