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
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
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