Moreover, structure-activity studies have shown that the substitution of methoxy groups for the hydroxyl groups in resveratrol significantly increases its cytotoxic activity [].
The modified derivatives of resveratrol are produced by glycosylation, methylation, oligomerization, isomerization, halogenation, or isoprenylation [—] Figure 3. Methylated resveratrol derivatives, namely, pinostibene and pterostilbene, were produced in recombinant E. A similar type of methylated derivative of resveratrol was also produced by Kang and colleagues by assembling codon-optimized S.
Moreover, the additional expression of the glycosyltransferase gene YjiC from Bacillus licheniformis DSM13 to the resveratrol biosynthesis monocistronic pathway produced 7. In a different approach of in vitro enzymatic glycosylation, ten different derivatives of resveratrol glycosides were produced [1].
Similarly, a hydroxylated product of resveratrol called piceatannol is biosynthesized in some of the plants because of the action of pinosylvin synthase, since it was suspected for its multifunctional activities [52]. About 1. Furthermore, 5. Similarly, Rimal et al. Structures of resveratrol derivatives produced using different post-modification enzymes. Figure 3. Methylated resveratrol derivatives, namely, pinostibene and pterostilbene, were produced in Furthermore, Yang and coworkers have observed the C-prenylation on resveratrol or recombinant E.
Such prenylated stilbenoids have shown very effective coumarate—coenzyme A ligase from S. A similar type of methylated derivative of resveratrol was also produced Additionally, by Kang andthe enzymesbyCloQ colleagues and Orf2, assembling obtained from codon-optimized S.
Moreover, Another enzyme the called additional expression NaphB that isof the glycosyltransferase obtained gene sp. Prenylated modified compounds are highly potent against many human diseases hence such a compound has high scope in the pharmaceutical aspect.
Molecules , 24, 14 of 21 3. Conclusions Because of its potent biological activities in terms of medical and nutraceutical values, resveratrol and its derivatives are of great interest and demand.
Recently developed biological tools and techniques help to produce such a bioactive plant product in microbial hosts with low cost and minimal time range. Despite the lack of resveratrol biosynthetic genes in microbial hosts, they are a great alternative source for the large-scale production of resveratrol and its derivatives because of the application of metabolic engineering and synthetic biology approaches.
Recent research has shown that a pure form of resveratrol can be produced in heterologously engineered microorganisms, which reduces extensive processing. However, still, the overall production of resveratrol and its derivatives is not adequate despite applying all the recent techniques. Therefore, each gene involved in the biosynthetic pathways should be well-optimized to improve enzyme activity in trans-located hosts by supplying sufficient precursors and regulating the concentration of resveratrol inside the cell, which could help to increase production.
Therefore, there should be a focus on a combinatorial approach to directing every metabolite and precursor towards resveratrol production. Moreover, complete knowledge of synthetic and molecular biology of each component involved, such as the whole genome, transcriptome, proteome, and metabolome, during the biosynthesis of resveratrol help to increase the production from the microbial platform.
Author Contributions: S. Conflicts of Interest: The authors declare no conflict of interest. References 1. Pandey, R. Enzymatic biosynthesis of novel resveratrol glucoside and glycoside derivatives. Gambini, J. Properties of resveratrol: In vitro and in vivo studies about metabolism, bioavailability, and biological effects in animal models and humans.
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Resveratrol was first identified in as a constituent of the roots of white hellebore Veratrum grandiflorum O. Plant sources of resveratrol. Resveratrol is now recognized as a naturally occurring phytoalexin produced by a wide variety of plants other than grapes such as peanuts and mulberries in response to stress, injury, ultraviolet UV irradiation, and fungal Botrytis cinerea infection as part of their defense mechanism.
In resveratrol was also detected in the leaf epidermis and the skin of grape berries but not in the flesh [7—9]. Fresh grape skins contain 50 to mg resveratrol per gram, and the concentration in wine may range from 0. Agents that can suppress inflammation thus have a potential in mitigating the symptoms of the disease. Resveratrol exhibits antioxidant and antiinflammatory activities and thus may have potential in the treatment of these diseases see Figure 1.
The numerous targets that have been identified for resveratrol are listed in Table 1. Microarray analysis has also shown that resveratrol differentially modulates the expression of many genes [12—15] in multiple cell-signaling pathways. One attractive alternative for treating proinflammatory diseases is resveratrol, which has been found to suppress COX-2 expression [16]. It has not yet been extensively tested in patients, however. Therefore its toxicity profile has not been definitively established.
