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Antitumor Activity and Mechanism of Action of the Cyclopenta[b]benzofuran, Silvestrol

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dc.contributor.author Cencic, Regina en_US
dc.contributor.author Carrier, Marilyn en_US
dc.contributor.author Galicia-Vázquez, Gabriela en_US
dc.contributor.author Bordeleau, Marie-Eve en_US
dc.contributor.author Sukarieh, Rami en_US
dc.contributor.author Bourdeau, Annie en_US
dc.contributor.author Brem, Brigitte en_US
dc.contributor.author Teodoro, Jose G. en_US
dc.contributor.author Greger, Harald en_US
dc.contributor.author Tremblay, Michel L. en_US
dc.contributor.author Porco, John A. en_US
dc.contributor.author Pelletier, Jerry en_US
dc.date.accessioned 2012-01-11T23:24:28Z
dc.date.available 2012-01-11T23:24:28Z
dc.date.issued 2009-4-29 en_US
dc.identifier.citation Cencic, 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.issn 1932-6203 en_US
dc.identifier.uri http://hdl.handle.net/2144/3348
dc.description.abstract BACKGROUND. 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.sponsorship Canadian 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 Award en_US
dc.language.iso en en_US
dc.publisher Public Library of Science en_US
dc.title Antitumor Activity and Mechanism of Action of the Cyclopenta[b]benzofuran, Silvestrol en_US
dc.type article en_US
dc.identifier.doi 10.1371/journal.pone.0005223 en_US
dc.identifier.pubmedid 19401772 en_US
dc.identifier.pmcid 2671147 en_US


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