RAM, an RGDS Analog, Exerts Potent Anti-Melanoma Effects In Vitro and In Vivo 英文参考文献.docVIP

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RAM, an RGDS Analog, Exerts Potent Anti-Melanoma Effects In Vitro and In Vivo 英文参考文献.doc

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RAM, an RGDS Analog, Exerts Potent Anti-Melanoma Effects In Vitro and In Vivo 英文参考文献

RAM,anRGDSAnalog,ExertsPotentAnti-Melanoma EffectsInVitroandInVivo MariaSimonaAguzzi1,DanielaD’Arcangelo1,ClaudiaGiampietri2,MaurizioC.Capogrossi1 ,Antonio Facchiano1* 1Laboratorio Patologia Vascolare, Istituto Dermopatico dell’Immacolata, IDI-IRCCS, Rome, Italy, 2D.A.H.F.M.O. Section of Histology Medical Embryology, Sapienza UniversityofRome,Rome,Italy Abstract PeptidescontainingtheRGDsequenceareundercontinuousinvestigationgiventheirabilitytocontrolcelladhesionand apoptosis. Since small peptides are quickly metabolized and degraded in vivo, developing analogs resistant to serum- induced degradation is a challenging task. RGD analogs developed so far are known as molecules mostly inhibiting cell adhesion;thisfeaturemayreducecellproliferationandtumordevelopmentbutmaynotinduceregressionoftumorsor metastasesalreadyformed.Inthecurrentstudy,carriedoutinmelanomainvitroandinvivomodels,weshowthatRAM,an RGD-non-peptideAnalog-Molecule,stronglyinhibitscells adhesionontoplastic, vitronectin,fibronectin,lamininandvon WillebrandFactorwhileitdoesnotinhibitcelladhesionontocollagenIV,similarlytotheRGDStemplatepeptide.Italso stronglyinhibitsinvitrocellproliferation,migrationandDNA-synthesis,increasesmelanomacellsapoptosisandreduces survivinexpression.AllsucheffectswereobservedincollagenIVseededcells,thereforearemostlikelyindependentfrom theantiadhesiveproperties.Further,RAMismorestablethanthetemplateRGDS;infactitmaintainsitsanti-proliferation andanti-adhesioneffectsafterlongserumexposurewhileRGDSalmostcompletelylosesitseffectsuponserumexposure. In a mouse metastatic melanoma in vivo model, increasing doses of RAM significantly reduce up to about 80% lung metastasesdevelopment,whilecomparabledosesofRGDSarelesspotent.InconclusionthesedatashowthatRAMisa potentinhibitorofmelanomagrowthinvitro,stronglyreducesmelanomametastasesdevelopmentinvivoandrepresentsa novelcandidateforfurtherinvivoinvestigationsinthecancertreatmentfield. Citation:AguzziMS,D’ArcangeloD,GiampietriC,CapogrossiMC,