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dc.contributor.authorCencic, Reginaen_US
dc.contributor.authorCarrier, Marilynen_US
dc.contributor.authorGalicia-Vázquez, Gabrielaen_US
dc.contributor.authorBordeleau, Marie-Eveen_US
dc.contributor.authorSukarieh, Ramien_US
dc.contributor.authorBourdeau, Annieen_US
dc.contributor.authorBrem, Brigitteen_US
dc.contributor.authorTeodoro, Jose G.en_US
dc.contributor.authorGreger, Haralden_US
dc.contributor.authorTremblay, Michel L.en_US
dc.contributor.authorPorco, John A.en_US
dc.contributor.authorPelletier, Jerryen_US
dc.date.accessioned2012-01-11T23:24:28Z
dc.date.available2012-01-11T23:24:28Z
dc.date.issued2009-4-29en_US
dc.identifier.citationCencic, Regina, Marilyn Carrier, Gabriela Galicia-Vázquez, Marie-Eve Bordeleau, Rami Sukarieh, Annie Bourdeau, Brigitte Brem, Jose G. Teodoro, Harald Greger, Michel L. Tremblay, John A. Porco, Jerry Pelletier. "Antitumor Activity and Mechanism of Action of the Cyclopenta[b]benzofuran, Silvestrol" PLoS ONE 4(4): e5223. (2009)en_US
dc.identifier.issn1932-6203en_US
dc.identifier.urihttp://hdl.handle.net/2144/3348
dc.description.abstractBACKGROUND. Flavaglines are a family of natural products from the genus Aglaia that exhibit anti-cancer activity in vitro and in vivo and inhibit translation initiation. They have been shown to modulate the activity of eIF4A, the DEAD-box RNA helicase subunit of the eukaryotic initiation factor (eIF) 4F complex, a complex that stimulates ribosome recruitment during translation initiation. One flavagline, silvestrol, is capable of modulating chemosensitivity in a mechanism-based mouse model. METHODOLOGY/PRINCIPAL FINDINGS. Among a number of flavagline family members tested herein, we find that silvestrol is the more potent translation inhibitor among these. We find that silvestrol impairs the ribosome recruitment step of translation initiation by affecting the composition of the eukaryotic initiation factor (eIF) 4F complex. We show that silvestrol exhibits significant anticancer activity in human breast and prostate cancer xenograft models, and that this is associated with increased apoptosis, decreased proliferation, and inhibition of angiogenesis. We demonstrate that targeting translation by silvestrol results in preferential inhibition of weakly initiating mRNAs. CONCLUSIONS/SIGNIFICANCE. Our results indicate that silvestrol is a potent anti-cancer compound in vivo that exerts its activity by affecting survival pathways as well as angiogenesis. We propose that silvestrol mediates its effects by preferentially inhibiting translation of malignancy-related mRNAs. Silvestrol appears to be well tolerated in animals.en_US
dc.description.sponsorshipCanadian Institutes of Health Research (16512, Cancer Consortium Training Grant Award, CancerConsortium Training Grant Award); US Lymphoma Foundation Award; National Institute of Health (RO1 GM073855); National Crime Information Center (017099); Cole Foundation Awarden_US
dc.language.isoenen_US
dc.publisherPublic Library of Scienceen_US
dc.titleAntitumor Activity and Mechanism of Action of the Cyclopenta[b]benzofuran, Silvestrolen_US
dc.typearticleen_US
dc.identifier.doi10.1371/journal.pone.0005223en_US
dc.identifier.pubmedid19401772en_US
dc.identifier.pmcid2671147en_US


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