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.
Highlights
Resveratrol (3,5,49-trihydrostilbene) is a natural polyphenolic alcohol (Figure S1 in File S1) expressed in plants as response to external stress, like UV irradiation, fungal infection or injury [1]
Important features for the identification of a HDAC inhibitors (HDACi) are both the structural property to fit into the binding pocket of histone deacetylases (HDACs) enzymes and the capacity to interact with key interaction points like the zinc ion in the catalytic center
We employed recently published in silico data by Berger et al of the well characterised HDACi trichostatin A (TSA) and the clinically used HDACi Suberoylanilide Hydroxamic Acid (SAHA) [42]
Summary
Resveratrol (3,5,49-trihydrostilbene) is a natural polyphenolic alcohol (Figure S1 in File S1) expressed in plants as response to external stress, like UV irradiation, fungal infection or injury [1]. The highest concentrations of resveratrol were detected in red grapes (100 mg/g) [2]. Beside the protection from cardiovascular diseases [7] and antioxidant properties [8] resveratrol was described to possess antiinflammatory [9] and antiproliferative effects [10,11]. These diverse modes of action are mainly driven by modulations of important intracellular proteins like NFkB, p53, survivin, Bcl and the sirtuin SIRT1 [12,13,14]. Due to its multiple molecular interactions, resveratrol was analyzed for the treatment of cancer and identified to inhibit initiation and/or progression of several tumor entities like leukaemia [15,16,17], breast cancer [18], colon cancer [19], pancreatic cancer [20], gastric cancer [21], prostate cancer [22], lung cancer [23], melanoma [24] and tumors of the liver [25,26]
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