title: Erufosine suppresses breast cancer in vitro and in vivo for its activity on PI3K, c-Raf and Akt proteins.
abstract: OBJECTIVE
  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 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.
authors: Toxicology and Chemotherapy Unit, German Cancer Research Center, INF 581, 69120 Heidelberg, Germany.
authors: Ilina K
authors: IK
authors: Dineva
authors: Maya M
authors: MM
authors: Zaharieva
authors: Spiro M
authors: SM
authors: Konstantinov
authors: Hansjörg
authors: H
authors: Eibl
authors: Martin R
authors: MR
authors: Berger
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D015151:Immunoblotting; D061986:MCF-7 Cells; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D008770:Methylnitrosourea; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D015394:Molecular Structure; D010755:Organophosphates / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D000644:Quaternary Ammonium Compounds / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D015431:Weight Loss / Q000187:drug effects; D018631:ras Proteins / Q000378:metabolism
chemical_list: D010755:Organophosphates; D000644:Quaternary Ammonium Compounds; C472787:erucylphospho-N,N,N-trimethylpropylammonium; D008770:Methylnitrosourea; D058543:Class Ia Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D019908:Proto-Oncogene Proteins c-raf; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins