The Therapeutic Potential of Resveratrol: A Review of Clinical Trials
 
Kanchan R. Pagar, Sarika V. Khandbahale, D. G. Phadtare
R. G.Sapkal Institute of Pharmacy, Nashik 

*Corresponding Author E-mail: sarikakhandbahale76@gmail.com

 

ABSTRACT:

Resveratrol a polyphenolic phytoalexin possesses a variety of bioactivities associated with health promotion. Resveratrol is readily absorbed along with the other human dietary sources like peanuts, peanut butter, grapes, and red wine. The polyphenolic structure of resveratrol confers antioxidant activity and may reduce oxidant-induced apoptosis and low-density lipoprotein (LDL) oxidation. The cardioprotective activity of resveratrol is associated with the inhibition of platelet aggregation and LDL oxidation and the promotion of artery vasorelaxation. As a chemopreventing agent, resveratrol has been shown to inhibit tumor initiation, promotion, and progression, as well as inhibit the growth of cancerous cells through increased apoptosis and/or cell cycle blockage. Inflammatory processes are associated with the pathogenesis of many chronic diseases including heart disease and diabetes. In addition, the estrogenic activity of resveratrol may help in the prevention of post-menopausal osteophoresis. This review reveals potential health benefits and discusses the current preclinical studies of resveratrol.

 

KEYWORDS: Resveratrol, pharmacokinetics, Antioxidant, Breast cancer.

 

 


INTRODUCTION:

One of the defence responses of plants to infection is the induced accumulation of antimicrobial, low molecular weight secondary metabolites known as phytoalexins (Fremont F, 2000). Resveratrol (3, 5, 4’-trihydroxy stilbene) is a polyphenolicphytoalexin produced naturally by several plants when attacked by bacteria and fungi. Phytoalexins are antibacterial and anti-fungal chemicals produced by plants for the defence against infections by pathogens. Resveratrol which is one of the potent antioxidant is present in red grapes, mulberries and in blue berries, bilberries (Philippe Marambaud et al., 2005), they are also present in other plants, such as eucalyptus, spruce, and lily, and in other foods such as peanuts.

 

 

Resveratrol's most abundant natural sources are Vitisvinifera, labrusca, and muscadine grapes, Polygonumcuspidatumsieb [1]

 

Properties of resveratrol:

Resveratrol is a stilbenoid, a derivative of stilbene, which is produced in plants with help of enzyme stilbene synthatase and it is a fat-soluble compound that exists in a trans-(E) and a cis-(Z) configuration. Both cis- and transresveratroloccur as glucosides (bound to a glucose molecule).

 

Molecular formula: C14H12O3

Molecular weight: 228.24

Melting point: 2530C-2570C

Solubility: Poor solubility in water, soluble in ether, chloroform, ethanol, acetic acid and acetone.

Appearance: fine crystal powder

Color: white

Specific Rotation [α]: -77.5° (c=0.2, EtOH)

 

Pharmacokinetics:

In humans, resveratrol rapidly undergoes phase II conjugation, both glucuronidation and sulphonation at multiple sites on the molecule. The effect of conjugation on efficacy is debated (Goddard I, 2007). The pharmacokinetics of resveratrol metabolism has not been investigated in humans. In rats its half-life is 1.6 h. In 2002, Marieret. al., reported that rats given a single oral dose of 50 mg/kg body weight initially experienced a rapid drop in serum resveratrol levels, the half life, or t1/2, of the drug was found to be 8 minutes. However, detectable levels of the drug remained for 12 hours, probably due to enterohepatic recirculation. Resveratrol’s bioavailability depends on its conjugate forms, glucoronate and sulfonate, despite, most of the in vitro studies use the aglycone form of resveratrol. Resveratrol was quickly metabolized at 25 mg dose in humans. Only trace amounts were found in human plasma, and that most of the oral dose was recovered in urine. In mice, on the other hand were found to have much larger amounts of resveratrol measured in their plasma using equivalent doses of resveratrol per kilogram of weight. It was also stated that the systemic bioavailability of resveratrol is very low in humans compared to mice, but that accumulation of resveratrol in the human epithelial cells along the digestive tract with potentially active resveratrol metabolites may still produce cancer-preventive and other effects. Large doses could theoretically increase the levels of resveratrol in human plasma. [2,3]

