Therapeutic potential of the translation inhibitor silvestrol in hepatocellular cancer

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 sy...

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Bibliographic Details
Published in:PloS one 2013-09, Vol.8 (9), p.e76136
Main Authors: Kogure, Takayuki, Kinghorn, A Douglas, Yan, Irene, Bolon, Brad, Lucas, David M, Grever, Michael R, Patel, Tushar
Format: Article
Language:English
Subjects:
Analysis of Variance
Animals
Anticancer properties
Antitumor activity
Apoptosis
Apoptosis - drug effects
Bcl-x protein
Biology
Blotting, Western
Cancer
Cancer therapies
Caspase
Caspase 3 - metabolism
Caspase 7 - metabolism
Caspase-3
Cell Line, Tumor
Cell Proliferation - drug effects
Chemical compounds
Departments
Dose-Response Relationship, Drug
Drug Synergism
Enzymes
Eukaryotic Initiation Factor-4A - metabolism
Fibrosis
Humans
Inhibitory Concentration 50
Internal medicine
Leukemia
Liver
Liver cancer
Liver Neoplasms - drug therapy
Lymphoma
Mcl-1 protein
Medicine
Membrane potential
Membrane Potential, Mitochondrial - drug effects
Mice
Mice, Nude
Microscopy
Mitochondria
Niacinamide - analogs & derivatives
Niacinamide - pharmacology
Peptide Chain Initiation, Translational - drug effects
Pharmaceutical sciences
Pharmacology
Pharmacy
Phenylurea Compounds - pharmacology
Protein biosynthesis
Protein synthesis
Proteins
Rapamycin
Sirolimus - pharmacology
Survival
Survival Analysis
Synergistic effect
Translation
Translation initiation
Triterpenes - pharmacology
Triterpenes - therapeutic use
Xenograft Model Antitumor Assays
Xenografts
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Summary: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. 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. 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. 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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0076136