title: Resveratrol as a pan-HDAC inhibitor alters the acetylation status of histone [corrected] proteins in human-derived hepatoblastoma cells.
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.
authors.affiliation: Department of Internal Medicine I, Medical University Hospital, Tuebingen, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Venturelli
authors.forename: Alexander
authors.initials: A
authors.lastname: Berger
authors.forename: Alexander
authors.initials: A
authors.lastname: Böcker
authors.forename: Christian
authors.initials: C
authors.lastname: Busch
authors.forename: Timo
authors.initials: T
authors.lastname: Weiland
authors.forename: Seema
authors.initials: S
authors.lastname: Noor
authors.forename: Christian
authors.initials: C
authors.lastname: Leischner
authors.forename: Sabine
authors.initials: S
authors.lastname: Schleicher
authors.forename: Mascha
authors.initials: M
authors.lastname: Mayer
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Weiss
authors.forename: Stephan C
authors.initials: SC
authors.lastname: Bischoff
authors.forename: Ulrich M
authors.initials: UM
authors.lastname: Lauer
authors.forename: Michael
authors.initials: M
authors.lastname: Bitzer
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002642:Chick Embryo; D003198:Computer Simulation; D018197:Hepatoblastoma / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D062105:Molecular Docking Simulation; D000077185:Resveratrol; D013267:Stilbenes / Q000097:blood / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; D013267:Stilbenes; D006655:Histone Deacetylases; D000077185:Resveratrol
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