Murias et al. Hydroxylated but not methoxylated resveratrol derivatives showed a high rate of inhibition. The effect of structural parameters on COX-2 inhibition was evaluated by quantitative structure—activity relationship analysis. Docking studies on both COX-1 and COX-2 protein structures also revealed that hydroxylated but not methoxylated resveratrol analogs bind to the previously identified binding sites of the enzymes.
Hydroxylated resveratrol analogs therefore represent a novel class of highly selective COX-2 inhibitors and promising candidates for in vivo studies. Additionally, tumors eventually develop resistance to chemotherapeutic agents.
Thus, agents that can sensitize tumors to chemotherapeutic agents are needed. Bcl-2 and Bcl-xl have been implicated in chemoresistance. Opipari et al. This mechanism may give resveratrol and its derivatives a distinct advantage in the treatment of ovarian cancer that is chemoresistant on the basis of ineffective apoptosis. Wu et al. They used the transplantable murine hepatoma22 model to evaluate the antitumor activity of resveratrol alone or in combination with 5-fluorouracil 5-FU in vivo [19].
These data demonstrated that the ortho-diphenoxyl functionality imparts much higher antioxidative activity against ROS-induced peroxidation in membrane mimetic systems [19]. In similar experiments, Blond et al.
Additionally, resveratrol was found to prevent metal-induced LP in microsomes and low-density lipoproteins LDLs. The authors compared the response of resveratrol to that of the polyphenols astringin and astringinin, and found that the presence of the para-hydroxy moiety in ring B and the meta-hydroxy moiety in ring A Figure 3.
Similarly, Sun et al. Resveratrol has also been shown to scavenge peroxyl and hydroxyl radicals in reperfused postischemic isolated rat hearts, to reduce infarct size and to reduce the formation of MDA [23,24].
Further evidence for the anti-LP activity of resveratrol was reported in peripheral blood mononuclear cells isolated ex vivo from healthy humans. Addition of resveratrol to the culture medium reduced the intracellular LP caused by dR [11]. Inhibition of LP by resveratrol was apparently due to the hydrogen donating properties rather than chelation of iron [18]. The inhibition of LP by resveratrol has also been shown in in vivo assays.
For example, it has been reported that after spinal cord injury there is augmented ROS generation. In a recent study, the administration of resveratrol in spinal-cord-injured rats significantly reduced the MDA content as an index of LP, indicating that resveratrol might have a significant effect on the pathway [25]. To define the molecular mechanism s of resveratrol inhibition of LP, Tadolini et al. Their results indicated that resveratrol inhibits LP mainly by scavenging lipid peroxyl radicals within the membrane, like a-tocopherol.
These data seem to support both anti- and pro-oxidant activity of this compound, depending on the concentration of resveratrol and the cell type. For example, Ahmad et al. Likewise, in rat hepatocytes exposed to ferrylmyoglobin-induced oxidative stress, physiological concentrations pM to nM of resveratrol exerted prooxidant activities [28].
In addition, it is well known that heme iron—protoporphyrin IX is a prooxidant and its rapid degradation by heme oxygenase is believed to be neuroprotective. Using primary neuronal cultures, resveratrol was able to induce significantly heme oxygenase 1.
This study indicated that the increase of heme oxygenase activity by resveratrol is a unique pathway by which this compound can exert its neuroprotective actions [30]. Further corroborating the prooxidant activity of resveratrol are data demonstrating its ineffectiveness in protecting proteins bovine serum albumin from oxidative damage induced by metal-catalyzed reactions or alkylperoxyl radicals [31]. Antioxidant polyphenolic compounds, relatively abundant in red wines, have been considered to be mainly responsible for such epidemiological observations [35].
This disease is characterized by lipid accumulation in the arterial wall, and starts with the attraction, recruitment, and activation of different cell types which provokes a local inflammatory response.
Several significant targets contribute to the development of atherosclerotic lesions. The major ones are LDLs which are generated in the circulation by remodeling of very low-density lipoproteins VLDLs through the mechanisms of lipolysis and the exchange of lipids and proteins with high-density lipoproteins HDLs.
