Differential Effects of Histone Deacetylase Inhibitors in Tumor and Normal Cells—What Is the Toxicological Relevance?

Abstract

Histone deacetylase (HDAC) inhibitors target key steps of tumor development: They inhibit proliferation, induce differentiation and/or apoptosis, and exhibit potent antimetastatic and antiangiogenic properties in transformed cells in vitro and in vivo. Preliminary studies in animal models have revealed a relatively high tumor selectivity of HDAC inhibitors, strenghtening their promising potential in cancer chemotherapy. Until now, preclinical in vitro research has almost exclusively been performed in cancer cell lines and oncogene-transformed cells. However, as cell proliferation and apoptosis are essential for normal tissue and organ homeostasis, it is important to investigate how HDAC inhibitors influence the regulation of and interplay between proliferation, differentiation, and apoptosis in primary cells as well. This review highlights the discrepancies in molecular events triggered by trichostatin A, the reference compound of hydroxamic acid-containing HDAC inhibitors, in hepatoma cells and primary hepatocytes (which are key targets for drug-induced toxicity). The implications of these differential outcomes in both cell types are discussed with respect to both toxicology and drug development. In view of the future use of HDAC inhibitors as cytostatic drugs, it is highly recommended to include both tumor cells and their healthy counterparts in preclinical developmental studies. Screening the toxicological properties of compounds early in their development process, using a battery of different cell types, will enable researchers to discard those compounds bearing undesirable adverse activity before entering into expensive clinical trials. This will not only reduce the risk for harmful exposure of patients but also save time and money.

Key words :

• Apoptosis
• Differentiation
• Hepatoma Cells
• Histone Deacetylase Inhibitor
• Pharmacotoxicology
• Preclinical Drug Development
• Preclinical Drug Development
• Primary Hepatocytes
• Proliferation
• Trichostatin A

NOTES

Notes

During the publication process of this manuscript, Chiba and colleagues showed that, like in primary rat hepatocytes and other non-malignant cell systems, TSA also induces a p21-independent proliferation arrest in primary human hepatocytes. Chiba, T., Yokosuka, O., Arai, M., Fukai, K., Imazeki, F., Kato, M., Seki, N., and Saisho, H. (2004). Identification of genes up-regulated by histone deacetylase inhibition with cDNA microarray and exploration of epigenetic alterations on hepatoma cells. J. Hepatol. 41:436–445.

During the publication process of this manuscript, Armeanu and colleagues reported on the selective induction of apoptosis by the HDAC inhibitors valproate and ITF2357 in hepatoma cells but not in primary human hepatocytes. This confirms our findings with TSA and TSA-analogues and highlights the high tumor-selectivity of HDAC inhibitors. Armeanu, S., Pathil, A., Venturelli, S., Mascagni, P., Weiss, T. S., Gottlicher, M., Gregor, M., Lauer, U.M., and Bitzer, M. (2005). Apoptosis on hepatoma cells but not on primary hepatocytes by histone deacetylase inhibitors valproate and ITF2357. J. Hepatol. 42:210–217.