Journal Article

Antitumor Activity and Mechanism of Action of the Cyclopentabbenzofuran, Silvestrol

Galicia-Vázquez, Gabriela, Porco, John A., Bordeleau, Marie-Eve, Pelletier, Jerry, Greger, Harald, Sukarieh, Rami, Tremblay, Michel L., Carrier, Marilyn, Teodoro, Jose G., Brem, Brigitte, Cencic, Regina, Bourdeau, Annie

2009

Overview

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. 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. 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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Angiogenesis / Animal models / Animals / Anticancer properties / Antineoplastic Agents, Phytogenic - chemistry / Antineoplastic Agents, Phytogenic - pharmacology / Antitumor activity / Apoptosis / Base Sequence / Benzofuran / Biochemistry / Breast cancer / Breast Neoplasms - drug therapy / Breast Neoplasms - genetics / Breast Neoplasms - pathology / Cancer / Cell cycle / Cell Line, Tumor / Cells, Cultured / Chemical Biology/Chemical Biology of the Cell / Cytotoxicity / DNA helicase / Drug dosages / Enzymes / Eukaryotic Initiation Factor-4E - metabolism / Female / Genetic translation / Humans / Inhibition / Initiation factor eIF-4A / Intellectual disabilities / Male / Malignancy / Mice / Mice, Nude / Molecular Biology/Translation Mechanisms / Molecular Biology/Translational Regulation / Natural products / Neoplasm Transplantation / Neovascularization, Pathologic - prevention & control / Phosphorylation / Prostate cancer / Prostatic Neoplasms - drug therapy / Prostatic Neoplasms - genetics / Prostatic Neoplasms - pathology / Protein Biosynthesis - drug effects / Protein synthesis / Proteins / Recruitment / Ribonucleic acid / RNA / RNA helicase / RNA, Messenger - genetics / RNA, Messenger - metabolism / RNA, Neoplasm - genetics / RNA, Neoplasm - metabolism / Translation initiation / Transplantation, Heterologous / Triterpenes - chemistry / Triterpenes - pharmacology / Xenografts