title: 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.affiliation: Department of Medicine I, University of Erlangen-Nuernberg, Ulmenweg 18, 91054, Erlangen, Germany. mocker@molmed.uni-erlangen.de
authors.forename: Matthias
authors.initials: M
authors.lastname: Ocker
authors.forename: Abdullah
authors.initials: A
authors.lastname: Alajati
authors.forename: Marion
authors.initials: M
authors.lastname: Ganslmayer
authors.forename: Steffen
authors.initials: S
authors.lastname: Zopf
authors.forename: Mike
authors.initials: M
authors.lastname: Lüders
authors.forename: Daniel
authors.initials: D
authors.lastname: Neureiter
authors.forename: Eckhart G
authors.initials: EG
authors.lastname: Hahn
authors.forename: Detlef
authors.initials: D
authors.lastname: Schuppan
authors.forename: Christoph
authors.initials: C
authors.lastname: Herold
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D015536:Down-Regulation; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005472:Fluorouracil / Q000008:administration & dosage; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D000077146:Irinotecan; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000077337:Vorinostat
chemical_list: D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D019253:Proto-Oncogene Proteins c-bcl-2; D000077337:Vorinostat; D000077146:Irinotecan; C505407:CASP3 protein, human; C505530:CASP8 protein, human; D053148:Caspase 3; D053181:Caspase 8; D020169:Caspases; D005472:Fluorouracil; D002166:Camptothecin