Resveratrol: A Natural Polyphenol with Multiple Chemopreventive Properties (Review)

Current Drug Metabolism, 2009, 10, 000-000

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Resveratrol: A Natural Polyphenol with Multiple Chemopreventive Properties § (Review) Fabrizia Brisdelli, Gabriele D’Andrea and Argante Bozzi* Department of Biomedical Sciences and Technologies, University of L’Aquila, L’Aquila, and Consorzio INBB, Italy Abstract: Resveratrol, a naturally occurring polyphenol, shows pleiotropic health beneficial effects, including antioxidant, anti-inflammatory, anti-aging, cardioprotective and neuroprotective activities. Due to the several protective effects and since this compound is widely distributed in the plant kingdom, resveratrol can be envisaged as a chemopreventive/curative agent introduced almost daily with the diet. Currently, a number of preclinical findings suggest resveratrol as a promising nature’s weapon for cancer prevention and treatment. A remarkable progress in elucidating the molecular mechanisms underlying anti-cancer properties of resveratrol has been achieved in the last years. Concerning the resveratrol mechanism of action as a protective (vs. normal cells and tissues) and toxic (vs. cancer cells) compound, many studies focus on its antioxidant capacity as well as on its ability to trigger and favor the apoptotic cascade in malignant cells. However, a generalized mechanism of action able to explain this dual effect of resveratrol has not yet been clearly established. In addition to these important functions, resveratrol is reported to exhibit several other biological/biochemical protective effects on heart, circulation, brain and age-related diseases which are summarized in this Review. Keywords: Resveratrol, polyphenols, chemoprevention, anti-cancer, apoptosis, cardioprotection, neuroprotection. §

This review is dedicated to all the victims of the earthquake that struck L’Aquila city on April 6 2009.

1. INTRODUCTION Resveratrol (3,5,4’-trihydroxy-trans-stilbene) (RES) (Scheme 1) is a phytoalexin synthesized in response to mechanical injury, UV irradiation and fungal attacks [1]. This natural polyphenol has been detected in more than 70 plant species and was found in discrete amounts in red wines and various human foods [2]. High concentrations are present in grapes, possibly because of the response of Vitis vinifera to fungal infection [2]. It has been estimated that fresh grape skin contains about 50-100
g of RES per gram. In red wine, the concentration of RES, according to some authors [4, 5], is in the range of 1.5-3 mg/L while other authors report substantially higher amounts (4-20 mg/L) [6, 7]. Significant quantities are also found in some white and rosè wines, while commercial grape juice contains around 4 mg/L of RES (Tables 1 and 2). Usually, this polyphenol is present in dietary products as cisand trans-resveratrol but essentially in glycosylated forms known as piceids (3-O--D-glucosides) (Fig.1). Plants and pathogens as well as the human digestive tract possess enzymes able to oxidize (and inactivate) polyphenols. Glycosylation inhibits enzymatic oxidation of RES, thereby preserving its biological activity and increasing its stability and bioavailability [10, 11]. Since intestinal cells are able to absorb only aglycone form of RES, the absorption process requires glycosidases. Therefore, the relative amounts of aglycone and glycosylated RES in foods and beverages may modulate its absorption rate. Different activities and expression levels of intestinal glycosidases may explain the differences in RES uptake rates observed in humans and animal models [12]. It has been hypothesized that RES may be the main active principle involved in the “French Paradox”, the inverse correlation between the red wine consumption and the incidence of cardiovascular diseases [13]. The real impetus to the interest in the biology of RES can be ascribed to the strict correlation between RES and inhibition of *Address correspondence to this author at the Department of Biomedical Sciences and Technologies, University of L’Aquila, L’Aquila, and Consorzio INBB, Italy; Tel: +390862433472; Fax: +390862433472; E-mail: [email protected] 1389-2002/09 $55.00+.00

Other names

trans-3,5,4'-Trihydroxystilbene; 3,4',5-Stilbenetriol; trans-Resveratrol; (E)-5-(p-Hydroxystyryl)resorcinol (E)-5-(4-hydroxystyryl)benzene-1,3diol

CAS number

501-36-0

ChemSpinder ID

392875

Molecular formula

C14H 12O3

Molar mass

228,25

Appearance

white powder with slight yellow cast

Solubility in water

0,03 g/L

Solubility in DMSO

16 g/L

Solubility in ethanol

50 g/L

Scheme 1. Resveratrol structures, identifiers and properties.

tumor initiation, promotion and progression in a murine model [14]. This first assumption was followed by further observations involving the apoptotic activity of RES in its cancer preventive effect [15]. Since then, burst of research activities followed resulting in its characterization as anti-inflammatory, cardioprotective, platelet aggregation inhibitory, anti-tumorigenic, antiaging, cell cycle inhibitory, and phytoestrogen [16-20]. A number of studies have clarified intracellular circuits and molecular pathways directly or indirectly involved in RES-mediated signalling [21, 22]. Nothwithstanding the massive literature on the multiple properties, the precise action mechanism of RES is not yet fully elucidated. This review will summarize either the well established and © 2009 Bentham Science Publishers Ltd.

2 Current Drug Metabolism, 2009, Vol. 10, No. 7 Table 1.

Resveratrol Content in Wines and Grape Juice [8] Beverage

Table 2.

Brisdelli et al.

Total resveratrol (mg/L)

Total resveratrol in 150 mL wine (mg)

Red Wines (Global)

1.98 - 7.13

0.30 - 1.07

Red Wines (Spanish)

1.92 - 12.59

0.29 - 1.89

Red grape juice (Spanish)

1.14 - 8.69

0.17 - 1.30

Rose Wines (Spanish)

0.43 - 3.52

0.06 - 0.53

Pinot Noir

0.40 - 2.00

0.06 - 0.30

White Wines (Spanish)

0.05 - 1.80

0.01 - 0.27

Food

Serving

Total resveratrol (mg)

Content in Selected Foods [9]

Peanuts (raw)

1 cup (146 g)

0.01 - 0.26

Peanuts (boiled)

1 cup (180 g)

0.32 - 1.28

Peanut butter

1 cup (258 g)

0.04 - 0.13

Red grapes

1 cup (160 g)

0.24 - 1.25

Fig. (1). Absorption, transport, metabolism and excretion of resveratrol. veratrol-3-O-beta-glucuronide (modified from Signorelli et al. [12]).

GLC

the more recent hypothesis of the activity exerted by this polyphenol. 2. CARDIOVASCULAR ACTIVITY OF RESVERATROL It has been reported a myriad of RES biological activities which improve endothelial function and the cardiovascular system in general, supporting a main role for RES as a cardioprotective agent.

RES, resveratrol-3-O-beta-glucoside;

SUL

RES, resveratrol-3-sulfate;

GLU

RES, res-

The cellular mechanisms by which RES exerts an antiatherogenic and thus cardioprotective effects have been reported including the stimulation of endothelial vasorelaxation through activation of the NO-cGMP cascade [23], the inhibition of LDL oxidation [24, 25], inhibition vascular NADH/NADPH oxidase [26], as well platelet aggregation and synthesis of eicosanoids [27, 28]. RES has been shown also to inhibit the production of reactive oxygen species