 

RECENT STUDIES:

Life Extension:

The groups of Howitz and Sinclair reported in 2003 in the journal Nature that resveratrol significantly extends the Lifespan of the yeast Saccharomyces cerevisiae [4]. Laterstudies conducted by Sinclair showed that resveratrol alsoprolongs the lifespan of the worm Caenorhabditis elegans and the fruit fly Drosophila melanogaster [5]. In 2007, a different group of researchers were able to reproduce Sinclair's results with Caenorhabditis elegans [6], but a third group could not achieve consistent increases in lifespan of D. melanogaster or C. elegans. In 2006, Italian scientists obtained the first positive result of resveratrol supplementation in a vertebrate. Using a short-lived fish, Nothobranchiusfurzeri, with a median life span of nine weeks, they found that a maximal dose of resveratrol increased the median lifespan by 56%. Compared with the control fish at nine weeks that is by the end of control fish’s life the fish supplemented with resveratrol showed significantly higher general swimming activity and better learning to avoid an unpleasant stimulus. The authors noted a slight increase of mortality in young fish caused by resveratrol and hypothesized that it is its weak toxic action that stimulated the defense mechanisms and resulted in the life span extension [7]

Later the same year, Sinclair reported that resveratrol counteracted the detrimental effects of a high-fat diet in mice. The high fat diet was compounded by adding hydrogenated coconut oil to the standard diet; it provided 60% of energy from fat, and the mice on it consumed about 30% more calories than the mice on standard diet. Both the mice fed the standard diet and the high-fat diet plus 22 mg/kg resveratrol had a 30% lower risk of death than the mice on the high-fat diet. Gene expression analysis indicated the addition of resveratrol opposed the alteration of 144 out of 153 gene pathways changed by the high-fat diet. Insulin and glucose levels in mice on the high-fat + resveratrol diet were closer to the mice on standard diet than to the mice on the high-fat diet. However, addition of resveratrol to the high-fat diet did not change the levels of free fatty acids and cholesterol, which were much higher than in the mice on standard diet [8] A further study by a group of scientists, which included Sinclair, indicated that resveratrol treatment had a range of beneficial effects in elderly mice but did not increase the longevity of ad libitum–fed mice when started midlife [9].

 

Various Potential Benefits of Resveratrol:

Anticancer Effects:

Resveratrol was studied for its effects like the initiation, promotion, and progression of cancer (Gusman J, Yang CS et al., 2001; Jang M et al., 1997). Resveratrol a tiny molecule penetrates the cell membrane and nucleus in an organism. There, Resveratrol selectively switches on genes that aid the survival of an organism, like the Sirtuin 1

 

