Venturelli, Sascha and Berger, Alexander and Boecker, Alexander and Busch, Christian and Weiland, Timo and Noor, Seema and Leischner, Christian and Schleicher, Sabine and Mayer, Mascha and Weiss, Thomas S. and Bischoff, Stephan C. and Lauer, Ulrich M. and Bitzer, Michael (2013) Resveratrol as a Pan-HDAC Inhibitor Alters the Acetylation Status of Jistone Proteins in Human-Derived Hepatoblastoma Cells. PLOS ONE, 8 (8): e73097. ISSN 1932-6203,
Full text not available from this repository. (Request a copy)Abstract
The polyphenolic alcohol resveratrol has demonstrated promising activities for the prevention and treatment of cancer. Different modes of action have been described for resveratrol including the activation of sirtuins, which represent the class III histone deacetylases (HDACs). However, little is known about the activity of resveratrol on the classical HDACs of class I, II and IV, although these classes are involved in cancer development or progression and inhibitors of HDACs (HDACi) are currently under investigation as promising novel anticancer drugs. We could show by in silico docking studies that resveratrol has the chemical structure to inhibit the activity of different human HDAC enzymes. In vitro analyses of overall HDAC inhibition and a detailed HDAC profiling showed that resveratrol inhibited all eleven human HDACs of class I, II and IV in a dose-dependent manner. Transferring this molecular mechanism into cancer therapy strategies, resveratrol treatment was analyzed on solid tumor cell lines. Despite the fact that hepatocellular carcinoma (HCC) is known to be particularly resistant against conventional chemotherapeutics, treatment of HCC with established HDACi already has shown promising results. Testing of resveratrol on hepatoma cell lines HepG2, Hep3B and HuH7 revealed a dose-dependent antiproliferative effect on all cell lines. Interestingly, only for HepG2 cells a specific inhibition of HDACs and in turn a histone hyperacetylation caused by resveratrol was detected. Additional testing of human blood samples demonstrated a HDACi activity by resveratrol ex vivo. Concluding toxicity studies showed that primary human hepatocytes tolerated resveratrol, whereas in vivo chicken embryotoxicity assays demonstrated severe toxicity at high concentrations. Taken together, this novel pan-HDACi activity opens up a new perspective of resveratrol for cancer therapy alone or in combination with other chemotherapeutics. Moreover, resveratrol may serve as a lead structure for chemical optimization of bioavailability, pharmacology or HDAC inhibition.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | HISTONE DEACETYLASE INHIBITORS; CHICK-EMBRYO; HEPATOCELLULAR-CARCINOMA; CHEMOPREVENTIVE AGENT; INDUCED APOPTOSIS; FRENCH PARADOX; CANCER; POLYPHENOLS; QUERCETIN; THERAPY; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Kinder- und Jugendmedizin |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 03 Apr 2020 05:17 |
| Last Modified: | 03 Apr 2020 05:17 |
| URI: | https://pred.uni-regensburg.de/id/eprint/16212 |
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