Resveratrol: A Natural Polyphenol with Multiple Chemopreventive

(ROS) in rat macrophages and human monocytes and granulocytes [29-31]. Thus, RES is a powerful scavenger of free radicals which have been identified as a key factor in the generation of oxidized LDL and in lipid peroxidation [32, 33]. RES even has been demonstrated to exhibit anti-inflammatory properties [14, 34], which are manifested as inhibition of ICAM-1 and VCAM-1 expression and attachment of monocytes to endothelial cells, inhibition of the lipopolysaccharide (LPS)-induced synthesis of TNF- and IL-1-, and release of IL-6 from monocytes [35]. Other authors have been reported that RES decreases the nitric oxide (NO) production, the NF-kB activation and the iNOS expression in activated macrophages [36]. In addition to effects on cytokine production, RES has also been shown to suppress the growth of endothelial cells, as well as cells derived from other tissues [14, 37, 38]. For example, the proliferation of bovine aortic endothelial cells was demonstrated to be strongly inhibited by RES  an effect that has been suggested to counteract atherogenic consequences [37]. Oral administration of RES has been demonstrated to exert a potent cardioprotective effect, offering new and interesting therapeutic perspectives [39]. The mechanism(s) responsible for the enhanced angiogenesis as well as the cardioprotective effect of resveratrol either in vivo and in vitro, operates through thioredoxin-1 (Trx-1), heme oxygenase-1 (HO-1) and vascular endothelial growth factor (VEGF) induction. These findings offer a potentially attractive approach to increasing endogenous protective mechanisms in the ischemic myocardium that may ultimately translate into novel therapeutic interventions [39]. 2.1. Nitric Oxide Production Endothelial NO conveys vasoprotective and antiatherosclerotic effects through a number of mechanisms, such as vasorelaxation, inhibition of platelet aggregation and adhesion to the vascular wall, regulation of the expression of genes involved in atherosclerosis [40]. There are some evidences that RES interacts with the vascular NO system. NO production from the endothelium may be regulated by changes in eNOS gene expression and/or activity. In human umbilical vein endothelial cells (HUVECs) RES produced a doseand time-dependent upregulation of eNOS expression and an increase of eNOS-derived NO [41]. The upregulation of eNOS expression by RES involves transcriptional and post-transcriptional (mRNA stabilizing) mechanisms. Polyphenolic compounds may additionally contribute to protective effects in cardiovascular disease altering biological functions, such as expression of cytokine-induced adhesion molecules during inflammation. Cytokines could play a key role in monocyte/endothelial cell interaction contributing to atherosclerosis [42]. When endothelial cells are exposed to various inflammatory cytokines, ICAM-1, an inducible cell adhesion glycoprotein, is upregulated. A recent study has shown that RES exerts an atheroprotective effect by attenuating ICAM-1 gene expression, via the inhibition of STAT3 signaling [43]. Although the precise inhibitory mechanisms need to be well elucidated, NO appears to play a role in the actions of RES by suppressing STAT3 activation (Fig. 2). The mechanism of NO inhibition of IL-6-induced STAT3 phosphorylation may result from reducing superoxide production, via an interaction with NADPH oxidase. Alternatively, NO may directly exert an antioxidative role against scavenging ROS or directly conjugate with specific signals. 2.2. Protective Effect Against Peroxynitrite Atherosclerotic lesions occur mainly in areas with altered blood flow where superoxide anion (O2–.) generation increases and ·NO concentration decreases [44]. Overproduction of (O2–.) prevent beneficial effects of ·NO because it is oxidized to the peroxynitrite (ONOO–), a short-lived reactive species that is able to modify several biomolecules, such as DNA, lipids and proteins, affecting cell signaling pathway and inducing cell death through both apoptosis and necrosis [45, 46].

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Fig. (2). Resveratrol inhibits IL-6-induced STAT3 activation; a possible mechanism is shown (modified from Wung et al. [43]).

The rate of peroxynitrite formation depends on the concentrations of O2–. and .NO, and even a relatively small increase of their concentrations may be responsible for a remarkable increase of ONOO– generation and its cytotoxic effects. Modification of proteins induced by peroxynitrite and its intermediates may lead to functional alterations of proteins as the result of the oxidation of tryptophan, cysteine and methionine and/or nitration of tyrosine and/or formation of dityrosine and/or carbonyl group formation and/or protein fragmentation [46-49]. It was shown that RES may partly reduce the formation of nitrotyrosine in platelet proteins and thiol oxidation [50]. The obtained results indicate that RES in vitro may also protect plasma proteins against oxidation and nitration caused by ONOO– or its intermediates. RES suppresses the peroxynitrite toxicity measured as the level of TBARS - marker of lipid peroxidation. Mechanisms of RES action on plasma components are not clear. It has reported that RES may prevent the effects of ONOO– and minimize LDL modifications by the inhibition (approximately 70%) of carbonyl group formation and by the reduction of LDL lipid peroxidation [51]. In vitro studies have shown that peroxynitrite could induce endothelial cell death either by an apoptotic or necrotic programmed pathway, depending on ONOO – cell exposure conditions and concentrations. Some authors have reported a non passive necrotic cell death initiated by DNA oxidative injury and subsequent activation of the nuclear enzyme poly (ADP-ribose) polymerase-1 followed by depletion of NAD+ and ATP intracellular pools [52]. On the contrary, other authors have observed morphological changes consistent with apoptosis in endothelial cells upon exposure to peroxynitrite [53, 54]. The same authors have shown that RES, at the concentration of 50
M, is able to prevent endothelial cell death through an indirect antioxidant activity by increasing the intracellular glutathione (GSH) content. However, at lower concentration (10
M) RES was able to counteract ONOO – deleterious effects on endothelial cells without increasing the cellular glutathione concentration; so other cellular mechanisms could be responsible of the cytoprotective effects of RES. The data reported in this recent study [54] shows that RES, at concentrations so low as 10
M, inhibited biochemical and cellular mechanisms underlying apoptosis elicited by peroxynitrite and that RES preferentially disrupted the mitochondrial apoptotic pathway than the death receptor apoptotic pathway, through modulation of Bcl-2 intracellular levels, considerably decreasing the Bax/Bcl-2 ratio. Furthermore, this study highlights the idea that RES cardioprotective effects go far beyond its direct antioxidant activity and that its cellular signaling and molecular effects have a putative role to play.

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2.3. Inhibition of Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) Expression The extracellular matrix metalloproteinase inducer (EMMPRIN) is significant in the regulation of matrix metalloproteinase (MMP) synthesis in atherosclerosis-related cells, and is possibly involved in the progression of atherosclerotic plaque [55]. EMMPRIN (CD147 or basigin), is a transmembrane glycoprotein and a member of immunoglobulin superfamily. EMMPRIN could be greatly up-regulated in atherosclerosis-related cells, for example monocyte/macrophages [56, 57] and coronary smooth muscle cells, by certain proatherogenic stimuli such as oxLDL [58]. These results therefore strongly suggest EMMPRIN’s significance in the development of atherosclerosis. A recent study was addressed to understand the inhibitory mechanism of RES on extracellular matrix metalloproteinase inducer (EMMPRIN) expression in phorbol 12-myristate 13-acetate (PMA)-induced human monocytic (THP-1) cells [55]. In this work, the authors found that RES markedly inhibits the ERK1/2 and p38 phosphorylation expression in PMA-induced THP-1 cells. In addition, their results suggest that the activation of the ERK1/2 and p38 pathways is necessary for EMMPRIN expression in PMA-induced THP-1 cells. Thus, it was clearly demonstrated that RES inhibits EMMPRIN expression through inhibition of the ERK1/2 and p38 pathways. In a previous study, the same authors showed peroxisome proliferator-activated receptor
(PPAR
) activation regarding RES’s effects on EMMPRIN expression in PMA-induced THP1 cells [59]. Therefore, the conclusion was that RES could downregulate EMMPRIN expression in PMA-induced THP-1 cells by inhibiting two types of mitogen-activated protein kinase (MAPK), ERK1/2 and p38 pathway, and by activating PPAR
. Noteworthy, it has been reported that the PPAR
transcriptional activity is negatively regulated by MAPK via its phosphorylation [60-62]. Consequently, there may be cross-talk between the MAP kinase signaling pathway and the PPAR
in the process where RES suppresses EMMPRIN expression in PMA-induced THP-1 cells. Then, it can be speculated that the inhibition of the ERK1/2 and p38 pathways by RES decreases the phosphorylation of PPAR
, afterward enhancing the PPAR
transcriptional activity in PMA-induced THP-1 cells. Hence, a link between MAP kinase signaling suppression and PPAR
activation may contribute to the down-regulation of EMMPRIN expression by RES in PMA-induced THP-1 cells [55]. In conclusion, RES can inhibit the up-regulated expression of EMMPRIN in PMA-induced THP-1 cells through suppression of both the ERK1/2 and p38 pathways, without affecting the Jun Nterminal kinase (JNK) pathway. Such findings demonstrate the related mechanism possibly involved in the pathogenesis of atherosclerosis and it help to explain, at least in part, the protective function of RES against cardiovascular disease. 2.4 Anti-Arrhytmic Effects The data presented in a recent study revealed the protective effect of RES against arrhythmia in different animal models and its mechanisms at cellular level [63]. Cardiac function, the cardiac electrical activity in particular, is a well organized process by an array of ion channels that activate in a manner with a delicate balance between inward and outward ion currents. Following an incoming impulse, cardiac cells excite with rapid membrane depolarization to which a relatively slow repolarization process goes after. Either excessive slowing or accelerating the rate of repolarization can produce electrical perturbations of cardiac rhytm. The rate of repolarization is determined by several ion currents such as L-type calcium current, the rapid delayed rectifier K+ current, and the slow delayed rectifier K+ current. Antiarrhythmic drug should affect multiple channels, be able to restore normal sinus rhytm in all patients, and keep patients free from further episodes of arrhythmia. The currently available drugs are far from perfect [64].

