The histone-deacetylase inhibitor SAHA potentiates proapoptotic effects of 5-fluorouracil and irinotecan in hepatoma cells.

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 microM) led to a moderate increase in apoptosis and proliferation inhibition. Adding 1 microM 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.

• Authors: Matthias Ocker, Abdullah Alajati, Marion Ganslmayer, Steffen Zopf, Mike Lüders, Daniel Neureiter, Eckhart G Hahn, Detlef Schuppan, Christoph Herold
• Journal: Journal of cancer research and clinical oncology (J Cancer Res Clin Oncol) Vol. 131 Issue 6 Pg. 385-94 (Jun 2005) ISSN: 0171-5216 [Print] Germany
• PMID: 15754201 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• Proto-Oncogene Proteins c-bcl-2
• Vorinostat
• Irinotecan
• CASP3 protein, human
• CASP8 protein, human
• Caspase 3
• Caspase 8
• Caspases
• Fluorouracil
• Camptothecin

Topics

• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Apoptosis (drug effects)
• Camptothecin (administration & dosage, analogs & derivatives)
• Carcinoma, Hepatocellular (drug therapy, metabolism, pathology)
• Caspase 3
• Caspase 8
• Caspases (metabolism)
• Down-Regulation
• Drug Synergism
• Enzyme Activation (drug effects)
• Enzyme Inhibitors (pharmacology)
• Fibroblasts (cytology, drug effects, metabolism)
• Fluorouracil (administration & dosage)
• Histone Deacetylase Inhibitors
• Humans
• Hydroxamic Acids (pharmacology)
• Irinotecan
• Liver Neoplasms (drug therapy, metabolism, pathology)
• Membrane Potentials (drug effects)
• Mitochondria (drug effects, metabolism)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Skin (cytology, drug effects, metabolism)
• Tumor Cells, Cultured
• Vorinostat