Antitumor Activity and Mechanism of Action of the Cyclopenta[b]benzofuran, Silvestrol 英文参考文献.docVIP

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Antitumor Activity and Mechanism of Action of the Cyclopenta[b]benzofuran, Silvestrol 英文参考文献.doc

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Antitumor Activity and Mechanism of Action of the Cyclopenta[b]benzofuran, Silvestrol 英文参考文献

AntitumorActivityandMechanismofActionofthe Cyclopenta[b]benzofuran,Silvestrol ReginaCencic1,MarilynCarrier1,GabrielaGalicia-Va′zquez1,Marie-EveBordeleau1,RamiSukarieh1, AnnieBourdeau2,BrigitteBrem4,JoseG.Teodoro1,3,HaraldGreger4,MichelL.Tremblay1,3,JohnA. Porco,Jr.5,JerryPelletier1,3* 1Department of Biochemistry, McGill University, Montreal, Quebec, Canada, 2Sunnybrook Health Sciences Centreand the Department ofImmunology, University of Toronto, Toronto, Ontario, Canada, 3Goodman Cancer Center, McGill University, Montreal, Quebec, Canada, 4Comparative Phytochemistry Department, Institute of Botany, University of Vienna, Vienna, Austria, 5Department of Chemistry, Center for Chemical Methodology and Library Development, Boston University, Boston, Massachusetts,UnitedStatesofAmerica Abstract Background:FlavaglinesareafamilyofnaturalproductsfromthegenusAglaiathatexhibitanti-canceractivityinvitroandin vivoandinhibittranslationinitiation.TheyhavebeenshowntomodulatetheactivityofeIF4A,theDEAD-boxRNAhelicase subunitoftheeukaryoticinitiationfactor(eIF)4Fcomplex,acomplexthatstimulatesribosomerecruitmentduringtranslation initiation.Oneflavagline,silvestrol,iscapableofmodulatingchemosensitivityinamechanism-basedmousemodel. Methodology/PrincipalFindings:Amonganumberofflavaglinefamilymemberstestedherein,wefindthatsilvestrolisthe morepotenttranslationinhibitoramongthese.Wefindthatsilvestrolimpairstheribosomerecruitmentstepoftranslation initiationbyaffectingthecompositionoftheeukaryoticinitiationfactor(eIF)4Fcomplex.Weshowthatsilvestrolexhibits significant anticancer activity in human breast and prostate cancer xenograft models, and that this is associated with increasedapoptosis,decreasedproliferation,andinhibitionofangiogenesis.Wedemonstratethattargetingtranslationby silvestrolresultsinpreferentialinhibitionofweaklyinitiatingmRNAs. Conclusions/Significance:Ourresultsindicatethatsilvestrolisapotentanti-cancercompoundinvivothatexertsitsactivity by affecting survival pathways as we