Resveratrol was first isolated in 1939 by Takaoka from
As described herein, nearly 60 years later, resveratrol was rediscovered and reported in a seminal paper describing pleiotropic activities related to cancer chemoprevention and other disease states (Jang
Interest in resveratrol as a bioactive molecule largely stemmed from the natural occurrence in grapes and grape products, primarily wine, which of course are consumed by humans. Once our report appeared, the sale of grape products containing resveratrol, particularly red wine, significantly increased. In fact, the sale of some grape products containing little or no resveratrol (e.g., grape juice) increased as well. Dietary consumption of resveratrol from natural sources continues to remain of interest. However, most animal, human, and
The fact that so much literature currently exists concerning resveratrol begs the question of why publish yet another manuscript? Here, the main objective is not to rehash the myriad activities that have already been reported and reviewed. Rather, the objective of this report is to present a perspective of events that have transpired in regard to resveratrol over the past 20 years, and a contemporary view of where things stand concerning the future of resveratrol. In addition, some controversy has been generated with resveratrol, as is often the case with substances receiving such colossal attention, and this will be addressed.
Finally, it has been clear from the outset that resveratrol does not abide by the concept of ‘one drug, one target’. In the case of resveratrol, this dogma simply does not apply. The molecule is incredibly promiscuous, interacting with a host of targets (Pezzuto, 2011). Bearing this in mind, a cursory analysis is presented that depicts a network or web of response that likely exists when resveratrol enters the biological milieu. Many literature reports have focused on single targets or isolated pathways but, realistically, resveratrol has the potential of mediating a response analogous to a biological tsunami.
Throughout history, natural products have played a dominant role in the treatment of human ailments. The association of salicylates with the willow, and quinine with cinchona, are renowned examples. Similarly, the legendary discovery of penicillin transformed global existence. Traditional remedies, largely based on terrestrial plants, still dominate therapeutic practices throughout the world, and natural products comprise a large portion of current-day pharmaceutical agents, most notably in the areas of antibiotic and cancer therapies.
For the treatment of cancer, early diagnosis and definitive tumor eradication through radiation therapy or surgical resection offer greatest hope. However, when dealing with malignant, metastatic disease, it is generally necessary to resort to chemotherapy. Although the therapeutic indices of cancer chemotherapeutic agents are often poor, many of the most useful agents have resulted from the systematic investigation of nature. Notable examples include taxol, vinblastine, and camptothecin, or derivatives thereof. These structurally unique agents function by novel mechanisms of action; isolation from natural sources is the only plausible method that could have led to their discovery. In addition to terrestrial plants as sources for starting materials, the marine environment (e.g., bathymodiolamides A and B, bryostatin, ecteinascidin 743, kahalalide F, salinosporamide A), microbes (e.g., bleomycin, doxorubicin, staurosporin), and slime molds (e.g., epothilone B) have yielded remarkable cancer chemotherapeutic agents (Cragg and Pezzuto, 2016).
Irrespective of these advances, cancer remains a leading cause of death worldwide. In the United States, for example, cancer is responsible for about one in every four deaths. Given the morbidity and mortality associated with the disease, as well as the significant economic burden, there continues to be a critical need for more effective strategies (Pezzuto, 1997).
Undoubtedly, the prevention of human cancer is highly preferable to treatment. In this sense, the advent of vaccines for the prevention of hepatitis and liver cancer is probably the greatest success, and the more recent development of vaccines for the prevention of cervical cancer offers promise. Cancer chemoprevention, the use of synthetic or natural agents to inhibit, retard, or reverse the process of carcinogenesis, is another important approach for easing this formidable public health burden. In an ideal world, cancer chemoprevention would work as well as vaccines for the prevention of human ailments. Although this has yet to be accomplished, proof-of-principal has been established by seminal clinical trials conducted for the prevention of breast cancer with tamoxifen, and more recently with tamoxifen relatives such as raloxifene, and a separate class of aromatase inhibitors. Agents such as finasteride have shown promise for the prevention of prostate cancer.