Brisdelli et al.

In animal models RES protective effects in arrhythmias induced by aconitine,ouabain and coronary ligation was investigated [63]. Aconitine increased sodium current and L-type calcium current [65]. Toxic ouabain dosage inhibits plasma membrane Na+/K+ATPase and rises intracellular Na+ concentration. The increased intracellular Na+ concentration causes intracellular Ca2+ overload due to activation of sarcolemmal Na+/Ca2+ exchange (NCX). The Ca2+ overload in turn induces oscillatory fluctuation in resting potential [66]. Thus, calcium channel blocker may protect animals from the toxicity of aconitine and ouabain. Myocardial ischemia results in changes in extracellular K+ that, in turn, make the resting potential less negative, inactivate Na+ channels, decrease Na+ current, and slow down the conduction. In addition, myocardial ischemia can result in the release of metabolites, such as lysophosphatidylcholine, which can alter ion channel function; ischemia may also activate ATP-inhibited K+ channels. Then, in response to myocardial ischemia, a normal heart displays changes in resting potential, conduction velocity, intracellular Ca2+ concentrations, and repolarization, any one of which may trigger arrhythmias [67-69]. Drugs affecting calcium channel and potassium channel may have protective effects on arrhythmia induced by myocardial ischemia. RES significantly and dose-dependently increased the doses of aconitine and ouabain required to induce the arrhythmia indexes. In coronary ligation induced rat arrhythmia model, RES shortened duration of arrhythmia, decreased incidence of ventricular tachycardia and mortality. Therefore, the low toxicity and multiple protective functions to humans, make RES superior to several currently used antiarrhythmic drugs in clinics. 2.5. Protective Effects Against Cardiotoxicity The protective effects of RES against doxorubicin- and arsenic trioxide (As2O3)-induced cardiotoxicity were investigated. In Wistar albino rats doxorubicin treatment induced cardiotoxicity with decrease of blood pressure and heart rate and increase of lactate dehydrogenase, creatine phosphokinase, total cholesterol, triacylglycerols, aspartate aminotransferase and 8-OHdG plasma levels [70]. Moreover, doxorubicin caused a significant decrease in plasma total antioxidant capacity along with a reduction in cardiac superoxide dismutase, catalase and Na+,K+-ATPase activities and glutathione contents. By contrast, malondialdehyde, myeloperoxidase activity and the generation of reactive oxygen species were increased in the cardiac tissue. On this context, RES markedly ameliorated the severity of cardiac dysfunction, while all oxidant responses were prevented leading to the conclusion that RES may be of therapeutic use in preventing oxidative stress due to doxorubicin toxicity [70]. The clinical use of As2O3, a potent antineoplastic agent, is limited by its cardiotoxic effects. QT interval prolongation and apoptosis have been implicated in the cardiotoxicity of arsenic trioxide. Due to these limitations, some patients are precluded from receiving a highly effective treatment. The use of cardioprotective agents is an alternative approach. In a mouse model, RES significantly reduced As2O3-induced QT prolongation, structural abnormalities and oxidative damage in the heart [71]. In H9c2 cardiomyocytes in vitro, RES decreased apoptosis, ROS production and intracellular calcium mobilization induced by As2O3 [71]. 3. NEURONAL PROTECTION BY RESVERATROL Accumulating experimental and epidemiological evidences have documented that some natural polyphenols can exert protective activity against a number of neurodegenerative disorder (e.g. Alzheimer’s and Parkinson’s diseases, multiple sclerosis, amyotrophic lateral sclerosis). Many studies highlighted that polyphenols could protect neurons against various toxic compounds. The emerging view is that polyphenolic compounds could exert beneficial effects on cells not only through their antioxidant potential but also through the modulation of different pathways

Resveratrol: A Natural Polyphenol with Multiple Chemopreventive

such as signaling cascades, anti-apoptotic processes or the synthesis/degradation of the amyloid  peptide. The concentrations of polyphenols from diet are high enough in vivo to display pharmacological activity in the brain [72]. The potential therapeutic function of polyphenols, among which RES is a preminent compound, is strictly related to their ability to cross blood brain barrier and exert their beneficial activity directly [73, 74]. 3.1 Amyloid-
Clearance Epidemiological studies have shown that moderate wine intake reduces the risk of Alzheimer’s disease (AD) [75-78]. RES, a polyphenol that occurs in abundance in grapes and red wine, is believed to contribute to the beneficial effects of wine consumption on this neurodegenerative process [79-81]. Histopathologic alterations in AD are characterized by the neurofibrillary tangles and senile plaques. The amyloid  peptide (A), the main component of plaques, has a key role in the development and progress of AD [82]. The A is toxic to neurons through different mechanisms, such as oxidative stress [83], apoptosis, mitochondrial dysfunction, activation of the nuclear transcription factor NF-kB [84]. A recent paper shows that RES strongly reduces the levels of secreted and intracellular amyloid- (A) peptides produced by different cell lines [85]. RES does not inhibit A synthesis, since it has no effect on the A-producing enzymes (- and -secretases). It acts, instead, by promoting the intracellular degradation of the amyloid peptide by a mechanism that does not engage the A-degrading metalloendopeptidases, NEP, ECE-1 and -2, or IDE, but involve proteasome [85]. It was observed that a decrease in proteasome activity occurs in AD brains [86, 87]. It has been proposed that A itself may lead to proteasome inhibition [88], suggesting that high levels of A in AD brain may inhibite the proteasome and block the degradation of critical regulators of its own clearance. The authors also demonstrate the anti-amyloidogenic activity of two other metoxy analogues of RES, suggesting that chemical modifications of the agent can be done in the context of improving its potency, stability, bioavailability and therefore its therapeutic use [85]. It was hypothesized that RES may act indirectly by specifically stimulating the proteasomal degradation of critical regulators of A clearance [85]. Resveratrol interacts with several proteins, including members of the sirtuin family. Sirtuins are protein deacetylases which have gained much attention as mediators of lifespan extension in several model organisms [89]. Induction of SIRT1 expression also reduces neuronal degeneration and death in animal models of AD’s and Huntington’s disease [90]. Overexpression of SIRT1 and RES treatment markedly reduced NF-kB signaling stimulated by A and had strong neuroprotective effects [91]. In AD, as in other neurodegenerative diseases, the beneficial effect of RES is multifaceted. Its immediate effect is probably associated with its antioxidant activity [92], but at a more extended time, its activation of SIRT1 and modulation of NF-kB signaling may result in other beneficial effects, such as inflammation. It was proposed other two roles of SIRT1 in the nucleus of AD-affected neurons: i) SIRT1 may deacetylate and repress p53 activity of the neurons and prevent the apoptotic death; ii) SIRT1 may deacetylate and suppress apoptotic activities of FOXO (forkhead transcription factor) proteins and promote neuronal survival [90]. It has been showed that RES, acting through SIRT1 activation, protected mouse neurons against the cytoxicity of the mutant polyglutamine protein huntingtin [93]. Huntingtin is produced by a gene mutated in the Huntington’s disease and could form cytotoxic aggregates in neurons [94]. RES decreased cell death associated with neurons cultured from a mutant huntingtin knockin mice, in manner that is reversible by two SIRT1 inhibitors, sirtinol and nicotinamide. Interestingly, the combination of RES with catechin in PC12 cells could exert a synergic protection against the A toxicity [95]. RES and catechin have different chemical and physical properties and may distribute themselves in different cell compartments. The

