Differential immunotoxicity of histone deacetylase inhibitors on malignant and naïve hepatocytes.
Histone deacetylases (HD) represent a novel target in cancer treatment, particularly for scattered small tumours such as the hepatocellular carcinoma (HCC). However, only few studies address the toxicological impact of HD Inhibitors (HDIs) on malignantly transformed cells versus primary hepatocytes. We examined whether and how different classes of HDIs sensitise the human HCC cell line HepG2, primary healthy murine and human liver cells towards the death receptor agonists TNFα and CD95L. Apicidin, M344 (N-hydroxy-7-(-4-dimethylaminobenzol)aminoheptanamide), CBHA (m-carboxycinnamic acid bis-hydroxamide) and VPA (valproic acid) sensitised liver cell cultures towards CD95-triggered apoptosis with the following potency: apicidin > M344 ≈ CBHA ≫ VPA. Apicidin sensitised towards CD95 also in the intact organ, i.e. in the isolated perfused mouse liver. No significant sensitisation towards TNFα was found in vitro. Western blot analysis showed that all HDIs studied downregulated the anti-apoptotic protein cFLIP, but only VPA additionally affected the expression level of XIAP. Furthermore, in models of the intrinsic apoptosis pathway, i.e. in HepG2 cells treated with Melphalan and in primary hepatocytes irradiated with UV light, only VPA exhibited significant sensitisation. These findings extend the biochemical, pharmacological and toxicological basis for HDI therapy and provide a caveat for clinical use in patients with an accompanying critical inflammatory state in which the CD95 system might be pre-activated.
Biochemical Pharmacology, Faculty of Biology, University of Konstanz, M668, D-78457 Konstanz, Germany.
Markus
M
Weiller
Timo
T
Weiland
Georg
G
Dünstl
Ulrike
U
Sack
Gerald
G
Künstle
Albrecht
A
Wendel
D000818:Animals; D000970:Antineoplastic Agents / Q000276:immunology* / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D018929:Cell Culture Techniques; D002470:Cell Survival / Q000187:drug effects; D053222:Fas Ligand Protein / Q000276:immunology / Q000378:metabolism; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D056572:Histone Deacetylase Inhibitors / Q000276:immunology* / Q000633:toxicity*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D010477:Perfusion; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
D000970:Antineoplastic Agents; D053222:Fas Ligand Protein; D056572:Histone Deacetylase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D053148:Caspase 3; D053179:Caspase 7; D053181:Caspase 8; D006655:Histone Deacetylases