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Erufosine suppresses breast cancer in vitro and in vivo for its activity on PI3K, c-Raf and Akt proteins

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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 IC50 (40 μM, 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.

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Acknowledgments

This study was supported by grants from the DAAD foundation for Ilina K. Dineva and the Alexander von Humboldt foundation for Maya M. Zaharieva.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Toxicology and Chemotherapy Unit, German Cancer Research Center, INF 581, 69120, Heidelberg, Germany

    Ilina K. Dineva, Maya M. Zaharieva & Martin R. Berger

  2. Laboratory for Molecular Pharmacology and Experimental Chemotherapy, Department for Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University of Sofia, Sofia, Bulgaria

    Ilina K. Dineva & Spiro M. Konstantinov

  3. Max Planck Institute of Biophysical Chemistry, Göttingen, Germany

    Hansjörg Eibl

Authors
  1. Ilina K. Dineva
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  2. Maya M. Zaharieva
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  3. Spiro M. Konstantinov
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  4. Hansjörg Eibl
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  5. Martin R. Berger
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Corresponding author

Correspondence to Martin R. Berger.

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Dineva, I.K., Zaharieva, M.M., Konstantinov, S.M. et al. Erufosine suppresses breast cancer in vitro and in vivo for its activity on PI3K, c-Raf and Akt proteins. J Cancer Res Clin Oncol 138, 1909–1917 (2012). https://doi.org/10.1007/s00432-012-1271-6

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  • DOI: https://doi.org/10.1007/s00432-012-1271-6

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