The potential drug use of Resveratrol (RSV) in the treatment of cancer, diabetes and heart disease.

By Kah Yan Ng and QinYi Wang

Resveratrol (RSV) is a phenolic compound that has various potential uses including but not limited to protection against cancer, diabetes and heart disease due to its antitumoral and antioxidant effects. Otherwise known as 3,5,4’trihydroxy-stillbene, RSV is a natural compound produced in various plant species such as Japanese knotweed, grapes, cranberries, peanut and blueberries to combat fungal infections (Drugs.com, 2018). RSV is also found in discrete amounts in red wine, giving a basis to the claim that an occasional glass of the drink is beneficial for one’s health. It exists as both cis and trans isomers (Figure 1), of which the trans isomer is commercially available and abundant in comparison to the less known cis isomer (Orallo, 2005; Cvejic et al., 2010). 

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There have been many researches carried out over the years to show the benefits and potential of RSV as summarized in Figure 2. 

According to Leonard et al. (2003), RSV is a potent antioxidant as it scavenges reactive free radicals such as OH and O2 radicals, thus preventing DNA damage which is mainly due to OH radicals. As cancer results from an accumulation of mutations due to various reasons including but not limited to DNA damage, RSV can act as a potential anti-cancer compound. Although, it is important to note that this is not the only mechanism that makes RSV a potential candidate to prevent cancer.

Various in vivo and in vitro studies have shown that RSV is able to inhibit all stages of carcinogenesis, making it a good chemopreventative agent (Varoni et al., 2016). Moreover, RSV is believed to be able to target intracellular signalling pathway components such as apoptosis and cell survival regulators, tumour angiogenic and metastatic switches and pro-inflammatory mediators. It does so by affecting various transcription factors, kinases and their regulator molecules (Salehi et al., 2018). Li et al. (2018) has demonstrated the ability for RSV to induce expression of pro-apoptotic proteins such as executioner caspase-3, pro-apoptotic B-cell lymphoma (Bcl)-2-associated X protein and downregulation of the expression of the anti-apoptotic proteins Bcl-2 and Bcl-extra-large in HeLa cells. This resulted in the shrinkage of HeLa cells and increased apoptosis. Pancreatic cancer cells were also subdued by RSV through Nfr2 signalling-induced intracellular ROS accumulation in another study (Cheng et al., 2018). These studies potentiate the use of RSV as not only a chemopreventative substance, but also as a chemotherapeutic agent.

Apart from this, RSV is explored to prevent aging whilst promoting longevity. This is possible as RSV activates the transcription of an enzyme, NAD-dependent deacetylase Sirtuin-1, via SIRT1 which causes further downstream effects via the p53 and NF-κB signalling pathways. As result, there is a general reduction in pro-apoptotic effect in cells, promoting longevity (Longevity regulating pathway).

Interestingly, administration of RSV has shown to reduce insulin resistance in animals as well as cause weight loss in mice  (Szkudelski and Szkudelska, 2015). For patients with Type 2 diabetes, a disease categorized by desensitized receptors which are more resistant to insulin and obesity, this could mean a potential ‘reverse’ in their conditions. 

RSV can also prevent strokes and heart attacks as it downregulates vasoactive peptides which controls the vasoconstriction and vasodilation of blood vessels. Moreover, RSV has been shown to improve left ventricle function, decrease cardiac hypertrophy, reduce interstitial fibrosis and many more. These benefits can be attributed to RSV’s molecular mechanisms, such as inhibiting prohypertrophic signalling molecules, enhance myocardial Ca2+ processing and reducing oxidative stress and inflammation, just to name a few. RSV may therefore be helpful in the development of therapies for ischemia, heart failure and atherosclerosis (Salehi et al., 2018)

The neuroprotective effects of RSV bring about another fascinating application for this molecule. RSV can alleviate the deleterious effects of oxidative stress in the brain by improving mitochondrial functions and biogenesis through the SIRT1/AMPK/PGC1α pathway (Sun et al., 2010), reducing neuronal apoptosis. A key feature of Alzheimer’s disease (AD) is the accumulation of amyloid-beta peptides in the brain, and RSV has been shown to promote their clearance while also increasing anti-amyloidogenic cleavage of amyloid precursor protein (APP). Several studies have also investigated the effect of RSV in experimental models of Parkinson’s disease (PD), whereby the damage is induced by certain neurotoxins targeting dopaminergic neurons. Activation of pro-survival signalling pathway PI3K/Akt by RSV increases the ratio of anti-apoptotic protein Bcl-2 compared to Bax (pro-apoptotic), and decreases caspase-3 activation to reduce apoptosis (Arbo et al., 2020). While this poses RSV as a promising compound for AD and PD, in reality, its rapid metabolism and low bioavailability limits the clinical applications. This is largely caused by the compound’s poor water solubility, extensive first-pass effect and phase II metabolism due to the hydroxyl groups (Arbo et al., 2020). However, researchers are developing derivatives of RSV that have higher bioavailability while retaining the key pharmacological properties and biological effects. These derivatives can aid the discovery of new drugs for use in AD and PD treatment.