DNA-repair gene. Using gene silencing, it switches off genes involved in the initiation and progression of disease, blocking replication of tumor cells. Few proposed mechanisms of the antitumor effects of resveratrol includes activation of the expression of p53 (Tang HY, 2006), Fas- Fas ligand system, and mitogen-activated protein kinase (MAPK) signaling pathway, inhibition of p450 1A1, ribonucleotide reductase, ornithine decarboxylase, protein kinase C, DNA polymerase, cyclo-oxygenase, cell cycle progression and induces cellular apoptosis. With regard to tumor initiation, it has been shown to act as an antioxidant by inhibiting free radical formation and as an anti-mutagen in rat models. Resveratrol also inhibits the formation of 12- O-tetradecanoylphorbol-13-acetate (TPA). It is a cancer chemo preventive agent that reduces the incidence of tumorgenesis (Savouret, 2002) by intervening at one or more stages of carcinogenesis (Yang CS et al., 2001) thus acting as an anti-initiation agent. Further evidence indicated that resveratrol selectively suppresses the transcriptional activation of cytochrome p450 1A1 and inhibits the formation of carcinogen-induced preneoplasticlesions in a mouse mammary organ culture model, promoted mouse skin tumors in a two-stage model. Resveratrol appears to decrease tumor promotion by inhibiting cyclooxygenase-1 (COX-1), an enzyme that converts arachidonic acid to pro-inflammatory substances that stimulate tumor-cell growth. The enzymatic activities of COX-1 and -2 are inhibited by resveratrol in cell-free models, and COX-2 mRNA, TPA-induced activation of protein kinase C and AP-1-mediated gene expression are suppressed by resveratrol in mammary epithelial cells. In addition, resveratrol strongly inhibits nitric oxide generation and inducible nitric oxide synthase protein expression [10]. NF-kB is important for the regulation of cell proliferation, cell transformation, and tumor development (Baldwon AS, 1996; Ghosh S et al., 1996). NF-kB is strongly linked to inflammatory and immune responses and is associated with oncogenesis in certain models of cancer (Marier JF et al., 2002). Resveratrol suppresses the induction of this transcription factor by a number of mechanisms. The mechanism may involve decreasing the phosphorylation and degradation of IkBα, SR-IkBα, which cannot be phosphorylated or degraded, binds to NF-kB and blocks the nuclear translocation and subsequent transactivation of NF-kB-responsive genes. At the cellular level, Resveratrol also induces apoptosis, cell cycle delay or a block in the G1􀃆 S transition phase in a number of cell lines. Studies related to progression have found that resveratrol induced human promyelocytic leukemia cell differentiation and inhibited ribonucleotide reductase, an enzyme needed for DNA synthesis in proliferating cells. Resveratrol could suppress the proliferation of multiple myeloma (MM) cells by interfering with NF-kB and STAT3 pathways. Resveratrol inhibits the proliferation of human multiple myeloma cell lines which is mediatedthrough suppression of constitutively active NF-kBthrough inhibition of IkBα kinase the phosphorylation of IkBα and of p65. Resveratrol inhibits both the constitutive and the interleukin 6–induced activation of STAT3. Thus resveratrol may have a potential in the treatment of multiple myeloma [11,12].

 

Treatment of Lung Cancer by Resveratrol:

Resveratrol is reported to have protective effects against lung cancer. It involves in the up-regulation of p53 and p21 and the induction of apoptosis by the activation of the caspases and the disruption of the mitochondrial membrane complex. It shows the arrest of A549 cells in the G1 phase of cell cycle. Resveratrol action is mediated via the transforming growth factor-β pathway, particularly through the Smad proteins. Resveratrol is a potent inhibitor of A549 lung cancer. [13]

 

Resveratrol Suppresses Breast Cancers:

Resveratrol suppresses the abnormal cell formation that leads to various types of breast cancer, suggesting its potential role in breast cancer prevention (Krappmann D et al., 1999). The formation of breast cancer is a multi-step process which differs depending on type of disease, a patient's genetic makeup and other factors. However, scientists know that many breast cancers are fueled by increased estrogen, which collects and reacts with DNA molecules to form adducts. Resveratrol has the ability to prevent the first step that occurs when estrogen starts the process that leads to cancer by blocking the formation of the estrogen DNA adducts [14]. Resveratrol induces an enzyme called quinone reductase, which reduces the estrogen metabolite back to inactive form. By making estrogen inactive, resveratrol decreases the associated risk. The researchers also found that resveratrol suppressed the expression of CYP1B1 and the formation of 2, 3, 7, 8 tetrachlorodibenzo-p-dioxin, two known risk factors for breast cancer. Resveratrol increases cAMP but it had no effect on cGMP levels. The stimulatory effects for resveratrol on adenylate-cyclase augmented maximal cAMP formation. The chemotherapeutic agent resveratrol is an agonist for the cAMP/kinase-A system, a pro-apopticand cell-cycle suppressor in breast cancer cells. Resveratrol is a phytoestrogen that displays estrogen-like agonistic (Gehm BD, 1997) and antagonistic activity (Basly JP et al., 2000), which appears to mediate some of its actions by modulating the estrogen machinery and act as an anti-breast cancer agent (Gehm BD, 1997; Srivastava RK et al., 1998). Interestingly, products of adenylatecyclase and guanylate-cyclase enzymes; namely cAMPand cGMP, can trigger both cytostatic and pro-apopticsignals in breastcancer cells (Bani D, 1995 and SovakMA et al., 1997). [15,16]

