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

  • Matthias Ocker
  • Abdullah Alajati
  • Marion Ganslmayer
  • Steffen Zopf
  • Mike Lüders
  • Daniel Neureiter
  • Eckhart G. Hahn
  • Detlef Schuppan
  • Christoph Herold
Original Paper

DOI: 10.1007/s00432-004-0664-6

Cite this article as:
Ocker, M., Alajati, A., Ganslmayer, M. et al. J Cancer Res Clin Oncol (2005) 131: 385. doi:10.1007/s00432-004-0664-6

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.

Keywords

Hepatocellular carcinoma5FUIrinotecanSAHAHDAC

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Matthias Ocker
    • 1
  • Abdullah Alajati
    • 1
  • Marion Ganslmayer
    • 1
  • Steffen Zopf
    • 1
  • Mike Lüders
    • 1
  • Daniel Neureiter
    • 2
  • Eckhart G. Hahn
    • 1
  • Detlef Schuppan
    • 1
  • Christoph Herold
    • 1
  1. 1.Department of Medicine IUniversity of Erlangen-NuernbergGermany
  2. 2.Department of PathologyUniversity of Erlangen-NuernbergGermany