Invited paper for Agro Food industry hi-tech Nutritional prevention by dietary resveratrol as chemopreventive agent: application to colorectal cancers

Resveratrol (3,4’,5 tri-hydroxystilbene) is a plant phytoalexin produced in massive amount in grapevine skin in response to stress such as UV, phytosanitary treatment, and mostly following infection by Bothrytis cinerea. In this later case, the production of resveratrol inhibits the proliferation of the pathogen, thereby acting as a natural antifungal. Many experimental studies have reported interesting properties of trans-resveratrol as a preventive agent against important pathologies i.e. vascular diseases, cancers, viral infection or neurodegenerative processes. In addition, several epidemiological studies indicated that resveratrol would be the main microcomponent of wine leading health benefits such as prevention of vaso-coronary diseases and cancer (so called the “French paradox”). Resveratrol prevent (or delay) carcinogenesis by inhibiting the three phases of cancer process: initiation, promotion, progression and invasion phases. It also exhibits pro-apoptic properties especially towards colorectal cancers. Importantly, resveratrol is not toxic in animal models even at high dosage. Moreover, plasmatic concentrations of resveratrol would to be sufficient for anti-invasive activity. The enterohepatic blood recirculation contributes to a delayed elimination of the molecule from the body which can also show a prolonged effect enhanced by its binding to plasmatic proteins. Interestingly resveratrol can sensitize to low doses of cytotoxic drugs and so provide new approaches to enhance the efficacy of anticancer therapy in human cancers. INTRODUCTION 1) Resveratrol : a plant phytoalexin Resveratrol or 3, 4’, 5 tri-hydroxystilbene (Figure 1) is a secondary metabolite produced in limited plant species (1). Phenylalanine is the precursor and the key enzyme is the stilbene synthase which orientates the synthesis pathway towards resveratrol, instead of towards flavonoids which involves the chalcone synthase (2). Several plant species are known to produce resveratrol (especially the trans isomers such as aglycone or in a glycosylated form), in significant to high amounts. Some of them are used as food, i.e. vine plant, peanuts, berries. In the vine plant, Vitis vinifera, resveratrol is a phytoalexin, e.g. produced in hudge amounts in grape vine skin in response to infection by Bothrytis cinerea, leading to a blockage of its proliferation. The mild stress triggered by resveratrol-dependent host pathogen interaction lead to a systemic response confering an extended protection against other pathogens (3,4). This process is known as xeno-hormesis (5). Obviously, resveratrol appears to be a real natural antibiotic. Interstingly, although other resveratrol producing plants are not used as 2 ha l-0 03 76 30 6, v er si on 1 17 A pr 2 00 9 dietary preparation, i.e. Polygonum cuspidatum or Yucca schidigera., extracts of Polygonum cuspidatum were already used in ancient Chinese natural medicine for their vaso-relaxing activity, while root extracts of Yucca schidigera were known for their anti-mutagen activity. Veratrum grandiflorum has been reported to synthesize resveratrol and analogues. By the way, root powder of Veratrum album has long been used for at medium altitude in Northern Europe, Asia and Japan to treat rheumatisms and nervous diseases. However, Veratrum album contains potent toxic alcaloids: the protoveratrines A & B. For review see (6). 2) Resveratrol and prevention of diseases Like many other plant polyphenols, resveratrol is a potent anti-oxidant and is considered to be a preventive food microcomponent as are the flavonoids and epicathechins of green tea or of cocoa (7). Indeed, numerous studies have reported interesting properties of trans-resveratrol as a preventive agent (figure 1) of several important pathologies: vascular diseases, cancers, viral infection, neurodegenerative processes such as Alzheimer (8) and Huntington diseases (9) (for reviews, see (10,11). Resveratrol protects LDL against oxidation (12). In addition, a novel discovery has been reported, showing that resveratrol increases lifespan (13). Moreover, several epidemiological studies (14) revealed that resveratrol may be one of the main wine microcomponents responsible for the health benefits (i.e. against vaso-coronary diseases and cancer mortality) in the case of moderate wine consumption. Moreover, due to its oestrogeno-mimetic properties, resveratrol may protect women against osteoporosis (15). An extensive and up to dated document has been recently published on resveratrol and health (16). CANCER CHEMOPREVENTIVE PROPERTIES OF RESVERATROL The antiproliferative effect of resveratrol has been shown in numerous in vitro studies, using several cell lines derived from tumors and its anticarcinogenic effects has been demonstrated in several animal models (17,18). As reported in table 1, resveratrol is able to prevent the tumor initiation by scavenging free radicals damaging DNA and by activation of detoxifying enzymes. Resveratrol inhibits also tumor promotion by modulation of polyamines metabolism and tumor progression, by modulation of cell cycle, apoptosis and angiogenesis. Despite efforts to characterize a major resveratrol affinity target, various resveratrol binding proteins have been identified in different biological models: Wang et al.(19), in CWR22vl prostate cancer cell lines, Lin et al. (20) in MCF7 mammary gland tumor cells or Han et al. (21), in 3 ha l-0 03 76 30 6, v er si on 1 17 A pr 2 00 9 plasma membrane of rat brain. 1Resveratrol acts on carcinogenesis by inhibiting the initiation phase Initiation phase of carcinogenesis is linked to DNA alteration (mutation) of a normal cell. The anti-initiation activity of resveratrol is linked to the suppression of the metabolic activation of carcinogens and/or to an increased detoxification via a modulation of the drugmetabolizing enzymes involved either in phase I reactions or in phase II conjugation. a)Resveratrol chemoprevention by ROS scavenging and DNA repair The inhibition of P450 enzymes by resveratrol can reduce the reactive activation of molecular oxygen. These antioxidant actions of resveratrol contribute to prevent oxidative DNA damage which plays a pivotal role in the carcinogenic activity of many genotoxic agents (23). Resveratrol is also able to promote DNA repair by increasing the activity of p53 in various cell lines. b)Resveratrol chemoprevention by induction of detoxification enzymes. Resveratrol chemoprevention by inhibition of phase I enzymes would be due to the prevention of metabolic activation of procarcinogens by a competitive inhibition of the aryl hydrocarbon receptor (AhR) (22). Phase II enzyme induction generally protects tissues and cells from endogen and/or exogen intermediate carcinogens. Resveratrol contributes to metabolic inactivation by inducing UDP glucuronosyltransferase (24), increases glutathione (GSH) levels and the activity of glutathione-S-transferase (GST) glutathione peroxidase (GPX) and glutathione reductase (GR). Resveratrol could activate the phase II detoxifying enzyme gene expression via a modulation of the mitogen-activated protein kinases (MAPK) pathway. 2Resveratrol acts on carcinogenesis by inhibiting the promotion and the progression