Similar to cancer chemotherapeutic agents, natural products play an important role in the field of cancer chemoprevention. Through serendipity or epidemiological observations, dietary phytochemicals such as sulforaphane and phenethyl isothiocyanate (cruciferous vegetables), epigallocatechin-3-gallate (green tea), curcumin (turmeric), sulfur-containing compounds and selenium (the genus
Using the approach of activity-guided fractionation with a battery of
In sum, natural product research is powerful approach for discovering biologically active compounds with unique structures and mechanisms of action. Given the unfathomable diversity of nature, it is reasonable to suggest that chemical leads can be generated that are capable of interacting with most or possibly all therapeutic targets. With the advent of high-throughput screening, a large number of potential starting materials can be readily evaluated, so informed selections can be made for unearthing prototype ligands worthy of further development as therapeutic agents. This is the backdrop leading to the resurrection of resveratrol.
During the course of the cancer chemopreventive drug discovery project described above, one of the most notable discoveries was the structurally simple stilbene known as resveratrol. Thousands of plant and marine extracts were tested. Some selections were based on literature reports or traditional use; most were randomly selected although factors such as uniqueness (e.g., lack of previous investigation) or endemicity was taken into account. One plant falling into the latter category was acquisition number 46,
At this point, from a phytochemical viewpoint, very little enthusiasm was engendered by a well-known simple stilbene that was devoid of structural novelty. Nonetheless, the fact of good inhibitory activity with COX remained, and it was recognized that significance could be heightened due to the presence of resveratrol in edible products, particularly the grape, and of course products derived from grapes, particularly wine. Accordingly, additional tests were performed and, surprisingly, significant activity was observed in every assay that was performed. In that the test panel had been designed to assess the potential of blocking multiple stages of carcinogenesis (i.e., initiation, promotion, progression), and every test showed a positive result, interest was further intensified.
Nevertheless, in spite of promising data obtained with
Subsequently, we continued to study mechanistic aspects of resveratrol, including interaction within the arachidonic acid binding site of the enzyme cyclooxygenase through crystallographic analysis, absorption and metabolism of resveratrol, production and testing of a series of resveratrol derivatives capable of demonstrating responses with much greater potency and specificity, cancer chemopreventive activity with additional animal models, etc. Obviously, many others in the scientific community did as well (Fig. 2).
Shortly after publication of the paper in
Of course, over the years, many studies have been performed to examine resveratrol absorption, metabolism, excretion, dose-responses, etc. The notion of resveratrol not being absorbed through the alimentary tract following oral administration was simply a ‘red herring.’ Which is not to say the situation is straightforward. For example, achievable serum concentrations are generally many orders of magnitude below the concentrations used in the labyrinth of
Another surprising development occurred within a year of publication of our
Using the same reporter cell line, and as similar experimental conditions as conceivable, our group was not able to reproduce the estrogenic response with resveratrol. There is no simple explanation for this discrepancy, but we felt confident with our results (Bhat
Nonetheless, as implied by Gehm
For time immemorial, human beings have been interested in life extension. Stories appear dating from writings in the 5th century BC and became especially prominent in the 16th century when the “Fountain of Youth” was associated with the Spanish explorer Juan Ponce de León. Resveratrol has been and still is touted as an antiaging concoction, based on reports in the scientific literature with mechanistic underpinnings [e.g., inhibition of IL6, TNFα, and activation of β-catenin (Palomera-Avalos
SIRT1 is a nicotinamide adenine dinucleotide (NAD+)-dependent, class III histone deacetylase (HDAC). Studies reporting activation of SIRT1 by resveratrol were touted to promote longevity and well as mimicking caloric restriction. As the story gained momentum, a company by the name of Sirtris Pharmaceuticals was formed with a proprietary formulation of resveratrol as the product (SRT501). Interestingly, this seemed to capture the attention of the pharmaceutical company Glaxo-SmithKline, and led to the purchased Sirtris Pharmaceuticals for the sum $720 million (US) in 2008 (Pollack, 2008).