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utilization of different polyphenols, as present in diet, may protect more efficiently from complex mechanisms of A toxicity. However, the relevance of these findings to in vivo models remains to be demonstred. 3.2 Modulation of Nitric Oxide Toxicity In the last years, nitric oxide (NO) and its reactive metabolites have been shown to play a key role in the processes causing neuronal cell death in Parkinson’s disease (PD) either in terms of prooxidants and mediators of inflammatory response. Therefore, the blockage of NO synthesis or the scavenging of reactive nitrogen species (RNS) could represent a novel and efficient tool against PD progression. In this context, RES is a promising natural antioxidant and anti-inflammatory molecule that is proposed to be used in neurodegenerative diseases associated with oxidative/nitrosative stress [96]. The antioxidant function likely depends on the scavenging capacity of free radicals among which are included NO-derived reactive species. Moreover, RES exhibits the ability to induce the expression of intracellular antioxidants enzymes. The antiinflammatory activity of RES depends on inhibition of the inflammatory genes expression such as eicosanoid generating enzymes and iNOS, mainly through interfering with the activation of the upstream NF-kB transcription factor [96]. In addition, some polyphenols may inhibit the release of pro-inflammatory molecules (IL1, TNF
and IL-6). Since PD is a multifactorial disease in which NO, inflammation and oxidative stress play important roles, the use of compounds such as RES, showing poly-pharmacological activities, appears greatly attractive. The schematic picture, reported in Fig. (3), illustrates the mechanisms by which polyphenolic agents (like RES), can modulate NO toxicity in Parkinson’s disease.

Fig. (3). NO involvement and anti-infiammatory, anti-oxidant activity of poliphenols in PD.  = increase;  = decrease (modified from Aquilano et al. [96]).

On the whole, the observations reported in literature strongly suggest that the anti-oxidant and anti-inflammatory agents based on polyphenols compounds could be proposed for PD treatment. Another recent study shows that resveratrol administration attenuates the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)induced parkinsonism, which includes motor coordination and function impairment. RES treatment also decreases the MPTPinduced neuronal damage and free radical overloading in the substantia nigra [97]. 4. ANTITUMORAL ACTIVITY OF RESVERATROL In addition to cardioprotective and neuroprotective effects, RES can affect the processes underlying all three stages of carcinogene-

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sis, involving tumor initiation, promotion and progression. It has also been shown to suppress angiogenesis and metastasis. The anticarcinogenic effects of RES appear to be closely associated with its capacity to interact with multiple molecular targets involved in cancer development, while minimizing toxicity in normal tissues as tested. The chemopreventive property of RES has been shown by its ability to block the activation of various carcinogens and /or to stimulate their detoxification, to prevent oxidative damage of target cell DNA, to reduce inflammatory responses and to decrease proliferation of cancer cells. The chemotherapeutic potential of RES is indicated by blockade of angiogenic and metastatic processes of tumor progression, and reduction of chemotherapy resistance (Fig. 4) [98]. RES inhibits in vitro cell growth of leukemias, prostate, breast, and other epithelial tumors [16, 37, 99-103]. Moreover, RES blocks the development of preneoplastic lesions in carcinogentreated mammary glands in culture [104]. In animal models of carcinogenesis, experiments to evaluate RES’s chemopreventive properties have been similarly encouraging. In mice, RES blocks tumorigenesis in skin damaged by UV radiation, and in rats it blocks mammary gland neoplasia [16, 105]. RES shows multiple molecular and biochemical properties: it produces antioxidant and prooxidant effects; it directly binds to several molecular targets including estrogen receptors and the F1 component of mitochondrial ATP synthase; it inhibits tubulin polymerization and it induces cell cycle arrest and apoptosis [99, 101-103, 105-107]. Overall, multiple overlapping mechanisms can contribute to the agent’s activity against precancerous or cancer cells. Some studies have focused on the possible molecular targets which could explain the antiproliferative/apoptotic effects of RES. Resveratrol could modulate some pathways responsible for inducing cell cycle arrest and eventually apoptosis as shown in Fig. (5) [12].

Fig. (4). Chemopreventive and chemotherapeutic potentials of resveratrol (modified from Kundu and Surh [98]).

4.1 Modulation of Cancer Cell Cycle The effect of RES in cell cycle progression is highly dependent on the cellular model investigated. Generally, RES has been reported as inducing S-phase arrest [102, 108-110], but it may block cells also in the G1 [109, 111] or, less frequently, in the G2/M phase [112,113]. Moreover, the RES-induced block in a specific cell cycle phase may be characterized by a different modulation of molecules involved in cell cycle control. Cell sensitivity to apoptotic agents may change throughout cell cycle phases; RES ability to arrest cancer cells in S-phase, which is the most vulnerable, may strongly increase its chemotherapeutic potential [114]. In in vivo experiments, it was demonstrated that, although RES could inhibit the growth of both leukemic and normal bone marrow progenitor cells, growth arrest of the normal hematopoietic progenitors was achieved at higher RES concentrations [115]. RES inhibited growth of normal progenitor cells at an IC50 of 59
M versus 18-34
M for the leukemic cells. Furthermore, in these experiments, it was shown that the normal progenitor cells significantly recovered their ability to engraft in vivo after an in vivo treatment with 80
M RES, whereas the anti-leukemic effect was found fully irreversible after treatment of the cells. The anti-proliferative effect of RES has been

Brisdelli et al.

Fig. (5). How resveratrol could possibly affect cell cycle arrest and apoptosis (modified from Signorelli et al. [12]).

attributed to its ability to interference with various stages of cell cycle progression [116] and arrest of DNA synthesis [117]. Various cyclins, cyclin-dependent kinases (CDK), CDK inhibitors and check point kinases (Chk1 and Chk2) are involved in the homeostatic maintenance of cell growth and differentiation [118]. Therefore, RES may inhibit abnormal cell proliferation by downregulating cyclin-CDKs and/or upregulating CDK inhibitors. RESstimulated S-phase arrest has been associated with: a) an increase in cyclin E and A without affecting cyclin D1 in HL60 leukemia cells [102], or b) with a downregulation of cyclin D1 and cyclin A with no alteration in cyclin E expression in SW480 colon carcinoma cells [108], or c) with a cyclin E and cyclin A increase and cyclin D1 downregulation in colon cancer Caco-2 cells [119]. RES treatment has been reported to suppress proliferation in cancer cells by decreasing the expression or activities of cell cycle regulators, such as the cyclin-dependent kinases CDK4 and Cdc2 and, subsequently decreasing the activities of the cyclin-CDK complexes which drive the cell to replicate [98]. The induction of cell cycle arrest by the polyphenol has been associated to an upregulation of both the oncosuppressor p53 and the cyclin kinase inhibitor p21/Waf1/Cip1 in SKH-1 hairless mouse skin stimulated with UV irradiation [120], in human prostate (DU145) [121], breast (MCF-7) [122] and lung (A549) cancer cells [123]. In human epidermoid carcinoma (A431), besides upregulation of p21/Waf1/Cip1 the anti-proliferative effect of RES was associated with the down-regulation of E2F transcription factor and the decrease of hyperphosphorylation of Rb protein [124]. RES was shown to inhibit other known key regulators of cell proliferation such as PKC [125]. It was observed that the polyphenol directly destroy the tyrosyl radical on the R2 subunit of ribonucleotide reductase, the enzyme

