A quadruple therapy synergistically blocks proliferation and promotes apoptosis of hepatoma cells.
Oncol Rep
; 11(5): 943-50, 2004 May.
Article
em En
| MEDLINE
| ID: mdl-15069530
ABSTRACT
Effective therapy for advanced hepatocellular carcinoma (HCC) is lacking. Conventional chemotherapy was judged to be ineffective. We previously demonstrated that the histone deacetylase inhibitor Trichostatin A (TSA) blocks growth of HCC cells in vitro. The anti-tumoral effect of a combination of more than 2 classes of drugs remains unexplored. Four hepatoma cell lines were incubated with increasing concentrations of Tamoxifen (TAM), 9-cis retinoic acid (CRA), the methioninaminopeptidase inhibitor TNP-470 and TSA as single agents and in combination. Anti-proliferative and pro-apoptotic effects were assessed using BrdU-incorporation, FACS analysis and immunocytochemistry. Central pro- and anti-apoptotic proteins were measured by semi-quantitative Western blotting and substrate assays. All single substances inhibited proliferation and induced apoptosis in HCC cells only at high concentrations. The combination of TAM/CRA/TNP/TSA multiplied the anti-tumoral effects, reaching up to 93% inhibition of proliferation and 63% induction of apoptosis after 24 h in Hep1B cells. Pro-apoptotic factors bax and caspase 3 were highly increased with quadruple therapy, while anti-apoptotic bcl-2 decreased to undetectable levels. Fibroblasts remained largely unaffected. While the single substances were not effective on hepatoma cells in tolerable doses, their combination significantly increases anti-tumoral efficacy. Combination therapy with biomodulators is a promising treatment option for HCC.
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Base de dados:
MEDLINE
Assunto principal:
Sesquiterpenos
/
Tamoxifeno
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Tretinoína
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Divisão Celular
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Apoptose
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Carcinoma Hepatocelular
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Ácidos Hidroxâmicos
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2004
Tipo de documento:
Article