Remarkably, however, employing NMR, surface plasmon resonance, and isothermal calorimetry, a report appeared definitively illustrating that resveratrol does not lead to activation of SIRT1 with native peptide or full-length protein substrates (Pacholec
Thus, in essence, the activation demonstrated in previous reports was an experimental artifact resulting from utilization of SIRT1 with peptide substrate containing a covalently attached fluorophore and not with native peptide or full length protein substrates. Frankly, this seemed intuitively apparent. The response reported to be mediated by resveratrol using an assay based on fluorometric output clearly was not specific. Similar results were observed with a variety of mundane compounds such as flavonoids (Howitz
At the time Sirtris Pharmaceuticals was acquired by Glaxo-SmithKline, a phase 2 trial was being conducted in patients with relapsed and or refractory multiple myeloma. The study was terminated noting five patients developed renal failure (Popat
Irrespective of these unusual events, SIRT1 remains one of the most extensively studied targets of resveratrol. It seems that the hype surrounding the direct activation of SIRT1 led to the burst of investment and media frenzy. Therefore, when Pacholec
One pathway that is obvious to satiate the desire to activate SIRT1 involves activation of AMPK which in turn may activate SIRT1 (Canto
In terms of the potential of resveratrol to extend the life of mammals, in a long-term study reported by Miller
Considering the data presented in our first publication regarding the cancer chemopreventive potential of resveratrol (Jang
Many reports in the literature dealing with resveratrol focus on a single target, a group of related targets, or a pathway influenced by an affected target. Given that ‘you find what you seek’, and resveratrol is extraordinarily promiscuous, many individual ‘findings’ have been reported. Naturally, limited data sets are typically presented in any given manuscript, but in a complex biological matrix, other actions are simultaneously mediated, even though the lens of the investigator may not be focused on those responses. In this context, we thought it might be worthwhile to use publicly available drug-target databases to explore a holistic view of targets influenced by resveratrol (Kumar
Based on this premise, protein-protein interaction networks found as targets of resveratrol were created. After combing DrugBank, ChEMBL (protein target classes), PubChem, BindingDB and a manual PubMed search (ABCG2_HUMAN, AMY1_HUMAN, ANO1_HUMAN, BACE1_HUMAN, CCR2_ HUMAN, NM3A_HUMAN, DNM3B_HUMAN, G3P_HUMAN, GSTP1_HUMAN, DM1A_HUMAN, TOP2A_HUMAN, VDR_ HUMAN), a resveratrol-target network was constructed using the STRING (Szklarczyk
As indicated by a search of PubMed, 79 clinical investigations have been reported with resveratrol (Fig. 5). However, 133 trials are listed at ClinicalTrials.gov(2018a). Most of the studies have been (or are being) conducted in the Europe (55) or the US (50), and others have been (or are being) performed in Canada (8), Mexico (4), the Mideast (4), South America (4), China (3), Southeast Asia (3), Australia (1), and Russia (1). We have recently summarized some of the work performed with animals and human beings (Park and Pezzuto, 2015) as have others (Smoliga
Type 2 diabetes (T2DM) is a good example of the dichotomy of results. When administrated for three months at a dose of 250 mg/day, glycemic control and the associated risk factors were improved in patients with T2DM. Resveratrol decreased the mean hemoglobin A1c, systolic blood pressure, low-density lipoprotein cholesterol (LDL-C), total cholesterol, urea nitrogen, and total protein (Bhatt
One might think results such as those described above might be adequate to recommend the use of resveratrol by T2DM patients. To the contrary, however, as reported by Kjaer
As noted above, based on a survey of the literature, there appears to be a high probability of resveratrol being of some value for neuronal diseases (FDR, 5.64e-47). To a large extent, this is based on animal models investigating conditions such as neuropathic pain [thermal hyperalgesia (Sharma
In clinical trials with post-menapausal women, when given a dose of 75 mg/day, it has been suggested that resveratrol can improve brain function by increasing cerebrovascular responsiveness to both hypercapnic and cognitive stimuli, and improve performance of cognitive tasks (verbal memory) and overall cognitive performance (Evans
Overall, however, at that present time, the consensus of expert opinion does not yet support the use of resveratrol for the treatment or prevention of any human ailment (Vang
