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  • 1
    Keywords: APOPTOSIS ; GROWTH ; AGENTS ; PATHWAY ; LINES ; EFFICACY ; BONE-MARROW-CELLS ; PERIFOSINE ; Hexadecylphosphocholine ; ALKYLPHOSPHOCHOLINE DERIVATIVES
    Abstract: PURPOSE: This study investigated the antineoplastic effect of the membrane active alkylphosphocholine erufosine in breast carcinoma models in vitro and in vivo and determined its influence on the PI3K/Akt and Ras/Raf/MAPK signaling pathways. METHODS: The antiproliferative effect of erufosine in vitro was determined by the MTT dye reduction assay, and the antineoplastic efficacy on tumor growth was investigated by relating the mean total tumor volumes of treated and control rats. Immunoblot analysis was used for detecting changes in the expression level of the signal molecules p-PI3K (p-p85), p-Akt at Thr 308 and p-cRaf. RESULTS: Based on their IC(50) (40 muM, respectively), the breast carcinoma cell lines MCF-7 and MDA-MB 231, which are estrogen receptor positive and negative, respectively, were equally sensitive to erufosine. In addition, erufosine caused dose-dependent decreases in the phosphorylation of PI3K (p85), Akt (PKB) at Thr 308 and cRaf in both cell lines. Moreover, administration of erufosine to rats bearing autochthonous methylnitrosourea-induced rat mammary carcinomas caused a significant dose-related tumor remission by more than 85 % (p 〈 0.05), which was well tolerated, as evidenced by a body weight loss of maximally 7 % and reduced tumor-related mortality (2 of 35 instead of 6 of 18 controls, p 〈 0.002). CONCLUSIONS: The results clearly indicate that erufosine possesses high antineoplastic activity not only in human breast cancer cell lines in vitro but also in rat mammary carcinoma in vivo. In addition, it can be derived that the mechanism of action of erufosine involves influence on both, PI3K/Akt and Ras/Raf/MAPK signaling pathways.
    Type of Publication: Journal article published
    PubMed ID: 22752602
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  • 2
    Keywords: IN-VITRO ; INDUCED APOPTOSIS ; CELL-CYCLE CONTROL ; DNA-DAMAGE ; MAMMALIAN-CELLS ; ABL TYROSINE KINASE ; TUMOR-SUPPRESSOR ; HUMAN CANCER ; ACUTE MYELOID-LEUKEMIA ; C-ABL
    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 erufosine 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.
    Type of Publication: Journal article published
    PubMed ID: 24987858
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  • 3
    Keywords: CANCER ; TUMOR-CELLS ; ACUTE MYELOGENOUS LEUKEMIA ; AGENT ; TRANSLATION INITIATION ; ERUCYLPHOSPHOCHOLINE-INDUCED APOPTOSIS ; AUTOPHAGY ; ANTINEOPLASTIC ACTIVITY ; erufosine ; Alkylphosphocholine ; ERUCYLPHOSPHOHOMOCHOLINE ; LINES IN-VITRO ; mTOR signaling cascade ; Oral squamous cell cancer
    Abstract: We investigated the anticancer activity of erufosine in oral squamous carcinoma cell lines in terms of cell proliferation, colony formation, induction of autophagy/apoptosis, cell cycle and mTOR signaling pathway. Erufosine showed dose-dependent cytotoxicity in all cell lines, it induced autophagy as well as apoptosis, G2 cell cycle arrest and modulation of cyclin D1 expression. Further erufosine downregulated the phosphorylation of major components of mTOR pathway, like p-Akt at Ser473 and Thr308 residues, p-Raptor, p-mTOR, p-PRAS40 and its downstream substrates p-p70S6K and p-4EBP1 in a dose-dependent manner. The pre-treatment of tumor cells with p-mTOR siRNA increased cytotoxic effects of erufosine comparable to cisplatin but higher than rapamycin.
    Type of Publication: Journal article published
    PubMed ID: 22202640
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  • 4
    Keywords: APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; IN-VITRO ; TUMOR-CELLS ; TOXICITY ; ACTIVATION ; COMPLEX ; COMPLEXES ; MECHANISM ; mechanisms ; FORM ; ASSAY ; CELL-DEATH ; ALKYLPHOSPHOCHOLINES ; ANTILEUKEMIC EFFICACY ; chemotherapy ; LIPID RAFTS ; cell lines ; N-TERMINAL KINASE ; CYTOTOXICITY ; cord blood ; multiple myeloma ; ONCOLOGY ; interaction ; erufosine ; MULTIPLE-MYELOMA CELLS ; HUMAN LEUKEMIC-CELLS ; ANTICANCER ALKYLPHOSPHOLIPIDS ; Antimigratory activity ; Haematopoietic progenitors ; SELECTIVE APOPTOSIS
    Abstract: PURPOSE: 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.
    Type of Publication: Journal article published
    PubMed ID: 20177898
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