Resveratrol: A Natural Polyphenol with Multiple Chemopreventive

responsible for the conversion ribonucleotides to 2’-deoxyribonucleotides which provides the precursor molecules necessary for both DNA synthesis and repair [117]. Inhibition of this enzyme results in arrest of the cell in the G1 phase of the cell cycle. 4.2 Inhibition of Cell Survival Signaling RES has been reported to induce apoposis in several cancer or transformed cells in culture, in chemically induced mouse skin tumours, in transplanted tumors in nude mice [98, 126, 127]. Induction of apoptosis by RES occurs through both CD95- and mitochondrial-mediated pathways depending on the cancer cell type. It may interfere with apoptotic pathways both directly triggering apotosis-promoting signaling cascades and by blocking anti-apoptotic mechanisms. By blocking survival and antiapoptotic pathways, RES can sensitize cancer cells, which may result in synergistic antitumor activities when RES is combined with conventional chemotherapeutic agents or cytotoxic compounds [128]. Mitochondrial-mediated apoptosis may be induced by RES through direct inhibitory action on the F0/F1-ATPase proton pump of the mitochondrial inner membrane [129]. RES decreases the expression of anti-apoptotic Bcl-2 proteins in several different cancer cells [21]. Bcl-2 inhibits Bax translocation from cytosol to mitochondria during drug-induced apoptosis of human tumor cells [130]. Indeed, the ratio between these two subsets determines, in part, the susceptibility of cells to a death signal [131]. Furthermore, these deathinducing proteins heterodimerize with members of the deathinhibitory family [132]. Overexpression of Bcl-2 and Bcl-xL protein protects a wide variety of cell types from many death-inducing stimuli [133-136]. Bcl-2 expression is regulated, among other pathways, by PI3K and NF-kB. PI3K activation leads to PKB/AKT-dependent phosphorylation of IKK, which in turn phosphorylates and causes degradation of I-kB. This process releases and allows nuclear translocation and transcriptional activation of NF-kB [137, 138]. Activated NF-kB induces transcription of target genes such as Bcl-2 [139] and MMP-9 [140, 141]. Both anti-apoptotic and pro-apoptotic Bcl-2 family members play an important role in regulating the integrity of the mitochondrial membrane [142]. Bcl-2 coordinates and processes multiple death signals that converge on the mitochondria [143, 144]. The anti-apoptotic proteins Bcl-2 and Bcl-xL, as well as the pro-apoptotic proteins Bax and Bak, interact with the adenine nucleotide translocase (ANT) that is part of the mitochondrial permeability transition pore (MPTP) [145-147]. It was suggested that targeting mitochondrial function with modulators of MPTP and RES to trigger apoptosis may be effective as an alternative and novel chemotherapeutic strategy in the treatment of acute lymphoblastic leukaemia [148]. RES induces apoptosis, at concentrations comparable to those found in wine and grapes, in human microsatellite-unstable colon carcinoma cell line HCT116 independently of p53 status [149]. In this cellular system, apoptosis was primarily mitochondriamediated and blocked by caspase-3 inhibitor. Bax is transiently overproduced in response to RES independently of p53. Cytochrome c release uncouples the respiratory chain and thereby favors the transfer of electrons to oxygen to generate ROS; thus, ROS production is a relatively late event in this apoptosic cascade. Other authors have furthermore shown that following apoptotic stimuli Bax levels do not always increase but that, instead, the occluded Nterminus of Bax may become exposed and the protein may then colocalize with the mitochondria in response to RES exposure, independently of the p53 tumor suppressor [150, 151]. RES induced apoptosis in various cancer cells in a cell typespecific manner, even within a specific disease, being p53dependent in certain cells, while p53-independent in others. In three

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7

gastric adenocarcinoma cancer cell lines, two of which (AGS and SNU-1) express p53 and one (KATO-


) with deleted p53, RES induced fragmentation of DNA and cleavage of nuclear lamins A and B and PARP, irrespective of their p53 status [152]. RES had no effect on either anti-apoptotic Bax or pro-apoptotic Bcl-2 and BclxL, did not promote cleavage of Bid and had no effect on subcellular redistribution of cytochrome c. RES up-regulated p53 protein in SNU-1 and AGS cells but the modulation of intracellular apoptotic signals between these cell lines was different. SNU-1 cells responded to RES treatment with down-regulation of survivin, whereas in AGS and KATO-III cells RES stimulated caspase 3 and cytochrome c oxidase activities [152]. In a previous paper, we have demonstrated a different sensitivity to RES-induced apoptosis of two human leukemia cell lines [153]. Human chronic myeloid (K562) cells, whose intracellular glutathione (GSH) content is almost ten times higher than acute lymphoblastic (HSB-2) leukemia cells, appeared more resistant to RES-induced apoptosis. However, the major resistance to apoptosis exhibited by K562 cells cannot be attributed to their higher pool of reducing power, since neither the inhibition of glutathione synthesis by buthionine sulphoximine nor glutathione depletion by diethylmaleate, sensitized these cells to RES exposure [153]. Our data indicated that RES commitment to apoptosis in both cell lines, is independent from the intracellular GSH concentration, whereas it is associated with either the enhanced expression of Bax and cytochrome c release. Other authors have reported experiments that show RES as a powerful inducer of programmed cell death in ovarian cancer cells [154]. The death mechanism has been characterized, revealing that RES not only triggers apoptosis but ultimately causes cell death through autophagocytosis (type II programmed cell death). Bcl-2 appears to have a relevant role in RES-induced apoptosis in MCF-7 cells. Its expression decreased in cells undergoing apoptosis and MCF-7-Bcl-2 cells, transfected to overexpress this protein, were insensitive to apoptosis. These data are in agreement with previous results showing that RES decreased Bcl-2 levels in human promyelocytic leukemia HL-60 cells [155]. In cancer cell lines derived from ovary [154], pancreas [156], immune system [157] and colon [150], RES-induced apoptosis involved cytochrome c release and caspase-3 activation. However, in MCF-7 cells, even at high concentrations, RES was unable to release cytochrome c to the cytosolic compartment in such a way that could explain the induction of apoptosis. Since cytochrome c is required to induce assembly of the apoptosome [158, 159], the possibility that formation of this complex could be impaired in MCF-7 cells exposed to RES, cannot be excluded. Although absence of cytochrome c release from mitochondria could, by itself, compromise the activation of effector caspases, the fact that MCF-7 lacks caspase-3 activity due to a point mutation in the caspase-3 gene [160] might suggest that mitochondria-dependent caspase activity is not involved in RESinduced apoptosis. Several studies have shown that RES can induce apoptosis by an alternative pathway mediated by caspase-8 [161, 162]. However, RES did not induce caspase-8 activity and downstream apoptotic events regulated by caspase activity, such as PARP proteolysis and nucleosomal DNA laddering in MCF-7 cells. It was suggested that in this cell line RES induced apoptosis should follow an alternative, non-caspase mediated mechanism. Another molecule that could participate in caspase-independent apoptosis is NO [163, 164]. Depending on cell type and intracellular redox status, NO can induce apoptosis or necrosis, acting as a molecular switch between the two processes [165]. RES-induced apoptosis in MCF-7 human breast cancer cells could take place through a caspase-independent mechanism, mediated by Bcl-2 downregulation and involving loss in
m and increase in ROS and NO production. Decreased Bcl-2 levels appears to be the consequence of NF-kB inhibition, which could be the result of lowered PI3K and calpain activities.

