Abstract
Erufosine is a new antineoplastic agent of the group of alkylphosphocholines, which interferes with signal transduction and induces apoptosis in various leukemic and tumor cell lines. The present study was designed to examine for the first time the mechanism of resistance to erufosine in malignant cells with permanently reduced expression of the retinoblastoma (Rb) protein. Bearing in mind the high number of malignancies with reduced level of this tumor-suppressor, this investigation was deemed important for using erufosine, alone or in combination, in patients with compromised RB1 gene expression. For this purpose, clones of the leukemic T-cell line SKW-3 were used, which had been engineered to constantly express differently low Rb levels. The alkylphosphocholine induced apoptosis, stimulated the expression of the cyclin dependent kinase inhibitor p27Kip1 and inhibited the synthesis of cyclin D3, thereby causing a G2 phase cell cycle arrest and death of cells with wild type Rb expression. In contrast, Rb-deficiency impeded the changes induced by eru-fosine in the expression of these proteins and abrogated the induction of G2 arrest, which was correlated with reduced antiproliferative and anticlonogenic activities of the compound. In conclusion, analysis of our results showed for the first time that the Rb signaling pathway is essential for mediating the antineoplastic activity of erufosine and its efficacy in patients with malignant diseases may be predicted by determining the Rb status.
Highlights
The ether lipid analogue erufosine is a new antineoplastic agent classified as a third generation alkylphosphocholine (APC) [1]
A transient retinoblastoma protein (Rb)-knockdown, which was caused in chronic myeloid leukemia cells, was associated with diminished sensitivity to erufosine, as determined by proliferation and clonogenicity assays [29]
The present study aimed to prove that the retinoblastoma protein pathway is central to erufosine’s antineoplastic activity and induction of apoptosis
Summary
The ether lipid analogue erufosine (erucylphospho-N,N,N,trimethyl-propylammonium, ErPC3) is a new antineoplastic agent classified as a third generation alkylphosphocholine (APC) [1]. Recent studies have shown that erufosine inhibits the activity of protein kinase B (PKB/Akt) and induces apoptosis in a variety of malignant cells [2,4,7,8]. It targets cell cycle regulators such as the retinoblastoma protein (Rb), p27Kip, transcription factors from the E2F family and cyclin D1 [2,9,10,11,12,13]. Welch and Wang have shown that the C-terminal region of Rb can bind to the Abl tyrosine kinase, leading to the inhibition of its kinase activity [24,28]
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