stilbenes and Hepatoblastoma

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.

Topics: Acetylation; Animals; Cell Death; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chick Embryo; Computer Simulation; Hepatoblastoma; Histone Deacetylase Inhibitors; Histone Deacetylases; Histones; Humans; Liver Neoplasms; Molecular Docking Simulation; Resveratrol; Stilbenes

This work reports significant advances on the transport in hepatic cells of resveratrol, a natural polyphenol with potent protective properties. First, we describe a new simple technique to qualitatively follow resveratrol cell uptake and intracellular distribution, based on resveratrol fluorescent properties. Second, the time-course study and the quantification of (3)H-labelled resveratrol uptake have been performed using human hepatic derived cells (HepG2 tumor cells) and hepatocytes. The temperature-dependence of the kinetics of uptake as well as the cis-inhibition experiments agree with the involvement of a carrier-mediated transport in addition to passive diffusion. The decrease of passive uptake resulting from resveratrol binding to serum proteins brings to light a mediated mechanism in physiological situation.

Topics: Biological Availability; Biological Transport, Active; Carrier Proteins; Cell Line; Cell Line, Tumor; Diffusion; Hepatoblastoma; Hepatocytes; Humans; Metabolic Clearance Rate; Resveratrol; Stilbenes; Temperature; Tissue Distribution

As a plant microcomponent, resveratrol is a polyphenolic compound produced by several species and found especially in Polygonum roots, peanuts seeds, berries and also grape and therefore can be present in human diet or beverages (red wine, for instance). Traditional chinese medicine and more recent epidemiological studies strongly suggested that resveratrol may act as a cancer chemopreventive compound. The biochemical mechanism by which resveratrol inhibits cell proliferation was provided by studies in numerous human cell lines including our work in hepatoblastoma HepG2 and colorectal tumor SW480 cells. The results show that resveratrol strongly inhibits cell proliferation at the micromolar range in a time- and dose-dependent manner. Resveratrol appears to block the cell cycle at the transition S to G2/M since there is no inhibition of [3H]-thymidine incorporation observed, while there is an increase of the cell number in S phase. On the other hand, in order to evaluate if the amount of resveratrol taken up during food or drink consumption is sufficient to ensure in the whole body the in vitro described beneficial effects, we evaluated the ratio between plasmatic level of resveratrol and its cell bioabsorption. Our study reports a higher uptake of resveratrol in the human hepatic derived HepG2 cells than in colorectal derived SW480 cells. In contrast, resveratrol is conjugated in these cells and derivatives are released in large amounts in the cell medium. Based on present knowledge, resveratrol appears to be a promising bioactive natural molecule with potential applications in phytotherapy, pharmacology or in nutriprotection (nutraceutic food) area.

Topics: Antineoplastic Agents, Phytogenic; Cell Division; Colonic Neoplasms; Flow Cytometry; Genistein; Hepatoblastoma; Humans; In Vitro Techniques; Neoplasms; Resveratrol; S Phase; Stilbenes; Tumor Cells, Cultured