Abstract
Treatment for advanced stages of hepatocellular carcinoma (HCC) remains unsatisfactory. While 5-fluorouracil (5-FU) and irinotecan are first-line treatment options for other gastrointestinal tumors, their effect on HCCs is low. Histone-deacetylase inhibitors such as suberoylanilide hydroxamic acid (SAHA) have shown antitumoral activity at micromolar concentrations in a variety of human cancers in vitro and in vivo. Here, we investigated the effects of a combination of 5-FU, irinotecan and SAHA on growth inhibition and apoptosis induction in HCC cell lines. HepG2, Hep1B and MH-7777A hepatoma cell lines and human foreskin fibroblasts as non-transformed controls were incubated with 5-FU, irinotecan and SAHA either alone or in combination. While the single agents did not show any effects on growth of the cell lines, the combination of 5-FU and irinotecan (both 10 μM) led to a moderate increase in apoptosis and proliferation inhibition. Adding 1 μM SAHA increased the apoptosis rate in hepatoma cell lines up to 92% after 72 h, while fibroblasts showed no response (5.5% apoptosis). Induction of apoptosis was paralleled by loss of the mitochondrial transmembrane potential, downregulation of bcl-2 expression and activation of caspase 3 but not caspase 8. In summary, SAHA sensitized HCC cell lines for treatment with an otherwise ineffective combination of 5-FU and irinotecan and led to mitochondrial apoptosis induction. The use of the triple combination could optimize treatment results in vivo and needs further evaluation.
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Acknowledgements
We thank S. Kareth, S. Leitner, A. Hartl and C. Kühl for excellent technical assistance. This work was supported by grants from the ELAN Program (Fund for Research and Teaching, University Erlangen-Nuernberg) and the FUTUR Program of the Bavarian Government.
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M. Ocker and A. Alajati contributed equally to this work.
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Ocker, M., Alajati, A., Ganslmayer, M. et al. The histone-deacetylase inhibitor SAHA potentiates proapoptotic effects of 5-fluorouracil and irinotecan in hepatoma cells. J Cancer Res Clin Oncol 131, 385–394 (2005). https://doi.org/10.1007/s00432-004-0664-6
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DOI: https://doi.org/10.1007/s00432-004-0664-6