 

Estrogenic Activity:

Resveratrol was found to have both estrogenic/antiestrogenic activities (Bowers JL et al., 2000). The similarity in structure between resveratrol and diethylstilbestrol (a synthetic estrogen) has prompted investigations into resveratrol's potential as a phytoestrogen (a plant compound that produces estrogen like effects). However, these properties also stimulate the growth of human breast cancer cells. This finding seems contrary to its other anticancer activities, and is a cause for concern. Thus, resveratrol holds great promise for future development as a chemo preventive agent that may be useful for several disorders. Preclinical toxicity studies are underway that should be followed by human clinical trials. However, other studies have found that resveratrol actually fights breast cancer. Citing the evidence that resveratrol is estrogenic, some retailers of resveratrol advice that the compound may interfere with oral contraceptives and that women who are pregnant or intend to become pregnant should not use the product. Still there are no studies which show how it affects natural development; others advise that resveratrol should not be taken by children or young adults under [17,18].

 

Prevention of Cardiovascular Diseases:

Recently the polyphenol resveratrol has been demonstrated to elicit a broad spectrum of biological responses in invitro and in animal studies, including effects that are compatible with the cardio protective roles. Recent studies relating exposure to resveratrol with reduction in myocardial damage during ischemia-reperfusion, modulation of vascular cell functions, inhibition of LDL oxidation, and suppression of platelet aggregation has been presented. It inhibits lipid peroxidation of low-density lipoprotein (LDL), prevents the cytotoxicity of oxidized LDL, and protects cells against lipid peroxidation. It is thought that as it contains highly hydrophilic and lipophilic properties, it can provide more effective protection than other well-known antioxidants, such as vitamin C and vitamin E. Research also indicates that resveratrol has direct inhibitory action on cardiac fibroblasts and may inhibit the progression of cardiac fibrosis. [19].

 

Anti-platelet Aggregation:

The clumping of blood platelets causes blood clotting and thrombosis. Resveratrol is active in preventing platelets from bunching up together and it keeps the blood smoothly flowing through arteries. Recent studies report that resveratrol freely dilates blood vessels bringing down the blood pressure [20].

 

Hypoglycemic and Hypolipidemic Effects:

Resveratrol is reported to possess hypoglycemic and hypolipidemic effects in streptozotocin-induced DM (STZDM) rats. Glucose uptake by hepatocytes, adipocytes, and skeletal muscle and hepatic glycogen synthesis were stimulated by resveratrol treatment. As the stimulation of glucose uptake was not attenuated in the presence of an optimal amount of insulin in insulin-responsive cells, the antihyperglycemic effect of resveratrol appeared to act through different mechanism (s) from that of insulin. In vitro, trans-resveratrol andrumexoid demonstrated a potent inhibitory effect on α-glucosidase activity. In addition, it inhibits production of cytokines which are involved in the development of obesity-related disorders [21].

 

Anti-Viral and Anti-Bacterial Activity:

Infection by Herpes simplex virus ordinarily activates the cell protein nuclear factor κB (NF-κB). Resveratrol suppresses the activation of this transcription and apoptosis-related protein in verocell [22].

