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Differential immunotoxicity of histone deacetylase inhibitors on malignant and naïve hepatocytes

Differential immunotoxicity of histone deacetylase inhibitors on malignant and naïve hepatocytes

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WEILLER, Markus, Timo WEILAND, Georg DÜNSTL, Ulrike SACK, Gerald KÜNSTLE, Albrecht WENDEL, 2011. Differential immunotoxicity of histone deacetylase inhibitors on malignant and naïve hepatocytes. In: Experimental and Toxicologic Pathology. Elsevier. 63(5), pp. 511-517. ISSN 0940-2993. eISSN 1618-1433. Available under: doi: 10.1016/j.etp.2010.04.001

@article{Weiller2011-07Diffe-51120, title={Differential immunotoxicity of histone deacetylase inhibitors on malignant and naïve hepatocytes}, year={2011}, doi={10.1016/j.etp.2010.04.001}, number={5}, volume={63}, issn={0940-2993}, journal={Experimental and Toxicologic Pathology}, pages={511--517}, author={Weiller, Markus and Weiland, Timo and Dünstl, Georg and Sack, Ulrike and Künstle, Gerald and Wendel, Albrecht} }

Weiland, Timo Weiland, Timo Weiller, Markus Dünstl, Georg 2020-09-30T06:46:25Z Differential immunotoxicity of histone deacetylase inhibitors on malignant and naïve hepatocytes Künstle, Gerald Wendel, Albrecht Wendel, Albrecht 2020-09-30T06:46:25Z 2011-07 Dünstl, Georg 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.<br /><br />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.<br /><br />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.<br /><br />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. eng Sack, Ulrike Künstle, Gerald Sack, Ulrike Weiller, Markus

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