Erufosine

Abstract

The ether lipid analog erufosine (erucylphospho-N,N,N,-trimethylpropylammonium, ErPC3) has high activity against leukemic cells without affecting the normal hematopoiesis. It belongs to the group of alkylphosphocholines (APC) that are inhibitors of protein kinase C and 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 two chronic myeloid leukemia (CML)-derived cell lines (K-562 and BV-173). The influence of erufosine on proteins involved in the phosphatidylinositol-3-phosphate pathway and on expression of the retinoblastoma protein Rb was studied, the latter being a key component for cell cycle entry and progression in mammalian cells. The consecutive treatment of K-562 and BV-173 cells with erufosine (2.5, 5, 15, 30 microM) and imatinib mesylate (0.05, 0.1 microM) led to synergism as measured by the MTT-dye reduction assay and this is reason to hypothesize that such combinations could be beneficial for relapsed patients with drug-resistant disease. Whole cell lysates from K-562 and BV-173 were investigated for the expression of Rb, PKB/Akt, pAkt, and p27 by Western blot. Erufosine caused decreases of pAkt and CML fusion protein p210 (BCR-ABL) protein expression, but induced the Rb protein expression in K-562 cells. A parallel increase in p27 level was observed after 24 and 48 h treatment. These alterations in signal transduction could be an explanation for the drug interaction found. Furthermore, Rb is a substrate of caspases and is cleaved during apoptosis as already evidenced for BV-173 cells. 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, for example, in combination with imatinib mesylate for treatment of CML.

PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes

“…Examples of anticancer APCs include the prototypic compound edelfosine and the novel drug octadecyl-(1,1-dimethyl-piperidinio-4-yl)-phosphate (D-21266, Perifosine), which affect apoptotic signaling. Studies on malignantly transformed hematopoietic cell lines showed that APCs reduce the levels of phosphorylated Akt (Figure 3) [112] . Perifosine is considered to be one of the first generation of Akt inhibitors.…”

Erufosine Induces Autophagy and Apoptosis in Oral Squamous Cell Carcinoma

“…It is well documented that erufosine prevents phosphorylation of PKB/Akt on both Ser473 and Thr308 residues in a number of malignant cell lines. First, downregulation of p-Akt (Thr308) and subsequent upregulation of P27 WAF1/CIP1 were observed in malignantly transformed hematopoietic cell lines after treatment with erufosine for 48 h (Zaharieva et al, 2007). This result was confirmed later in prostate cancer cell lines and glioma cells (Handrick et al, 2006;Rudner et al, 2010).…”

“…Our earlier studies demonstrated that erufosine inhibits the phosphoinositide pathway, leads to dephosphorylation of Akt, and dephosphorylation as well as induction of Rband JNK (Berger et al, 2003;Zaharieva et al, 2007;Dineva et al, 2012;Yosifov et al, 2012). Furthermore, we examined its antitumor activities and effect on the mTOR signaling pathway in oral squamous cell carcinoma cell lines.…”

Nanoencapsulação do fármaco miltefosina em micelas poliméricas de poli(óxido de etileno)-poli(óxido de propileno)

“…As APC exibem significativa atividade citotóxica e pró-apoptótica frente a um grande número de linhagens celulares (KONSTANTINOV et al,1998; VAN BLITTERSWIJK, VERHEIJ, 2013). Além disso, elas não são mielotóxicas e podem estimular a hematopoese normal (BAGLEY et al, 2011;GEORGIEVA et al, 2002;ZAHARIEVA et al, 2007;YOSIFOV et al, 2011) o que implica que poderiam ser utilizadas em tratamentos combinados a fim de melhorar a toxicidade de agentes citotóxicos convencionais sensibilizando as células tumorais à morte celular induzida por radiação, por exemplo (RUBEL et al, 2006).…”