When considering the potential clinical usefulness of resveratrol, it seems rational to take into account actual blood or tissue levels that can realistically be achieved. In the case of normal dietary consumption, resveratrol intake is frankly minuscule. Thus, most studies involve supplementation, generally through oral administration. However, even following the oral administration of relatively large quantities of resveratrol, average serum concentrations remain in the low to mid nM range. On the other hand, appreciable average plasma concentrations (e.g., 5 μM) of metabolites (resveratrol-3-
Irrespective of these considerations, it seems reasonable that high affinity targets warrant greater attention, and a few have been identified (Kumar
Taking anti-inflammatory activity into account, as well as the pragmatic issue of having effective concentrations reach the target tissue, the use of resveratrol for the prevention of colon cancer is especially noteworthy. Particularly, positive responses have been reported in many animal studies (Park and Pezzuto, 2015). Moreover, in clinical studies performed by Patel
Further, again considering the anti-inflammatory effect of resveratrol, it seems apparent a superlative use of the compound should be the prevention of skin cancer. In our first report describing the cancer chemopreventive potential of resveratrol (Jang
This inhibitory response has subsequently been studied by numerous investigators using a variety of models including DMBA/TPA (Kapadia
With UVB models, resveratrol decreased bi-fold skin thickness (Afaq
Oral administration of resveratrol also resulted in positive effects, including decreases in the tumor multiplicity and volume, and delay in the onset of tumorigenesis (Kim
With a human cutaneous skin squamous carcinoma A431 cell line xenograft model, tumor volume was decreased by resveratrol treatment, along with increased expression levels of p53 and ERK, and decreased levels of survivin. Although ERK is considered as a proliferation and survival protein in general, ERK was also reported to form a complex with p53, leading to an increase in p53 phosphorylation and expression. Also, resveratrol enhanced the activation of caspase-3 (Hao
In addition, the antitumor effect of resveratrol was reduced with genetically engineered animals including TLR4 deficient C3H/HeJ mice in the DMBA model (Yusuf
A graphic representation of some of the numerous responses mediated by resveratrol in skin models is depicted in Fig. 6. Obviously, since resveratrol can be applied as a topical, perhaps in conjunction with a sun block, high concentrations can readily be achieved and thereby issues of absorption and metabolism are largely subjugated. Used as a topical in human trials, resveratrol has been reported to improve Acne vulgaris (Fabbrocini
In sum, amelioration of skin issues and diseases by topical application of resveratrol is particularly encouraging. Somewhat logically, resveratrol has been incorporated into a number of cosmetic products (Baxter, 2008; Ndiaye
“For rheumatism, neuralsia, sciatica, lame back, lumbaro, contracted cords, toothache, sprains, swellings, etc. For frost bite, bruises, sore throat, bites of animals, insects and reptiles. Good for man or beast. It gives immediate relieve. It is good for everything…” These claims are from an advertisement produced by the Clark Stanley Snake Oil Lintment Company for his product, snake oil (
Given that evidence-based responses are sparse and controversial, such claims, innuendo and hyperbole are atrocious. Nonetheless, irrespective of scientific underpinning, as noted above, a company was created and acquired for hundreds of millions of dollars, and dietary supplements currently on the market are estimated to yield about $50 million (US) per year (Bomgardner, 2017). There is even a piece of jewelry available that has been fashioned after the chemical structure of resveratrol. At least in the case of resveratrol-shaped jewelry, true market value can be determined by the weight of gold, silver or platinum.
In terms of the therapeutic effect of the actual compound, at the present time, there is a close parallel to past practice of marketing snake oil. It is highly disconcerting to think consumers could actually believe taking resveratrol will extend their lifespan, reduce their body weight, and fulfill all of the other numerous claims of vibrancy and contentment. But on the positive side, it is generally agreed that the safety profile of resveratrol is pristine (Johnson
So, in the end, perhaps the most important thing is to abide by ethical rules of modern medicine (
The author declares no conflict of interest.
The author is grateful to Dr. Eun-Jung Park for her invaluable help in accumulating some of the data given in this report, as well as exceptional assistance with the graphics.