The first two authors contributed equally to this work. The ninth and tenth authors share senior authorship.
Epigenetic combination therapy as a tumor-selective treatment approach for hepatocellular carcinoma
Article first published online: 3 APR 2007
Copyright © 2007 American Cancer Society
Volume 109, Issue 10, pages 2132–2141, 15 May 2007
How to Cite
Venturelli, S., Armeanu, S., Pathil, A., Hsieh, C.-J., Weiss, T. S., Vonthein, R., Wehrmann, M., Gregor, M., Lauer, U. M. and Bitzer, M. (2007), Epigenetic combination therapy as a tumor-selective treatment approach for hepatocellular carcinoma. Cancer, 109: 2132–2141. doi: 10.1002/cncr.22652
- Issue published online: 25 APR 2007
- Article first published online: 3 APR 2007
- Manuscript Accepted: 29 JAN 2007
- Manuscript Revised: 6 JAN 2007
- Manuscript Received: 21 SEP 2006
- Wilhelm Sander Foundation, Munich, Germany. Grant Number: 2002.051.2
- Medical Faculty of the University of Tubingen, Germany. Grant Number: 1050-0-0
- Jurgen-Manchot-Foundation, Germany
- hepatocelluar carcinoma;
- histone deacetylase inhibitors;
- DNA methylation;
- xenograft hepatoma model
Innovative epigenetic therapeutics comprise histone deacetylase inhibitors (HDAC-I) and demethylating agents (DA). It was recently found that HDAC-I compounds exhibit profound therapeutic activities against hepatocellular carcinoma (HCC). A comprehensive preclinical investigation was performed on the potential of a combined HDAC-I/DA epigenetic regimen for the highly chemotherapy-resistant HCC entity.
Human HCC-derived cell lines or primary human hepatocytes (PHH) were treated with HDAC-I compound suberoylanilide hydroxamic acid (SAHA) or DA compound 5-aza-2′-deoxycytidine (5-aza-dC) or both and examined for cellular damage, proliferation, histone acetylation pattern, and DNA methylation. In vivo activities were investigated in a xenograft hepatoma model.
Monotherapeutic application of SAHA or 5-aza-dC was found to induce substantial antiproliferative effects in HCC-derived cells, strongly enhanced by combined SAHA and 5-aza-dC treatment. PHH from different human donors did not exhibit any relevant cellular damage even when applying high doses of the combination regimen, whereas HCC-derived cell lines showed a dose-dependent damage. In vivo testing demonstrated a statistical significant inhibition of hepatoma cell growth for the combined treatment regime.
Because the combined HDAC-I/DA epigenetic approach was found to produce significant antitumor effects in HCC model systems and did not impair cellular integrity of untransformed hepatocytes, this combination therapy is now considered for further investigation in clinical trials. Cancer 2007;109:2132–41. © 2007 American Cancer Society.