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

• Published in: Journal of cancer research and clinical oncology 2005-06, Vol.131 (6), p.385-394
• Main Authors: OCKER, Matthias, ALAJATI, Abdullah, GANSLMAYER, Marion, ZOPF, Steffen, LUDERS, Mike, NEUREITER, Daniel, HAHN, Eckhart G, SCHUPPAN, Detlef, HEROLD, Christoph
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis - drug effects; Biological and medical sciences; Camptothecin - administration & dosage; Camptothecin - analogs & derivatives; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Caspase 3; Caspase 8; Caspases - metabolism; Cell culture; Chemotherapy; Colorectal cancer; Down-Regulation; Drug Synergism; Enzyme Activation - drug effects; Enzyme Inhibitors - pharmacology; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - metabolism; Fluorouracil - administration & dosage; Gastroenterology. Liver. Pancreas. Abdomen; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids - pharmacology; Liver Neoplasms - drug therapy; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; Membrane Potentials - drug effects; Mitochondria - drug effects; Mitochondria - metabolism; Oncology; Pharmacology. Drug treatments; Proto-Oncogene Proteins c-bcl-2 - metabolism; Skin - cytology; Skin - drug effects; Skin - metabolism; Tumor Cells, Cultured; Tumors
• ISSN: 0171-5216; 1432-1335
• DOI: 10.1007/s00432-004-0664-6

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.