8 Current Drug Metabolism, 2009, Vol. 10, No. 7

Prostate cancer prevention by elements present in human nutrients derived from plants and fruits has been confirmed in various cell cultures and tumor models [166, 167]. RES inhibited growth and induced apoptosis of androgeninsensitive prostate cancer cells (PC-3 and DU-145) through multiple mechanisms [168]. RES induced the expression of pro-apoptotic proteins Noxa, Bim, Bak, and Bax, and inhibited anti-apoptotic proteins Bcl-2 and Bcl-xL . It caused translocation of Bax to mitochondria, release of mitochondrial proteins (Smac/DIABLO, cytochrome c, and AIF), ROS generation, survivin inhibition, and activates caspase(s). Furthermore, RES upregulated TRAIL-R1/DR4 and TRAIL-R2/DR5 which, in turn, enhanced the apoptosis-inducing potential of TRAIL. Thus, RES alone or in combination with TRAIL could be used to prevent and/or treat human prostate cancer [168]. Treatment of androgen-sensitive prostate cancer cells (LNCaP) with RES at the concentration of 10
M for 48 h have demonstrated alterations in the expression of p53 target genes associated with cell cycle arrest and apoptosis [169]. Activation of pro-apoptotic genes including p53, p21/Waf1/Cip1, PIG 7 and PIG 8, p300/CBP, Apaf1, BAK and zinc finger proteins by RES was consistent with the downregulation of androgen receptor-associated-protein 24 (ARA 24), prostate-specific antigen (PSA), NF-kB p65 and Bcl2. The effect of RES on p300/CBP plays a key role in its cancer preventive mechanism(s) in LNCaP cells. These results implicate activation of more than a single set of functionally related molecular targets [169]. Recently, it was observed an intracellular accumulation of ceramide associated to RES treatment in breast and prostate cancer cells [170, 171]. Ceramide is the key component of complex sphingolipids and the mediator of many intracellular events such as proliferation, differentiation, senescence and cell death [172]. Ceramide from de novo synthesis is the plausible mediator of the growth inhibitory/apoptotic effects induced by RES in metastatic breast cancer cells (MDA-MB-231) (170). A recent paper reported that differences in the pharmacokinetic behaviour of RES can be responsible of the different mode of cell death [173]. In the metabolically active hepatoma (H4IIE) cells apoptosis was elicited by RES while the percentage of necrotic cells was negligible. Despite formation of DNA strand breaks, no sign of apoptosis could be detected upon RES treatment in metabolically scarcely active glioma (C6) cells which rather died by necrosis. It appears that a moderately high RES concentration present only in the very beginning of the damage is sufficient to trigger the initial stimulus for the programmed cell death. However, to maintain the sequence of events which ultimately lead to manifest apoptosis, RES concentrations must then decrease below toxic levels; otherwise the cell will be driven into necrosis. These results suggest that the usefulness of RES for cancer prevention and treatment strongly depends on the metabolic capacity of the tumor cells to be eradicated. 4.3. CHEMOSENSITIZING EFFECTS The use of cancer chemopreventive phytochemicals in combination with chemotherapeutic agents has been shown to be an approach to sensitize chemoresistant cancer cells to apoptosis or growth arrest, while minimizing the side effects arising from the conventional therapy [174]. Tumor cells may acquire resistance through upregulation of key antiapoptotic components or by downregulation of proapoptotic signaling molecules. Chemotherapy resistance is further reinforced by the emergence of multidrug resistant phenotypes following initial chemotherapy administration due to the action of membrane-bound drug efflux pumps [175-177]. The multidrug resistant phenotype plays a role in the drug resistance of multiple myeloma (MM) and non-Hodgkin’s lymphoma (NHL) [176, 177]. Therefore, non-toxic agents that interfere with the function of drug efflux pump or negatively modulate the ex-

Brisdelli et al.

pression of Bcl-2 and IAP family members can be effectively used in combination with the conventional chemotherapy in the clinical treatment of drug-resistant tumors. Despite several efforts, the clinical management of patients with NHL and MM with conventional treatment regimes remains unsuccessful [178-180]. In an attempt to cure such patients, “third-line” chemotherapeutic agents such as paclitaxel have been used with variable and often limited success. Strategies to increase the efficacy and reverse the intrinsic or acquired resistance to these agents are crucial in the treatment of patients with NHL and MM. There is accumulating evidence that paclitaxel, either alone or in combination with other drugs, can be used in the treatment of patients with NHL and MM [179, 180]. Previous papers have reported that tumor cells resistant to chemotherapeutic drugs can be sensitized to apoptosis by the same or other drugs or other agents such as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) [181, 182]. The sensitization was due to the modification of apoptotic gene products involved in the resistance. Because RES can signal for apoptosis in sensitive lines, these authors hypothesized that paclitaxel-resistant NHL and MM cells that are also resistant to RES-induced cytotoxicity may be sensitized by RES to paclitaxel-induced apoptosis. In addition, the same researchers suggested that RES exerts its effects by interfering with signal transduction pathway(s) resulting in selective down-regulation of antiapoptotic factors and chemosensitization. Recently, the above hypotheses were demonstrated providing evidence that treatment with RES can sensitize B-cell-derived tumor cells to apoptosis by subtoxic concentrations of paclitaxel [113]. RES exerts its sensitizing effects by interruption with the cellular signaling pathways, induction of cell cycle arrest, and selective modification of apoptosis regulatory proteins. Paclitaxel also modified several apoptotic regulatory proteins. RES and paclitaxel, separately, were able to modulate the expression of apoptotic regulatory gene products, but these events were insufficient to induce apoptosis. Through functional complementation, however, the combination of both drugs induced synergistic apoptosis. These findings suggest that RES can overcome paclitaxel resistance in B-cellderived tumor cell lines in an in vitro model system [113]. Both RES and paclitaxel shared similar modifications of apoptosis regulatory proteins (Bcl-xL, Mc1-1, and Apaf-1) and exhibited unique modifications (Bax for RES and c-IAP-1 and Bid for paclitaxel). The combination treatment, through complementation of these apoptotic regulatory proteins, resulted in the execution of the apoptotic signaling pathway. Bax up-regulated by RES and tBid, caspase-8 cleaved form of Bid, both undergo insertion into the mitochondrial membrane to form oligomers large enough to allow the diffusion of apoptogenic proteins from the mitochondria to the cytosol [183, 184]. Bax overexpression enhances the sensitivity of ovarian cell lines to paclitaxel-mediated apoptosis in in vitro and in vivo model systems and induces apoptosis in Burkitt’s lymphoma cell lines [185-187]. Additionally, induction of Bax decreases the threshold of tumors to paclitaxel-induced apoptosis [188, 189]. Since RES has been shown to increase intracellular levels of Bax [149], the above reported data concur with these findings. P-glycoprotein, a product of multi drug resistant gene (MDR-1), reduces intratumoral concentrations of chemotherapeutic drugs by effluxing drugs from cells. It plays a key role in developing chemoresistance. RES was shown to inhibit the P-glycoprotein function and increase accumulation of daunorubicin in multidrugresistant KB-C2 cells, thereby sensitizing them to apoptosis [190]. 5. GENOTOXIC ACTIVITY OF RESVERATROL Although, great interest in RES as a cancer chemopreventive or even cancer therapeutic agent has been raised, in contrast to this view, some authors claim that RES exhibits a genotoxic potential on in vitro systems [191]. Investigations on the genotoxic potential of RES have found an induction of micronuclei and mitotic chromosome displacement in L5178Y mouse lymphoma cells and the

Resveratrol: A Natural Polyphenol with Multiple Chemopreventive

induction of micronuclei in Chinese hamster V79 cells [191]. In line with these results are the observations of Matsuoka et al. [192, 193] who described that in Chinese hamster lung cells RES induced chromosomal aberrations at 10.9–87.6 μM, micronuclei and sister chromatid exchanges dose dependently up to 43.8 μM but the bacterial reverse mutation assay (Ames test) was negative. On the other hand there are observations that RES acts as effective radicalscavenger and therefore, might be a natural anti-oxidant against oxidative DNA-damage [194]. More recently, safety studies conducted on high-purity trans-resveratrol showed non-mutagenic, in a bacterial reverse mutation assay in Salmonella typhimurium and Escherichia coli, but clastogenic activity in a chromosomal aberration test in human lymphocytes. However, in an in vivo bone marrow micronucleus test in rats, RES was non-genotoxic [195]. The achievable plasma level for human exposure is also close to the range of genotoxicity. It has been reported [196, 197] that RES could accumulate in peripheral tissues after daily ingestion; a significant cardiac accumulation and a strong affinity for the kidney and the liver were found. Therefore, concentrations that were genotoxic in vitro might be reached in human exposure. Although RES is an antioxidant and a potential cancer chemopreventive agent, it cleaves DNA strongly in the presence of Cu(II), without oxidative transformation to the catechol structure [198]. Catechol is the typical polyphenol that is essential for generating oxygen radical in the presence of Cu(II) [199]. The DNA cleavage is attributed to the generation of copper-peroxide complex that is formed by electron transfer from RES to molecular oxygen [198]. The oxidative product of RES is a dimer and formation of the catechol structure has not been reported [200]. Therefore, the oxidative dimer might be formed by dimerization of RES radical as a result of the reductive activation of molecular oxygen. RES alone, at any of the concentrations tested, did not damage the lymphocyte DNA whereas on addition of Cu(II) DNA damage to varying degrees was observed. Therefore, RES–Cu(II) system is capable of causing DNA degradation in cells such as lymphocytes. Further, the DNA degradation of lymphocytes is inhibited by scavengers of reactive oxygen and neocuproine, a Cu(I) specific sequestering agent [201]. The RES–Cu(II) system for DNA breakage is physiologically feasible and could be of biological significance. In a recent work, the number and positions of the hydroxyl groups in the stilbene structure were associated with DNA-cleaving activity and the 4-hydroxy group of stilbene played an especially critical role in DNA cleavage [202]. The high binding affinity of a hydroxyl group at the 4-position with both Cu(II) and DNA makes it possible to form a ternary complex and therefore could cleave DNA efficiently. When the heats of formation (Hf) of three types of resveratrol radicals are compared (Fig. 6), the 4-oxyl radical of RES is the most stable, thus indicating that the hydroxyl group at the 4-position is much more subjected to oxidation than other –OH groups [202]. These results suggest that the ability of RES to induce oxidative DNA damage in the presence of Cu(II) can be ascribed to the structure of 4-hydroxystilbene which is comparable to that of catechol. It is possible that cellular DNA fragmentation by plant polyphenolics that involves mobilization of intra-cellular and extracellular copper could be one of the mechanisms involved in the chemopreventive properties of these compounds. However, further studies of RES-induced genotoxicity including in vivo investigations and elucidation of the molecular mechanism(s) underlying genotoxic activity would be desirable to clarify and possibly prevent a potential risk for the human health. 6. HORMONAL ACTIVITY OF RESVERATROL Epidemiological evidence indicates that phytoestrogens inhibit cancer formation and growth, reduce cholesterol levels and show benefits in treating osteoporosis (203). Some of these activities are mediated through the interaction of phytoestrogen with estrogen receptors
and  (ER
and ER). RES was shown to bind ER in

