Abstract | BACKGROUND & AIMS: 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.
|
Authors | Takayuki Kogure, A Douglas Kinghorn, Irene Yan, Brad Bolon, David M Lucas, Michael R Grever, Tushar Patel |
Journal | PloS one
(PLoS One)
Vol. 8
Issue 9
Pg. e76136
( 2013)
ISSN: 1932-6203 [Electronic] United States |
PMID | 24086701
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
|
Chemical References |
- Phenylurea Compounds
- Triterpenes
- silvestrol
- Niacinamide
- Sorafenib
- Eukaryotic Initiation Factor-4A
- Caspase 3
- Caspase 7
- Sirolimus
|
Topics |
- 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, pharmacology)
- Peptide Chain Initiation, Translational
(drug effects)
- Phenylurea Compounds
(pharmacology)
- Sirolimus
(pharmacology)
- Sorafenib
- Survival Analysis
- Triterpenes
(pharmacology, therapeutic use)
- Xenograft Model Antitumor Assays
|