Antitumor activity and mechanism of action of the cyclopenta[b]benzofuran, silvestrol.
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.
Cencic
Regina
R
Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
Carrier
Marilyn
M
Galicia-Vázquez
Gabriela
G
Bordeleau
Marie-Eve
ME
Sukarieh
Rami
R
Bourdeau
Annie
A
Brem
Brigitte
B
Teodoro
Jose G
JG
Greger
Harald
H
Tremblay
Michel L
ML
Porco
John A
JA
Pelletier
Jerry
J
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
D000972:Antineoplastic Agents, Phytogenic; D039561:Eukaryotic Initiation Factor-4E; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D014315:Triterpenes; C489897:silvestrol; D001572:Benzofurans