Even with the aforementioned benefits, some researches have reported negative effects as well as contradictory claims. Depending on the different concentration or treatment time, the biological effects of RSV can be modulated via various pathways. An example would be RSV’s potential in behaving like a pro-oxidizing agent despite being categorized as an antioxidant (Salehi et al., 2018). 

Contradictory results suggest that RSV activates the transcription of genes regulated by both androgens and estrogens via their individual receptors, resulting in cancer cell proliferation instead of the opposite. This could perhaps be explained by the structure of the more available trans-RSV that is similar to that of 17-β-estradiol, an estrogen hormone, as seen in Figure 3. Upon receiving high dosage of RSV, a group of multiple myeloma patients encountered adverse effects which involved renal failure. RSV also results in reduced enzyme activity in drug metabolism, but it is inconclusive if this effect is significant.

RSV had been first isolated in 1939 and has been marketed commercially for some time now (Pezzuto, 2019). Since then, scientists have managed to unveil some of the potential roles of RSV in combating diseases. However, it is still an ongoing challenge to identify its effectiveness in combating various diseases as well as to translate preclinical studies into clinical application. One key issue is determining the pharmacokinetics of the compound to ensure increased bioavailability, that enough reaches the target area within the body. RSV still cannot be absorbed effectively via oral ingestion, hence it is micronized to smaller average particles or taken with other compounds for increased absorption (Smoliga and Blanchard, 2014). 

References:

Arbo, B. D. et al. (2020) ‘Resveratrol Derivatives as Potential Treatments for Alzheimer’s and Parkinson’s Disease’, Frontiers in Aging Neuroscience, 12(April), pp. 1–15. doi: 10.3389/fnagi.2020.00103.

Cheng, L. et al. (2018) ‘Resveratrol-induced downregulation of NAF-1 enhances the sensitivity of pancreatic cancer cells to gemcitabine via the ROS/Nrf2 signaling pathways’, Oxidative Medicine and Cellular Longevity. Hindawi, 2018. doi: 10.1155/2018/9482018.

Cvejic, J. M. et al. (2010) ‘Determination of trans- and cis-resveratrol in Serbian commercial wines’, Journal of Chromatographic Science. Oxford University Press, 48(3), pp. 229–234. doi: 10.1093/chromsci/48.3.229.

Drugs.com (2018) Resveratrol. Available at: https://www.drugs.com/resveratrol.html (Accessed: 13 August 2019).

Gambini, J. et al. (2015) ‘Properties of Resveratrol: In Vitro and In Vivo Studies about Metabolism, Bioavailability, and Biological Effects in Animal Models and Humans’, Oxidative Medicine and Cellular Longevity, 2015. doi: 10.1155/2015/837042.

‘Longevity regulating pathway’ (no date).

Orallo, F. (2005) ‘Comparative Studies of the Antioxidant Effects of Cis- and Trans- Resveratrol’, Current Medicinal Chemistry. Bentham Science Publishers Ltd., 13(1), pp. 87–98. doi: 10.2174/092986706775197962.

Pezzuto, J. M. (2019) ‘Resveratrol: Twenty years of growth, development and controversy’, Biomolecules and Therapeutics, 27(1), pp. 1–14. doi: 10.4062/biomolther.2018.176.

Salehi, B. et al. (2018) ‘Resveratrol: A double-edged sword in health benefits’, Biomedicines, 6(3), pp. 1–20. doi: 10.3390/biomedicines6030091.

Smoliga, J. M. and Blanchard, O. (2014) ‘Enhancing the delivery of resveratrol in humans: If low bioavailability is the problem, what is the solution?’, Molecules, 19(11), pp. 17154–17172. doi: 10.3390/molecules191117154.

Sun, A. Y. et al. (2010) ‘Resveratrol as a Therapeutic Agent for Neurodegenerative Diseases’, Molecular Neurobiology, 41(2–3), pp. 375–383. doi: 10.1007/s12035-010-8111-y.

Szkudelski, T. and Szkudelska, K. (2015) ‘Resveratrol and diabetes: From animal to human studies’, Biochimica et Biophysica Acta – Molecular Basis of Disease. Elsevier B.V., 1852(6), pp. 1145–1154. doi: 10.1016/j.bbadis.2014.10.013.

Varoni, E. M. et al. (2016) ‘Anticancer Molecular Mechanisms of Resveratrol’, Frontiers in Nutrition, 3(April). doi: 10.3389/fnut.2016.00008.

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