title: Perifosine as a potential novel anti-cancer agent inhibits EGFR/MET-AKT axis in malignant pleural mesothelioma.
abstract: BACKGROUND
  PI3K/AKT signalling pathway is aberrantly active and plays a critical role for cell cycle progression of human malignant pleural mesothelioma (MMe) cells. AKT is one of the important cellular targets of perifosine, a novel bio-available alkylphospholipid that has displayed significant anti-proliferative activity in vitro and in vivo in several human tumour model systems and is currently being tested in clinical trials.
  
  
  METHODS
  We tested Perifosine activity on human mesothelial cells and different mesothelioma cell lines, in order to provide evidence of its efficacy as single agent and combined therapy.
  
  
  RESULTS
  We demonstrate here that perifosine, currently being evaluated as an anti-cancer agent in phase 1 and 2 clinical trials, caused a dose-dependent reduction of AKT activation, at concentrations causing MMe cell growth arrest. In this study we firstly describe that MMe cells express aside from AKT1 also AKT3 and that either the myristoylated, constitutively active, forms of the two proteins, abrogated perifosine-mediated cell growth inhibition. Moreover, we describe here a novel mechanism of perifosine that interferes, upstream of AKT, affecting EGFR and MET phosphorylation. Finally, we demonstrate a significant increase in cell toxicity when MMe cells were treated with perifosine in combination with cisplatin.
  
  
  CONCLUSIONS
  This study provides a novel mechanism of action of perifosine, directly inhibiting EGFR/MET-AKT1/3 axis, providing a rationale for a novel translational approach to the treatment of MMe.
authors.affiliation: Department of Pharmaceutical Sciences and Drug and Food Biotechnology Center, University of Piemonte Orientale A. Avogadro, Novara, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Pinton
authors.forename: Arcangela Gabriella
authors.initials: AG
authors.lastname: Manente
authors.forename: Giovanni
authors.initials: G
authors.lastname: Angeli
authors.forename: Luciano
authors.initials: L
authors.lastname: Mutti
authors.forename: Laura
authors.initials: L
authors.lastname: Moro
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D008654:Mesothelioma / Q000188:drug therapy* / Q000201:enzymology; D010766:Phosphorylation / Q000187:drug effects; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D010767:Phosphorylcholine; C105905:perifosine; C512478:EGFR protein, human; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; C494918:AKT1 protein, human; C491754:AKT3 protein, human; D051057:Proto-Oncogene Proteins c-akt; D002945:Cisplatin