Visit our Expo - Redox and Inflammation signaling 2012

Session XVII : Cell signaling in health and disease Poster XVII, 57
Erufosine: a membrane targeting antineoplastic agent with signal transduction
modulating effects
Maya M. Zaharieva1,2, Spiro M. Konstantinov1,2, Martin R. Berger2
1Faculty of Pharmacy, Medical University of Sofia, 2 Dunav Str, 1000 Sofia, Bulgaria
2German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg,
Germany
The ether lipid analogue erufosine (erucylphospho-N,N,N,-trimethyl-propylammonium,
ErPC3) has high activity against leukaemic cells without affecting the normal hematopoiesis.
It belongs to the group of alkylphosphocholines that are inhibitors of protein kinase C and of
phospholipase C. However, the mechanism of action of erufosine remains rather unclear. We
focused on combination effects with the tyrosine kinase inhibitor imatinib mesylate (gleevec,
former STI-571 or CGP-57148) against chronic myeloid leukemia (CML) derived cell lines.
The influence of erufosine on proteins involved in the phosphatidylinositol-3-phosphate
pathway and on the expression of the retinoblastoma protein Rb as key component for the cell
cycle entry and progression in mammalian cells was studied. A panel of three cell lines:
SKW-3 (chronic T-cell leukemia), BV-173 and K-562 (CML) were treated with erufosine (at
concentrations ranging from 2 to 50 mcM). Whole cell lysates were prepared for Western
Blot analysis. The combination effect of erufosine with imatinib on BV-173 and K-562 was
estimated after the treatment using MTT-dye reduction assay. The consecutive treatment of
K-562 and BV-173 cells with erufosine (2.5, 5, 15, 30 mcM) and imatinib (0.05, 0.1 mcM)
led to synergism and therefore such combinations could be beneficial for relapsed patients
with drug resistant disease. Erufosine caused decrease of pAkt and BCR-ABL protein
expression, while it induced the Rb in K-562 cells. These alterations in the signal
transduction could be an explanation for the drug interaction found. Furthermore, Rb is a
substrate of caspases and it is cleaved during apoptosis. Such Rb degradation was observed in
SKW-3 and BV-173 cells after incubation with erufosine for 14 h. Our experimental findings
suggest that erufosine acts through induction of changes in protein signaling and especially
through Rb induction. This unique mode of action makes it an attractive partner for
combination therapies, e.g. with imatinib-based therapy for CML.
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