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cytosolic extracts from MCF-7 cells (estrogen receptor positive) and rat uteri, to induce estrogen responsive genes and thus it could be considered a phytoestrogen [204, 205]. RES binds ER
and ER with comparable affinity, but with much lower affinity than estradiol; it appears to be an agonist for ER and an antagonist for ER
in a majority of models and in some cases a weak agonist of ER
[19]. The relative abundance of ER
and ER could determine whether RES acts as an estrogen-agonist or antagonist. This indicates that those tissues that uniquely express ER or that express more ER than ER
may be more sensitive to RES’s estrogen agonist activity. In absence of estradiol, RES appears to be both estrogenagonist and antagonist; in presence of estradiol, it is an antiestrogen [105] and inhibits human breast cancer cell growth [206]. It antagonizes the growth-promotion and the expression of progesterone receptor induced by estradiol in MCF-7 cells. The mechanism could mainly be a direct competition with estradiol for its receptor, but could also involve other activities such as the prevention of ER binding to the estrogen responsive element or the inhibition of ER-mediated transactivation [116]. In mouse mammary glands grown in culture, RES inhibited the formation of atypical ductal hyperplasia induced by 7,12dimethylbenz(a)anthracene and promoted by estradiol. Furthermore, RES inhibited the early stages of N-methyl-N-nitrosoureainduced mammary carcinogenesis when administered to female Sprague Dawley rats. These studies support the hypothesis that RES is a novel selective estrogen receptor modulator (SERM) that may be useful for the chemoprevention of breast cancer [105]. Hormone replacement therapy has long been recommended for osteoporosis, but has been attributed to an increased risk of breast cancer and cardiovascular disease. RES could be used in reducing postmenopausal osteoporosis without enhancing the risk of breast cancer. RES was found to exhibit bone-protective effects equivalent to those exerted by hormone replacement therapy and decrease the risk of breast cancer in the in vivo and in vitro models [207]. Bone-protective effects of RES occurs by the induction of bone morphogenetic protein-2 via SRC kinase-estrogen receptor-FOXA1 axis. RES minimizing the tumor potential inactivating Akt and accumulating FOXO3a in the nucleus [207]. 7. RECENT ADVANCES ON RESVERATROL ACTIVITY Additionally, Some Papers have Added New Data on RES Effects i) Recent in vitro and in vivo studies have shown RES to display antidiabetic properties [208-212]. RES has been also reported to stimulate glucose uptake [212] and suppress the palmitate-induced impairment in insulin signaling in C2C12 muscle cells [211]. In in vivo experiments, RES was proved to protect mice against high-fat diet-induced insulin resistance [208, 212] and to attenuate the increase in blood glucose, lipid levels and diabetic symptoms in streptozotocin-induced diabetic rats [210]. The mechanism(s) by which RES exerts its anti-diabetic properties are not yet fully elucidated. A potentiation of the insulin signaling cascade and/or activation of AMP-activated protein kinase (AMPK) have been proposed [208, 209, 213]. SIRT1 has been postulated to play a key role in regulating glucose homeostasis [209, 214] and may be implicated in the insulin signaling cascade [215]. The role of sirtuins on muscle glucose transport has not been fully examined. In addition, although stimulation of glucose transport by RES has been previously reported, its mechanism of action and the effect on glucose transporters is at present unknown. In a very recent paper, the effects of RES on glucose uptake and glucose transporter translocation in L6 skeletal muscle cells were investigated [216]. The results of this study show for the first time that RES stimulates glucose uptake in L6 cells in a dose- and time-dependent fashion, independent of insulin. Akt/PKB, and GLUT4 or GLUT1 translocation do not appear to be

10 Current Drug Metabolism, 2009, Vol. 10, No. 7

Brisdelli et al. OH

.

O

. H



H f = + 4,2 kc al mo l-1 OH

. H

O

.

OH HO HO

OH

OH

. H

OH HO

O

.



H f = +4,4 k cal mol -1

Fig. (6). Three types of resveratrol radicals.

involved in RES’s action but the mechanism seems to involve SIRT-dependent AMPK activation that may lead to stimulation of the intrinsic activity of the GLUT4 glucose transporters [216]. ii) More recently, a study on in human breast epithelial cells (MCF-10F) showed that RES can completely inhibits estrogenDNA adduct formation through its antioxidant properties, as well as induction of the phase II enzyme NAD(P)H quinone oxidoreductase 1 (NQO1), providings evidence that RES may be a new tool for prevention of breast cancer [217]. The inhibitory effects of RES are due to three factors. Firstly, NQO1 induction provides a decrease in estrogen quinones and an increase in catechol estrogens [218]. Secondly, it is the inhibition of CYP1B1 expression which decreases the formation of 4-catechol estrogens [218, 219]. Thirdly, it is the antioxidant properties of RES that reduce the estrogen semiquinones to catechol estrogens, as indirectly determined in vitro [220]. Thus, RES may be very effective in preventing cancer initiation by estrogens because it induces the protective enzyme NQO1, inhibits overexpression of CYP1B1 and acts as an antioxidant, presumably reducing catechol estrogen semiquinones to catechol estrogens. iii) Intriguingly, recent studies have shown that RES blocks the IL-1-induced apoptosis in cultured human chondrocytes by inhibiting caspase-3, cleavage of PARP and p53 activation [221] The mechanism by which RES blocks the apoptotic effects of IL-1 may involve suppression of the transcription factor NF-kB and its downstream gene targets. NF-kB plays an important role in normal physiological and immune mediated functions. However, inappropriate regulation of NF-kB activity has been involved in the pathogenesis of several diseases including rheumatoid arthritis (RA) and osteoarthritis (OA) [222, 223]. Furthermore, it has been shown that both subunits (p50 and p65) of NF-kB are abundant in RA, OA and in synovitis [224]. As a matter of fact, pro-inflammatory cytochines such as IL-1 and TNF-
are known to activate NF-kB [225], which in cartilage stimulates further pro-inflammatory cytochine expression and leads to increased cartilage degradation [226]. Overall, NF-kB plays a pivotal role in inflammatory processes such as RA and OA, leading to cartilage degradation and joint disease. NF-kB is therefore an attractive therapeutic target in the clinical treatment of RA and OA. Moreover, RES displays, as a naturally occurring anti-inflammatory agent, potential capacity of treating OA through suppression of NF-kB and of NF-kB-regulated gene

