Therapeutic Potential of the Translation Inhibitor Silvestrol in Hepatocellular Cancer

PLoS One. 2013 Sep 26;8(9):e76136. doi: 10.1371/journal.pone.0076136. eCollection 2013.

Abstract

Background & aims: Although hepatocellular cancers (HCC) frequently arise in the setting of fibrosis and a hepatic regenerative response requiring new cell growth, therapeutic strategies for these cancers have not targeted protein synthesis. Silvestrol, a rocaglate isolated from Aglaiafoveolata, can inhibit protein synthesis by modulating the initiation of translation through the eukaryotic initiation factor 4A. In this study, we evaluated the therapeutic efficacy of silvestrol for HCC.

Methods: The efficacy of silvestrol was examined using human HCC cells in vitro using an orthotopic tumor cell xenograft model in a fibrotic liver. The impact of silvestrol on the liver was assessed in vivo in wild-type mice.

Results: Silvestrol inhibited cell growth with an IC50 of 12.5-86 nM in four different HCC cell lines. In vitro, silvestrol increased apoptosis and caspase 3/7 activity accompanied by loss of mitochondrial membrane potential and decreased expression of Mcl-1 and Bcl-xL. A synergistic effect was observed when silvestrol was combined with other therapeutic agents, with a dose-reduction index of 3.42-fold with sorafenib and 1.75-fold with rapamycin at a fractional effect of 0.5. In vivo, an antitumor effect was observed with 0.4 mg/kg silvestrol compared to controls after one week, and survival of tumor-bearing mice was improved with a median survival time of 42 and 28 days in the silvestrol and control groups, respectively. The effect on survival was not observed in orthotopic xenografts in non-fibrotic livers. Silvestrol treatment in vivo did not alter liver structure.

Conclusions: These data identify silvestrol as a novel, structurally unique drug with potent anticancer activity for HCC and support the potential value of targeting initiation of translation in the treatment of HCC.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Apoptosis / drug effects
  • Blotting, Western
  • Caspase 3 / metabolism
  • Caspase 7 / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Eukaryotic Initiation Factor-4A / metabolism
  • Humans
  • Inhibitory Concentration 50
  • Liver Neoplasms / drug therapy*
  • Membrane Potential, Mitochondrial / drug effects
  • Mice
  • Mice, Nude
  • Niacinamide / analogs & derivatives
  • Niacinamide / pharmacology
  • Peptide Chain Initiation, Translational / drug effects
  • Phenylurea Compounds / pharmacology
  • Sirolimus / pharmacology
  • Sorafenib
  • Survival Analysis
  • Triterpenes / pharmacology*
  • Triterpenes / therapeutic use
  • Xenograft Model Antitumor Assays

Substances

  • Phenylurea Compounds
  • Triterpenes
  • silvestrol
  • Niacinamide
  • Sorafenib
  • Eukaryotic Initiation Factor-4A
  • Caspase 3
  • Caspase 7
  • Sirolimus