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The histone-deacetylase inhibitor Trichostatin A blocks proliferation and triggers apoptotic programs in hepatoma cells

Lookup NU author(s): Professor Albert Geerts

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Abstract

Background/Aims: Effective treatment for hepatocellular carcinoma is urgently needed. The histone-deacetylase inhibitor Trichostatin A (TSA) was shown to induce apoptosis in non-hepatic cells at submicromolar concentrations. However, the effect of TSA on hepatoma cells is unknown. Methods: The hepatoma cells HepG2, MH1C1, Hepa1-6 and Hep1B as well as human fibroblasts (control cells) were exposed to TSA (10(-6) to 10(-9) M). Cell proliferation was assessed by measuring DNA-synthesis and cell numbers. Apoptosis was quantified by flow cytometry and by the TdT-mediated dUTP nick-end labeling method. Expression patterns of cell cycle- and/or apoptosis-associated p27, p21(cip/waf), bax, bcl-2, cyclin A and (pro)-caspase 3 were studied using quantitative Western blotting. Activation of caspase 3 was analyzed via a colorimetric assay. Results: 10(-6) M TSA inhibited DNA-synthesis by 46% (HepG2) to 64% (MH1C1) after 24 h, inducing a G(1)/M-phase arrest and apoptosis. TSA increased activation of caspase 3 and expression of cyclin A, p21(cip/waf) bax and (pro)-caspase 3, while bcl-2 was downregulated. Human fibroblasts remained unaffected. Conclusions: TSA inhibits hepatoma cell growth in vitro, which are otherwise particularly resistant to chemotherapy. Its anti-proliferative activity is paralleled by a comparable rate of apoptosis. TSA may be a promising agent for treatment of hepatocellular carcinoma in vivo. (C) 2002 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved.

Publication metadata

Author(s): Herold C, Ganslmayer M, Ocker M, Hermann M, Geerts A, Hahn EG, Schuppan D

Publication type: Article

Publication status: Published

Journal: Journal of Hepatology

Year: 2002

Volume: 36

Issue: 2

Pages: 233-240

ISSN (print): 0168-8278

ISSN (electronic): 1600-0641

Publisher: Elsevier BV

URL: http://dx.doi.org/10.1016/S0168-8278(01)00257-4

DOI: 10.1016/S0168-8278(01)00257-4

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