products, thus providing a novel and mechanistic explanation for resveratrol’s actions on the NF-kB pathway as a proteasome inhibitor [227]. v) Contrarily to RES’s plethora of health benefits including protection against cardiovascular disease, various cancers, type II diabetes, and also life extending properties, the beneficial effects of RES in skeletal muscle have been given less attention in the literature compared to other tissues. Therefore, the focus of a very recent review [228] has been to highlight the cellular effects of RES in skeletal muscle. RES has been shown to alter protein catabolism and muscle function, and confer resistance against oxidative stress, injury, and cell death of skeletal muscle cells. The mechanisms underlying these RES-induced adaptations in skeletal muscle are then reported [228]. 8. CONCLUSIONS AND PERSPECTIVES In spite of the huge efforts to search for a cure, tumors still remain a fearful challenge for human health. It has been predicted that the number of cancer-related deaths may double in the next 50 years [229]. Although chemotherapy is until now the most practiced tool to fight cancer, it can only contribute to overall patient’s survival with often compromised quality of life. Moreover, an increasing rise of chemoresistance and the recurrence of secondary neoplasias put chemotherapy at the back foot in the struggle against cancer. In this context, the practice of cancer prevention by using nontoxic chemical agents, commonly termed “chemoprevention”, is considered to be not only a promising alternative, but a more realistic and fundamental strategy for the management of this fearful disease. A wide variety of preclinical studies demonstrate the outcome of chemoprevention in reducing the burden of cancer. Increasing evidence from clinical-based and laboratory studies suggests that regular consumption of fruits and vegetables is inversely correlated with the risk of several neoplasms [230]. Besides antioxidant vitamins, many non-nutritive substances present in vegetable-based diet, collectively called phytochemicals, have been identified as promising chemopreventive agents not only against cancer, but even against cardiac, brain and age-related diseases. Some of these dietary chemopreventive compounds have been reported to display chemotherapeutic potential as well. Therefore, fighting cancer and other severe diseases with naturally occurring sub-

Resveratrol: A Natural Polyphenol with Multiple Chemopreventive

stances, especially those derived from plant-based diet, appears to be a fascinating strategy. It is currently running an accelerated phase of developing dietary phytochemicals as potential chemopreventive/chemotherapeutic agents. Because of the wide heterogenity of tumors, it is hard to find a specific molecular target for the prevention or treatment of cancer. Thus, a cancer preventive/therapeutic agent should affect multiple biochemical pathways involved in the process leading to malignancy, while it should minimize or lack any undesired toxicity or noxious side effects in normal tissues. Among the ever-increasing number of naturally occurring anticarcinogenic agents, RES has been extensively investigated with respect to its underlying molecular and cellular mechanisms. As described in previous sections of this review, RES has been shown to target different molecular switches involved in carcinogen metabolism (either activation and detoxification), inflammation, cell proliferation, cell cycle, apoptosis, angiogenesis, cardioprotection, neural tissue degeneration, tumour metastasis, lifespan control, etc. Taking into account its multifactorial molecular targets, Pezzuto asserted very timely that RES induces “biologically specific tsunami” [231]. Despite strong advances in the understanding of the molecular basis of anti-tumoral activity of RES, there have been scarce clinical studies compared to its preclinical findings. A recent phase-I clinical trial demonstrates that RES daily intake (5 g), does not cause any noxious side effects in healthy individuals, but the peak plasma level (2.4
mol/L) remains quite below the minimum required concentration (5
mol/L) of the polyphenol to exert the chemopreventive effect in cultured cells [232]. The study also indicates the presence of several fold higher plasma levels of RES monoglucuronides and RES-3-sulphate. Another phase-I clinical trial for evaluating the safety and the pharmacokinetic profile of repeated administration of RES has recently been initiated, while a phase-I colon cancer prevention trial is currently under development at the University of California, Irvine, USA [213]. Results of these phase I trials will provide significant basic informations useful in planning large scale clinical studies to assess the chemopreventive and chemotherapeutic efficacy of RES. However, pharmacokinetic data from investigations already performed with animal models indicate a poor bioavailability of RES. Thus, further studies are necessary to enhance the bioavailability of the drug by modulating its metabolism, discovering new appropriate formulations, identifying possible interactions with other dietary factors, and developing more bioavailable analogues of RES [98]. Nevertheless, currently available preclinical and mechanistic data suggest that RES might be a promising candidate to be applied for the molecular target-based cancer prevention and therapy as well as for other severe and/or fatal diseases. Finally, because RES is nontoxic to the pancreatic cells, this natural polyphenol has the potential to be developed as drug candidate for type II diabetes [233]. ACKNOWLEDGEMENTS The authors are grateful to Italian Ministry of the University and Research (PRIN 2004) for partial support of this research. ABBREVIATIONS RES = Resveratrol ERKs = Extracellular regulated kinases CYP1A1 and CYP1A2 = Cytochrome P450 isoenzymes DMBA = 7,12-Dimethylbenzanthracene CHD = Coronary heart disease NO = Nitric oxide cGMP = Cyclic guanosin monophosphate LDL = Low density lipoproteins ROS = Reactive oxygen species ICAM-1 = Intracellular adhesion molecule-1

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VCAM-1 LPS TNF- IL-1- NF-kB iNOS nNOS PKC COX-2 AP-1 MAPK Raf-1 MEKK-1 CDK7 kinase BCNU AKT FAK VEGF PIDD IAP MM NHL TRAIL

= = = = = = = = = = = = =

Vascular cell adhesion molecule-1 Lipopolysaccharide Tumor necrosis alpha Iterleukin, 1 beta Nuclear factor-kB Inducible nitric oxide synthase Neuronal nitric oxide synthase Protein kinase C Cyclooxigenase-2 Activator protein-1 Mitogen-activated protein kinase Cellular homolog of viral raf gene Mapk kinase kinase 1

= = = = = = = = = =

Mcl-1 Bid PI3K IKK MMP-9 PARP Bim PUMA MOMP

= = = = = = = = =

AIF Smac/ DIABLO

=

Cyclin-dependent kinase 7 Carmustine (1-3-bis-chloroethyl-nitrosurea) Protein kinase B Focal adhesion kinase Vascular endothelial growth factor p53-induced protein with a death domain Islet amyloid polypeptide Multiple myeloma Non-Hodgkin’s lymphoma Tumor necrosis factor-related apoptosisinducing ligand Myeloid cell leukemya sequence 1 BH3 interacting domain death agonist Phosphatidylinositol-3 kinase IkB kinase Matrix metalloproteinase-9 Poly (ADP-ribose) polymerase BH3-domain protein p53-upregulated modulator of apoptosis Mitochondrial outer-membrane permeabilization Apoptosis-inducing factor

Cdc 2 CDK4 p21Cip1/WAF1

= = =

E2F MCP-1 ICAM-1 STAT3

= = = =

Rac1 AD NEP ECEs IDE

= = = = =

=

second mitochondria-derived activator of caspases/direct inhibitor of apoptosis-binding protein with low pI Cell division cycle 2 Cyclin-dependent kinase 4 Protein mediator of cell cycle arrest in response to DNA damage Proteins of the family of transcription factors Monocyte chemoattractant protein-1 Intercellular adhesion molecule 1 Signal transducer and activator of transcription 3 Ras-related C3 botulinum toxin substrate 1 Alzheimer’s disease Neutral endopeptidase Endothelin converting enzymes Insulin-degrading enzyme

12 Current Drug Metabolism, 2009, Vol. 10, No. 7

SIRT1

=

Trx-1 HO-1 NCX EMMPRIN PMA PPAR JNK GLUTs GSH MPTP PD RNS RA OA 8-OH-dG UGT SULT ER
m

= = = = = = = = = = = = = = = = = = =

Sirtuin (silent mating type information regulation 2 homolog) 1 Thioredoxin-1 Oxygenase-1 Na+/Ca2+ exchange protein Extracellular matrix metalloproteinase inducer Phorbol 12-myristate 13-acetate Peroxisome proliferator-activated receptor  Jun N-terminal kinase glucose transport isoforms reduced glutathione 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Parkinson’s disease Reactive nitrogen species Rheumatoid arthritis Osteoarthritis 8-Hydroxy-2’-deoxyguanosine UDP glucuronosyltransferase Sulfotransferases Endoplasmic reticulum Mitochondrial membrane potential.

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