 

Cancer prevention:

In 1997, Jang reported that topical resveratrol applications prevented skin cancer development in mice treated with a carcinogen1 [23]. There have since been dozens of studies of the anti-cancer activity of resveratrol in animal models [24]. No results of human clinical trials for cancer have been Reported [25]. However, clinical trials to investigate the effects on colon cancer and melanoma (skin cancer) are currently recruiting patients. In vitro resveratrol interacts with multiple molecular targets, and has positive effects on the cells of breast, skin, gastric, colon, esophageal, prostate, and pancreatic cancer, and leukemia. However, the study of pharmacokinetics of resveratrol in humans concluded that even high doses of resveratrol might be insufficient to achieve resveratrol concentrations required for the systemic prevention of cancer [26]. This is consistent with the results from the animal cancer models, which indicate that the in vivo effectiveness of resveratrol is limited by its poor systemic bioavailability [27,28]. The strongest evidence of anti-cancer action of resveratrol exists for tumours it can come into direct contact with, such as skin and gastrointestinal tract tumours. For other cancers, the evidence is uncertain, even if massive doses of resveratrol are used. Thus, topical application of resveratrol in mice, both before and after the UVB (Ultraviolet B or medium wave) exposure, inhibited the skin damage and decreased skin cancer incidence. However, oral resveratrol was ineffective in treating mice inoculated with melanoma cells. Resveratrol given orally also had no effect on leukemia and lung cancer; however, injected intraperitoneally, 2.5 or 10mg/kg of resveratrol slowed the growth of metastatic Lewis lung carcinomas in mice [29]. Resveratrol (1 mg/kg orally) reduced the number and size of the esophageal tumors in rats treated with a carcinogen [30]. In several studies, small doses (0.02–8 mg/kg) of resveratrol, given prophylactically, reduced or prevented the development of intestinal and colon tumours in rats given different carcinogens. Resveratrol treatment appeared to prevent the development of mammary tumours in animal models, however, it had no effect on the growth of existing tumours. Paradoxically, treatment of pre pubertal mice with high doses of resveratrol enhanced formation of tumours. Injected in high doses into mice, resveratrol slowed the growth of neuroblastomas.

 

Other applications:

Johan Auwerx (at the Institute of Genetics and Molecular and Cell Biology in Illkirch, France) and coauthors published an online article in the journal Cell in November, 2006. Mice fed resveratrol for fifteen weeks had better treadmill endurance than controls. The study supported Sinclair's hypothesis that the effects of resveratrol are indeed due to the activation of the Sirtuin 1 gene.

 

Nicholas Wade's interview-article with Dr. Auwerx states that the dose was 400mg/kg of body weight (much higher than the 22mg/kg of the Sinclair study). For an 80kg (176 lb) person, the 400mg/kg of body weight amount used in Auwerx's mouse study would come to 32,000mg/day. Compensating for the fact that humans have slower metabolic rates than mice would change the equivalent human dose to roughly 4571mg/day. Again, there is no published evidence anywhere in the scientific literature of any clinical trial for efficacy in humans. There is limited human safety data. Long-term safety has not been evaluated in humans. In a study of 123 Finnish adults, those born with certain increased variations of the SIRT1 gene had faster metabolisms, helping them to burn energy more efficiently—indicating that the same pathway shown in the lab mice works in humans.

 

Neuroprotective effects:

In November 2008, researchers at the Weill Medical College of Cornell University reported that dietary supplementation with resveratrol significantly reduced plaque formation in animal brains, a component of Alzheimer and other Neurodegenerative diseases [31]. In mice, oral resveratrol produced large reductions in brain plaque in the hypothalamus (-90%), striatum (-89%), and medial cortex (-48%) sections of the brain. In humans it is theorized that oral doses of resveratrol may reduce beta amyloid plaque associated with aging changes in the brain. Researchers theorize that one mechanism for plaque eradication is the ability of resveratrol to chelate (bind) copper. The neuroprotective effects have been confirmed in several animal model studies [32,33].

 

Anti-inflammatory effects:

The anti-inflammatory effects of resveratrol have been demonstrated in several animal model studies. In a rat model of carrageenan-induced paw edema, resveratrol inhibited both acute and chronic phases of the inflammatory process [34]. Similarly, preincubation with resveratrol decreased arachidonic acid release and COX-2 induction in mouse peritoneal macrophages stimulated with tumour promoter PMA, ROI, or lipopolysaccharides (LPS) [35]. In an experimental rabbit inflammatory arthritis model, resveratrol has showed promise as a potential therapy for arthritis. When administered to rabbits with induced inflammatory arthritis, resveratrol protected cartilage against the progression of inflammatory arthritis [36].

