Reduced Expression of the Retinoblastoma Protein Shows That the Related Signaling Pathway Is Essential for Mediating the Antineoplastic Activity of Erufosine

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.

Alkyl ether lipids, ion channels and lipid raft reorganization in cancer therapy

“…Erufosine interferes with survival signals (Chometon, et al, 2014), and interacts with the 18 kDa mitochondrial translocator protein leading to activation of the mitochondrial apoptosis cascade (Veenman, et al, 2014). The retinoblastoma signaling pathway has been shown to be essential for mediating the antitumor activity of erufosine, and hence its efficacy might be predicted by determining the retinoblastoma protein status (Zaharieva, et al, 2014;Zaharieva, et al, 2007). Both in vitro and in vivo assays have shown promising antitumor activity of erufosine alone and in combination with radiation on astrocytoma and glioblastoma cell lines (Awde, et al, 2013;Rubel, et al, 2006).…”

Conditional Knockdown of Osteopontin Inhibits Breast Cancer Skeletal Metastasis

“…Erufosine is a third-generation alkylphosphocholine with remarkable antineoplastic properties [30,31,32,33]. Its efficacy is related to changes in the expression of certain components of vital signaling pathways (for review see [34]).…”

Upregulation of miR-130b Contributes to Risk of Poor Prognosis and Racial Disparity in African-American Prostate Cancer

“…We found that FHIT and CDKN1B, known as haploinsufficient tumor suppressors (24,34,35), were significantly upregulated in MDA-PCa-2b cells upon miR-130b inhibition and luciferase reporter assay showed that both genes are a direct miR-130b target. A previous study found that stimulation of CDKN1B caused G 2 arrest by repressing cyclin D3 (36). In non-small cell lung cancer (NSCLC), SIRT1 silencing suppresses proliferation and induces senescence in a CDKN1B (p27Kip1)-dependent manner (37).…”