Back to Search
Start Over
The histone-deacetylase inhibitor Trichostatin A blocks proliferation and triggers apoptotic programs in hepatoma cells.
- Source :
-
Journal of hepatology [J Hepatol] 2002 Feb; Vol. 36 (2), pp. 233-40. - Publication Year :
- 2002
-
Abstract
- Background/aims: Effective treatment for hepatocellular carcinoma is urgently needed. The histone-deacetylase inhibitor Trichostatin A (TSA) was shown to induce apoptosis in non-hepatic cells at submicromolar concentrations. However, the effect of TSA on hepatoma cells is unknown.<br />Methods: The hepatoma cells HepG2, MH1C1, Hepa1-6 and Hep1B as well as human fibroblasts (control cells) were exposed to TSA (10(-6) to 10(-9)M). Cell proliferation was assessed by measuring DNA-synthesis and cell numbers. Apoptosis was quantified by flow cytometry and by the TdT-mediated dUTP nick-end labeling method. Expression patterns of cell cycle- and/or apoptosis-associated p27, p21(cip/waf), bax, bcl-2, cyclin A and (pro)-caspase 3 were studied using quantitative Western blotting. Activation of caspase 3 was analyzed via a colorimetric assay.<br />Results: 10(-6)M TSA inhibited DNA-synthesis by 46% (HepG2) to 64% (MH1C1) after 24h, inducing a G(2)/M-phase arrest and apoptosis. TSA increased activation of caspase 3 and expression of cyclin A, p2l(cip/waf), bax and (pro)-caspase 3, while bcl-2 was downregulated. Human fibroblasts remained unaffected.<br />Conclusions: TSA inhibits hepatoma cell growth in vitro, which are otherwise particularly resistant to chemotherapy. Its anti-proliferative activity is paralleled by a comparable rate of apoptosis. TSA may be a promising agent for treatment of hepatocellular carcinoma in vivo.
- Subjects :
- Apoptosis physiology
Caspase 3
Caspases metabolism
Cell Cycle Proteins metabolism
Cell Division drug effects
Cyclin-Dependent Kinase Inhibitor p21
Cyclin-Dependent Kinase Inhibitor p27
Cyclins metabolism
Dose-Response Relationship, Drug
Humans
Proto-Oncogene Proteins metabolism
Proto-Oncogene Proteins c-bcl-2 metabolism
Tumor Cells, Cultured cytology
Tumor Cells, Cultured drug effects
Tumor Cells, Cultured enzymology
Tumor Suppressor Proteins metabolism
bcl-2-Associated X Protein
Apoptosis drug effects
Carcinoma, Hepatocellular
Enzyme Inhibitors pharmacology
Histone Deacetylase Inhibitors
Hydroxamic Acids pharmacology
Liver Neoplasms
Subjects
Details
- Language :
- English
- ISSN :
- 0168-8278
- Volume :
- 36
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Journal of hepatology
- Publication Type :
- Academic Journal
- Accession number :
- 11830335
- Full Text :
- https://doi.org/10.1016/s0168-8278(01)00257-4