Perifosine as a Potential Novel Anti-Cancer Agent Inhibits EGFRMET-AKT Axis in Malignant Pleural Mesothelioma 英文参考文献.docVIP

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Perifosine as a Potential Novel Anti-Cancer Agent Inhibits EGFRMET-AKT Axis in Malignant Pleural Mesothelioma 英文参考文献.doc

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Perifosine as a Potential Novel Anti-Cancer Agent Inhibits EGFRMET-AKT Axis in Malignant Pleural Mesothelioma 英文参考文献

PerifosineasaPotentialNovelAnti-CancerAgent InhibitsEGFR/MET-AKTAxisinMalignantPleural Mesothelioma GiuliaPinton1,ArcangelaGabriellaManente1,GiovanniAngeli2,LucianoMutti3.,LauraMoro1*. 1DepartmentofPharmaceuticalSciencesandDrugandFoodBiotechnologyCenter,UniversityofPiemonteOrientaleA.Avogadro,Novara,Italy,2ServiceofPathology, VercelliHospital,Vercelli,Italy,3DepartmentofMedicine,VercelliHospital,Vercelli,Italy Abstract Background:PI3K/AKTsignallingpathwayisaberrantlyactiveandplaysacriticalroleforcellcycleprogressionofhuman 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 tumourmodelsystemsandiscurrentlybeingtestedinclinicaltrials. Methods:WetestedPerifosineactivityonhumanmesothelialcellsanddifferentmesotheliomacelllines,inordertoprovide evidenceofitsefficacyassingleagentandcombinedtherapy. Results:Wedemonstrateherethatperifosine,currentlybeingevaluatedasananti-canceragentinphase1and2clinical trials,causedadose-dependentreductionofAKTactivation,atconcentrationscausingMMecellgrowtharrest.Inthisstudy wefirstlydescribethatMMecellsexpressasidefromAKT1alsoAKT3andthateitherthemyristoylated,constitutivelyactive, forms of the two proteins, abrogated perifosine-mediated cell growth inhibition. Moreover, we describe here a novel mechanismofperifosinethatinterferes,upstreamofAKT,affectingEGFRandMETphosphorylation.Finally,wedemonstrate asignificantincreaseincelltoxicitywhenMMecellsweretreatedwithperifosineincombinationwithcisplatin. Conclusions: This study provides a novel mechanism of action of perifosine, directly inhibiting EGFR/MET-AKT1/3 axis, providingarationaleforanoveltranslationalapproachtothetreatmentofMMe. Citation:PintonG,ManenteAG,AngeliG,MuttiL,MoroL(2012)PerifosineasaPotentialNovelAnti-CancerAgentInhibitsEGFR/MET-AKTAxisinMalignant PleuralMesothelioma.PLoSONE7(5):e36856.do