During transit in the circulation, oxidative changes may occur affecting the lipids. Although the exact mechanism whereby LDLs are oxidized in vivo is unclear, several studies indicate that LDL oxidative modification is a result of the interaction between the products of polyunsaturated fatty acid PUFA oxidation and apolipoprotein B molecules Apo B Unlike the physiologic LDL receptor, the scavenger receptor is not downregulated when the cell cholesterol content increases and the process leads to abnormal accumulation of cholesterol, cell activation, and transformation [37].
Uptake of ox-LDL foam cells by subendothelial macrophages is the initial process of the formation of atherosclerotic plaque [38]. In recent studies carried out with human hepatocarcinoma cell-line HepG2, which retain most of the functions of normal liver parenchymal cells, the addition of resveratrol to the culture medium resulted in a significant decrease in the intracellular concentration of APO B and its secretion which may be responsible for impaired LDL and part VLDL synthesis [39].
There is evidence to support the suggestion that resveratrol interferes with a number of antioxidant mechanisms leading to the inhibition of the development of atherosclerosis.
As a matter of fact, resveratrol may protect LDL molecules against peroxidation through antioxidative activity and metal chelation [40]. Frankel et al. The high capacity of the stilbene to chelate copper is potentially useful in vivo since LDLs are known to have a high ability to bind copper, preventing oxidative modification of LDL [36,41].
Fremont [36] found that the chelating capacity of the cis isomer was about half that of the trans isomer, suggesting that the special position of hydroxyl groups is of prime importance for chelation of copper.
Ferroni et al. However, some in vivo studies using hypercholesterolemic rabbits have not provided evidence for antilipogenic effects of resveratrol [43,44]. In addition, Ray et al. Blood platelets are found at the sites of early atherosclerotic lesions. When activated, blood platelets may produce ROS and secrete potent mitogenic factors such as platelet-derived growth factor, which lead to smooth muscle proliferation and progression of atherosclerotic lesions.
Blood platelets are the target cells of ROS action in the local environment; ROS function as signaling molecules in the stimulation of platelet activation [46].
Preliminary results obtained by Olas et al. Olas et al. Resveratrol also reduced oxidative stress induced by vitamin C at a pro-oxidative dose mM. Under physiological conditions a moderate upregulation of eNOS is associated with beneficial effects, e.
NO maintains coronary vasodilatory tone and inhibits adhesions of neutrophils and platelets to vascular endothelium. Several reports have shown a role for resveratrol in the regulation of the production of NO from vascular endothelium [49,50].
Abnormally high concentrations of NO and its derivatives peroxynitrite or nitrogen dioxide are devastating agents causing another form of cellular stress based on the generation of reactive nitrogen species RNS which causes cellular degeneration in various tissues, contributing to the development of neurodegenerative damage. In addition, increased NOS induction and activity have been associated with tumor growth and vascular invasion.
Lorenz et al. It also induced an inhibitory effect on the iNOS enzyme activity. Similar data were found by Matsuda et al. In this model, resveratrol also inhibited NO production. Similarly, in another study using rat macrophages stimulated with thioglycollate, resveratrol at concentrations of 10 to mM significantly and dose-dependently inhibited reactive nitrogen intermediate production.
The results obtained demonstrate that resveratrol is a potent inhibitor of the antipathogen responses of rat macrophages and, thus, suggest that this agent may have applications in the treatment of diseases involving macrophage hyperresponsiveness [54]. For this reason, they are particularly susceptible to oxidative stress and have been widely used as a model for oxidative stress and antioxidant studies [55,56].
Cai et al. Nevertheless, in spite of little information available related to the hepatoprotective effects of resveratrol, there is evidence that this polyphenol has been used as a positive free radical scavenger control against hepatotoxic effects induced by tacrine [57] through a mechanism that involves oxidative stress [58].
Stellate cells are now known to play central roles in hepatic fibrogenesis induced by viral infection, alcohol, and various drugs. These cells are the major source of extracellular matrix components ECM in normal and pathological conditions [59].
There is evidence that oxidative stress enhances the proliferation of cultured stellate cells and their collagen synthesis [60,61].
Furthermore, an independent stimulation of ECM deposition seems to occur at a prenecrotic stage during oxidative stress-associated liver injury [62,63]. Kawada et al. This fact suggests that resveratrol might affect the posttranscriptional process of generating these proteins. Arterial thrombosis induced by atherosclerosis is a common cause of cerebral infarct. Several studies have suggested a relation between cerebral Resveratrol as an Antioxidant 45 recirculation after an ischemic process and ROS [65,66].
