title: Antitumor activity and mechanism of action of the cyclopenta[b]benzofuran, silvestrol.
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.
  
  
  RESULTS
  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
  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.
authors.affiliation: Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
authors.forename: Regina
authors.initials: R
authors.lastname: Cencic
authors.forename: Marilyn
authors.initials: M
authors.lastname: Carrier
authors.forename: Gabriela
authors.initials: G
authors.lastname: Galicia-Vázquez
authors.forename: Marie-Eve
authors.initials: ME
authors.lastname: Bordeleau
authors.forename: Rami
authors.initials: R
authors.lastname: Sukarieh
authors.forename: Annie
authors.initials: A
authors.lastname: Bourdeau
authors.forename: Brigitte
authors.initials: B
authors.lastname: Brem
authors.forename: Jose G
authors.initials: JG
authors.lastname: Teodoro
authors.forename: Harald
authors.initials: H
authors.lastname: Greger
authors.forename: Michel L
authors.initials: ML
authors.lastname: Tremblay
authors.forename: John A
authors.initials: JA
authors.lastname: Porco
authors.forename: Jerry
authors.initials: J
authors.lastname: Pelletier
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D001483:Base Sequence; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D014176:Protein Biosynthesis / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology*; D001572:Benzofurans
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D039561:Eukaryotic Initiation Factor-4E; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D014315:Triterpenes; C489897:silvestrol; D001572:Benzofurans