Abstract
BackgroundFlavaglines 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 FindingsAmong 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/SignificanceOur 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.
Highlights
Cyclopenta[b]benzofuran flavaglines are inhibitors of translation initiation isolated from Asian plants of the genus Aglaia of the family Meliacae [1,2,3,4]
Translation initiation is regulated by eIF4F at the level of the ribosome recruitment step. eIF4F is composed of three subunits: eIF4E, which binds to the cap structure present at the 59 end of mRNAs; eIF4A, a DEAD-box RNA helicase implicated in preparing a ribosome landing pad for 43S pre-initiation complexes (40S ribosomal subunit and associated factors) by unwinding 59
To determine how extensive this property is among flavaglines, we tested members of the cyclopenta[b]benzofurans, cyclopent[bc]benzopyrans, and benzo[b]oxepines family for their potential to inhibit protein synthesis
Summary
Cyclopenta[b]benzofuran flavaglines are inhibitors of translation initiation isolated from Asian plants of the genus Aglaia of the family Meliacae [1,2,3,4] These compounds show in vitro activity against tumor cell lines [1,2], promising activity in xenograft cancer models [2,5,6] and appear to block G2/M cell cycle progression [7]. 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. Silvestrol, is capable of modulating chemosensitivity in a mechanism-based mouse model
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