The delayed neuronal death that appears as a consequence of a transient ischemia in cerebral ischemic damage, in rodent models, is the result of augmented NO production and the attenuated redox regulatory system. Either of them leads to the development of apoptosis and an increase of oxidative stress, respectively.
Some investigators have indicated a potential neuroprotective activity for resveratrol based on its beneficial effects in cerebral ischemia models [67]. For example, it has been evaluated as a neuroprotective agent by virtue of its antioxidant properties, being effective in focal cerebral ischemia caused by middle cerebral artery occlusion [68], preventing motor impairment, increasing levels of MDA and GSH, and decreasing the volume of infarct as compared to control [69]. Other investigators have shown that resveratrol inhibits apoptotic neuron cell death induced by ox-LDLs [70,71] through inhibition of nuclear factor kappa B NF-kB and activator protein AP -1 pathways [70,72].
Its antiapoptotic effects also involve activation of caspase and degradation of poly ADP-ribose -polymerase route through inhibition of the mitochondrial cell death pathway [73]. Resveratrol is also able to protect against excitotoxic brain damage induced by kainic acid administration [74].
Chronic ethanol ingestion is known to cause oxidative damage in the brain, among other organs, as a consequence of the ability of ethanol to enhance ROS production and LP [75—77]. These radicals are related to XO and 6-hydroxydopamine [78,79] and can cause more cellular damage than OH radicals because they are more reactive and have a longer half-life.
The consumption of red wine containing high levels of polyphenolic compounds together with a high-fat diet in France are related to low incidences of coronary heart diseases. Some authors have demonstrated that resveratrol protects neurons against oxidative stress [70,71], and also that it reduces neuron cell death induced by ethanol [22].
Sun and Sun [77] also reported that resveratrol protected the brain from neuronal damage due to chronic ethanol administration and suggested that it might be used as a therapeutic agent to ameliorate neurodegenerative processes. However, moderate wine consumption correlates with a lower risk for this disease, suggesting an. These plaques can mediate oxidative stress and induce neuronal toxicity through their ability to disrupt ion homeostasis [82,83] and so contribute to cell death.
The protein oxidation and LP resulting from the increase in ROS generated from amyloid plaques affect the functionality of cell membranes [84]. There is evidence that resveratrol is able to restore intracellular GSH levels following oxidative stress induced by b-amyloid plaques [81].
Other effects of resveratrol in protecting brain cells from injury are related to the antiinflammatory activity that it exerts in astrocytes and their ability to inhibit NO production induced by cytokines [5]. Neuronal damage may be produced by an increase in oxidative and inflammatory mechanisms which are associated with glial cell activation. This free radical may cause oxidation of biomolecules resulting in alteration of important enzymes and proteins such as glutamine synthetase and synaptophysin [77].
As mentioned above, the antioxidant properties of resveratrol ameliorate intracellular ROS and attenuate hippocampal cell death [81]. Furthermore, resveratrol is able to downregulate the expression of iNOS protein without altering iNOS activity derived from microglial cell activation [5].
In the CNS the heme oxygenase HO system has been reported to be active and to operate as a fundamental defensive mechanism for neurons exposed to an oxidant challenge.
In this sense, exposure of astrocytes to resveratrol resulted in an increase of HO-1 mRNA, but it was not able to induce HO-1 protein expression and activity [88]. In another study, Czapski et al. They demonstrated that resveratrol was the most potent among the investigated antioxidants. Resveratrol as an Antioxidant 47 Kiziltepe et al. For this reason, they suggest the use of resveratrol in humans as a new neuroprotective agent to avoid paraplegia that results from spinal cord ischemia caused by thoracic and thoracoabdominal aorta surgical procedures.
Previously, Yang and Piao [25] showed that resveratrol has neuroprotective effects, including protecting axon, neuron, myelin, and subcellular organelles, and reducing local spinal tissue edema as secondary damage of spinal cord injury through improving the energy metabolism system and suppressing LP, preventing nerve functions being exacerbated progressively, preventing mitigating nerve damage, and maybe promoting nerve regeneration.
These agents could contribute to diverse cellular events associated with tumorigenesis causing structural alterations in DNA, affecting cytoplasmic and nuclear signal transduction pathways, and modulating the activity of proteins and genes that regulate cell proliferation-, differentiation-, and apoptosis-related genes Figure 3. However, O2 and H2O2 do not react with DNA bases at all, but both of them can release iron from ferritin or heme proteins, respectively, and this metal ion could then bind to DNA damaging it as a consequence of a chelating ability of DNA.