 

Anti Aging effect:

Research started with an obvious theory that caloric restriction extends life by reducing cell damage from free radicals, which are generated when cells burn nutrients in the mitochondria to produce energy. Indeed, a reduction in free radical levels does appear to have some role. But in addition to this, Caloric restriction seems to trigger very specific cellular mechanisms of self-preservation whose biological role is to extend survival of the organism until food intake increases sufficiently to ensure successful reproduction. One biochemical pathway triggered by caloric restriction involves a class of enzymes called sirtuins (named after the corresponding gene sir2). The main role of sirtuins is to selectively regulate the activity of many key genes responsible for metabolism, cell defense, reproduction and other functions. Sirtuins are NAD-dependent histone deacetylases, the enzymes which inhibit the activity of genes by making DNA more tightly packed and thus less accessible for the cell's gene-copying machinery. Resveratrol is a potential sirtuin activator. This potential sprinkler of youth can activate sirtuins and extend lifespan in various species, from yeast to worms to rodents [37].

 

Other Actions:

Resveratrol was reported effective against neuronal cell dysfunction and cell death, and in theory could helpagainst diseases such as Huntington's disease and Alzheimer's disease (Palamara AT and Parker JA et al., 2005). Again, this has not yet been tested in humans for any disease [38].

 

Side Effects of Resveratrol:

Resveratrol is a copper chelator and excessive chelation will impair the availability of copper which is needed for collagen formation and nerve regeneration. There is also evidence that supra-high dose resveratrol inhibits the absorption of folic acid (vitamin B9), an essential nutrient needed for DNA repair (Lemos C et al., 2007). Use of mega-doses of resveratrol (more than 500 mg) has initiated the side effects like anemia, achilles heel tendonitis, anxiety reactions, and numbness in the fingers [39].

 

Safe Dose:

Now an authoritative gene array study, conducted at the William S. Middleton Memorial Veterans Hospital and Lifegen Technologies in Madison, Wisconsin, showed that a dose of resveratrol ~343 milligrams per day (4.9 mg per kilogram of body weight) produces a gene activation profile similar to a calorie restricted diet. Supra-high doses (greater than 500 milligrams) are not required and may produce side effects [40].

 

CONCLUSIONS:

The clinical trials presented in this review show that resveratrol’s therapeutic efficacy depends on several factors. Resveratrol was more effective in certain types of cancer than in others. For example, it seems to epigenetically reduce the expression of certain breast cancer-related genes, but caused severe adverse events specifically in multiple myeloma patients. The vast amount of preclinical data in support of resveratrol’s use as chemopreventive or chemotherapeutic agents warrant further clinical studies. Treatment of patients with AD and stroke was beneficial in all three clinical trials presented, suggesting that resveratrol would be an effective treatment for neurological disorders. However, more clinical trials in this area must be conducted in order to validate this trend. Resveratrol was found to be beneficial for patients with cardiovascular disorders, but perhaps more so in certain demographics than in others, as it was not found to be effective in extremely overweight individuals, and detrimental in schizophrenic patients. In diabetic patients, resveratrol was able to increase insulin sensitivity, decrease blood glucose levels, and positively regulate several other biomarkers associated with diabetes. The effects of resveratrol on NAFLD remain inconclusive, as half of the clinical trials found that resveratrol positively affected NAFLD biomarkers, while the other half observed no changes in those same biomarkers. Similarly, clinical trials of resveratrol in obesity provided conflicting results. Overall, more clinical data are necessary in order to fully understand resveratrol’s therapeutic potential. In addition, future clinical trials should study whether resveratrol is more efficacious in certain patient types.

Pharmaceutical efforts should focus on developing a resveratrol derivative with better bioavailability.

 

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Received on 06.05.2019        Accepted on 14.06.2019

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Asian J. Pharm. Res. 2019; 9(3):193-199.

DOI: 10.5958/2231-5691.2019.00031.5