The chemical modification of DNA bases induces a change in their hydrogen bonding specificity with subsequent mutation. Local DNA structure can change due to a nonplanar disposition of the oxidized bases. Thereby, not only changes in bases could be produced, but also changes in DNA conformation [91]. For example, H2O2 is able to induce the activation of the transcription factor NF-kB through the displacement of the inhibitory subunit, or stimulate the transcription or the activation of stress-induced proteins and genes.
Furthermore, oxidation by this reactive agent not only could affect the activity of DNA repair enzymes as a consequence of protein damage, but also produce a range of mutagenic carbonyl products through ROS attack on lipids [91].
The suggestion that resveratrol affects tumor cells in vitro and in vivo is based on a large number of publications in recent years. Nevertheless, the precise mechanism through which resveratrol exerts its antitumor effects and the molecule targets remain unclear and seem to depend on cell type and tumor model. Thus, resveratrol has been suggested as a potential chemopreventive agent based on the inhibitory effects that it exerts on cellular events involved in the three stages of carcinogenesis: tumor initiation, promotion, and progression [16].
Resveratrol prevents the initial DNA damage by two different pathways: i acting as an antimutagen through the induction of phase II enzymes, such as quinone reductase, capable of metabolically detoxifying carcinogens by inhibiting the COX and cytrochrome P 1A1 enzymes known to be able to convert substances. It has been proposed that free radicals derived from LP may function as tumor initiators. Recently, Leonard et al. The antipromotional and anticarcinogenic properties of resveratrol can be partly attributed to its ability to enhance gap-junctional intercellular communications in cells exposed to tumor promoters such as TPA [29].
The development of skin cancer is related to cumulative exposure to solar UVB as well as the nuclear transcription factor NF-kB, which plays a critical role in skin biology.
This important factor is involved in the inflammatory and carcinogenic signaling cascades, and resveratrol is able to prevent the activation of NF-kB caused by free radicals: resveratrol has a significant inhibitory effect on the NF-kB signaling pathway after cellular exposure to metal-induced radicals [8]. Resveratrol may also protect cells against endotoxin-induced inflammation by preventing NF-kB activation through the blockage of IkB kinase activity.
As tissue inflammation is provoked by tumor promoters and serves as a driving force in tumor promotion, the use of antiinflammatory agents as chemopreventives at this stage of carcinogenesis has also been evaluated [95]. Resveratrol has been shown to exert antiinflammatory activity, reducing arachidonic acid release and induction of COX-2 by an antioxidant action [12].
Finally, resveratrol also possesses chemotherapeutic potential because it is able to inhibit tumor progression. Indeed, it suppresses growth of various cancer cell lines, partly by an inhibition of DNA polymerase and inhibition of deoxyribonucleotide synthesis through its ability to scavenge the essential tyrosyl radical of the ribonucleotide reductase [96] and partly by inducing cell cycle arrest [29].
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Breast Cancer. Resveratrol as a Phytoestrogen. In Vitro Studies. In Vivo Studies. Prostate Cancer. Colon and Digestive Tract Cancers. Lung Cancer. Melanoma and Skin Cancer. Cancer of the Brain and Other Nervous Tissues. Cancers of the Female Genital Apparatus. Cancers from Other Sites. Kidney Cancer. Thyroid Cancer. Oral Carcinoma. Conclusions and Perspectives. Resveratrol has been shown to affect several intracellular targets that are key regulators of cell cycle and cell survival or death.
Resveratrol may therefore counteract the altered functionality of proliferative versus apoptotic pathways, exerting an antitumor activity either as a cytostatic or as a cytotoxic agent that depends on cellular specific pattern of expression of proteins related to tumorigenesis processes. In this chapter the action of resveratrol on intracellular targets is reviewed in a variety of human cancer cell lines as well as in in vivo studies on tumor-bearing animals.
It is extensively studied and potentially curable by hormonal therapy or by drugs specifically directed against tumor antigens. Estrogens are prosurvival hormones and their withdrawal may result in development of enhanced survival pathways that increase cellular proliferation rate and resistance. Preliminary clinical studies indicate that estrogens are able to act as apoptotic agents and that high doses can cause tumor regression in postmenopausal women [1,2].
The remaining hormone-independent tumors are associated with a higher rate of proliferation and metastatization, are less differentiated, and are not responsive to common therapy [3].
A therapeutic approach is offered by selective estrogen receptor modulators SERMs that may provide agonistic and antagonistic effects [2]. Retinoic acid receptor and peptide growth Resveratrol as an Antiproliferative Agent for Cancer 59 factor receptors are implicated i.
The activity of the transcriptional factor NF-kB, implicated in the organogenesis of the mammary gland, is upregulated in many breast tumors, being a downstream target of hormone-activated receptors and an upstream modulator of breast cancer tumor promoters such as cyclin D1, cyclooxygenase COX -2, matrix metalloproteinases MMPs , etc.
Moreover gene mutations in the cell cycle controller p53 and in the oncosuppressors DNA-repairing enzymes BRCA1 and 2 [3,6] and prosurvival factors survivin and Bcl-2 family members [7] are frequently present and may serve for detection of the risk of cancer developing. Resveratrol as a Phytoestrogen Resveratrol binds ERa and ERb with an affinity lower than 17b-estradiol [8], and is classified as a type I estrogen.
Efficacy Ref. Mechanism of Apoptosis by Resveratrol 97 and daunorubicin. However, in contrast to its apoptosis-inducing activity, resveratrol has also been shown to inhibit apoptosis in some systems.
In this regard, an earlier report indicated that resveratrol interfered with H2O2induced apoptotic signal [62]. Our recent in vitro data seem to suggest a biphasic concentration—response relationship. Contrary to the apoptosis-inducing activity at relatively high concentrations 30 to mM , we showed that prior exposure of cells to low concentrations of resveratrol 4 to 8 mM could create an intracellular milieu resistant to apoptosis induced by either H2O2 or anticancer drugs [67,68].
These data sound a cautionary note for the use of resveratrol in combination chemotherapy regimens as the slight prooxidant effect of resveratrol could provide cancer cells with a survival advantage by impeding death execution signals. Obviously, these data are in contradiction to earlier reports describing the ability of resveratrol to enhance sensitivity of tumor cells to drug-induced apoptosis.
However, in the reports demonstrating sensitizing effect of resveratrol, cells were preexposed for 24 hours with resveratrol followed by subsequent treatment with the chemotherapeutic agent [54].
Whereas preexposure with 30 to mM resveratrol for 24 hours had some effect on cell proliferation, there was no significant effect induced at 10 mM. The relatively low bioavailability of resveratrol, its rapid clearance, and relatively poor accumulation in specific tissues in rats as detailed earlier, suggest that a long preincubation of cells with resveratrol may not represent the true clinical scenario.
The arrested lymphocytes following 24 hour treatment with 50 mM RES had minimal RNA content, the feature characteristic of G0 cells, and were blocked at the stage past the induction of cyclin D2 and D3 and prior to induction of cyclin E.
RES causes downregulation of hyperphosphorylated pRb protein with a relative increase in hypophosphorylated pRb that, in turn, compromises with the availability of free E2F. Furthermore, consistent with entry of LNCaP cells into S phase, there was a dramatic increase in nuclear cdk 2 activity associated with both cyclin A and cyclin E. Therefore, this unique ability of RES to exert opposite effects on two important processes in cell cycle progression, induction of S phase and inhibition of DNA synthesis, may be responsible for its apoptotic and antiproliferative effects.
The compound inhibited the growth and proliferation of Caco-2 cells in a dose-dependent manner Perturbed cell cycle progression from S to G2 phase was observed for concentrations up to 50 mM, whereas higher concentrations led to reversal of the S-phase arrest. These effects were specific for RES; they were not observed after incubation with the stilbene analogs stilbene methanol and rahpontin.
The phosphorylation state of the Rb protein in Caco-2 cells was shifted from hyperphosphorylated to hypophosphorylated at mM which may account for the reversal of the S-phase block at concentrations exceeding 50 mM. These findings Resveratrol in Health and Disease suggest that RES exerts chemopreventive effects on colonic cancer cells by inhibition of the cell cycle [31].
Western blot analysis of positive cell cycle regulators cdc2, cdk2, cdk4, cdk6, cyclin A, cyclin D1, and cyclin E showed a dose-dependent increase in cyclin E levels and an increase in cyclin A levels only at concentrations up to mM, suggesting the presence of an S to G2 block. As a positive regulator of cdk4 and cdk6, cyclin D1 has been implicated in controlling the G1 phase of the cell cycle and is frequently overexpressed in human colon adenocarcinoma [32]. RES inhibits the proliferation of pulmonary artery endothelial cells, which, based on flow cytometric analysis, correlates with the suppression of cell progression through S and G2 phases of the cell cycle [33].
All of the observed effects of RES, including induction of apoptosis at its higher concentration, are also compatible with its putative chemopreventive or antitumor activity. Based on flow cytometric analysis, RES inhibited the proliferation of HT29 colon cancer cells and resulted in their accumulation in the G2 phase of the cell cycle. Western blot analysis and kinase assays demonstrated that the perturbation of G2 phase progression by RES was accompanied by the inactivation of p34cdc2 protein kinase, and increase in the tyrosine phosphorylated inactive form of p34cdc2.
The active mitotic kinase MPF, or mitosis-promoting factor is a dimer comprised of a catalytic subunit, p34cdc2, and a regulatory subunit, a B-type cyclin [37]. The cyclins are a class of proteins that are synthesized during the interphase of each cell cycle and rapidly degraded at the end of mitosis [38].
The activity of the p34cdc2 kinase not only depends on its association with Resveratrol as Inhibitor of Cell Cycle Progression cyclin B, but also on its phosphorylation state.
Phosphorylation of either Thr14 or Tyr15 inhibits p34cdc2 kinase activity, while phosphorylation of Thr by CDK7 kinase is required for kinase activity [39]. In addition, the dephosphorylation of Thr14 and Tyr15 by CDC25A phosphatase is a final step for performing p34cdc2 kinase activity [40,41]. It is obvious that the target sites for RES arresting in cell cycle progression is varied with different origins of cancer cell lines studied. Different exogenous and endogenous factors involving in the testing cultures might also affect the onset of RES arresting.
Piceatannol differs from RES by having an additional aromatic hydroxyl group Figure 7. RES undergoes metabolism by the cytochrome p CYP1B1 to give a metabolite which has been identified as the known antileukemic agent piceatannol [42].
This observation provides a novel explanation for the cancer chemopreventive properties of RES. It demonstrates that a natural dietary cancer-preventive agent can be converted to a compound with known anticancer activity by an enzyme that is found in human tumors [42].
This result gives an insight into the function role of xenobiotic metabolizing enzyme CYP1B1 and provides evidence for the concept that CYP1B1 in tumors may be functioning as a growth and tumor suppressor enzyme. One of the RES derivatives, trans-3,30 ,40 ,5,50 -pentahydroxystilbene Figure 7.
Compared to RES, this compound also caused cell cycle arrest in the G1 phase, but did not induce p53 activation and Resveratrol in Health and Disease apoptosis. One analog, trans-3,4,40 ,5-tetramethoxystilbene DMU, Figure 7. RES was metabolized to its sulfate or glucuronide conjugates, while DMU underwent metabolic hydroxylation or single or double O-demethylation.
In the light of the superior levels achieved in the gastrointestinal tract after the administration of DMU when compared to RES, the results provide a good rationale to evaluate DMU as a colorectal cancer chemopreventive agent [44]. The increased drug levels in the liver, kidney, lung, and heart obtained after ingestion of RES in comparison to those after DMU reflect the difference in availability observed in the plasma.
The higher availability of DMU in the brain suggests that it is capable of crossing the blood—brain barrier more easily than RES, which is probably a consequence of the higher lipophilicity of DMU [44].
In conclusion, the work described here provides an initial pharmacokinetic groundwork, which contributes to rational decision-making as to the choice of RES analogs that should be selected for comparative testing for cancer chemopreventive potency in preclinical models. Among them, seven compounds displayed marked cytotoxicity. Vaticanol C Vat C, an oligomer derived from four molecules of RES as a major component induced a considerable cytotoxicity in all cancer cell lines tested and exhibited growth suppression in colon cancer cell lines at low dose.
The apoptosis in SW colon cancer cells was executed by the activation of caspase-3, which was shown by Western blot and apoptosis inhibition by caspase inhibitor assay. Overexpression of Bcl-2 protein in SW cells significantly prevented the cell death induced by Vat C.
In summary, Vat C induced marked apoptosis in malignant cells mainly by affecting mitochondrial membrane potential [45]. Further investigations on the cytotoxicity and cancer chemopreventive activities of these derivatives are highly recommended. The author would like to thank his research associates including Prof. Lin-Shiau, Prof. Ho, Prof. Liang, Prof. Tsai and others for their excellent collaboration which made the completion of this chapter possible.
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