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Updates of Resveratrol in Cancer Prevention and Treatment: Preclinical and Clinical Studies

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Bioactives and Nutraceuticals".

Deadline for manuscript submissions: closed (30 August 2023) | Viewed by 9245

Special Issue Editors


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Guest Editor
1. Instituto Nacional de Cancerología (INCAN), Avenida San Fernando No. 22, Sección XVI Tlalpan, Ciudad de México 14080, Mexico
2. Unidad de Investigación Biomédica en Cáncer, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México (UNAM), Coyoacán, Ciudad de México 04510, Mexico
Interests: resveratrol; cancer; DNA repair
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Guest Editor
Research Center “The Great Senescence”, University of Catania, 95100 Catania, Italy
Interests: resveratrol; gut microbiota; metabolites; metabolism; Alzheimer’s disease; retina; diabetes; nutrition; pharmacology; gastrointestinal diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Humans have used natural products to treat diseases since ancient times. Among the natural compounds, polyphenols are the most attractive due to their modulation of inflammation and oxidative stress. One of the most exciting polyphenols is resveratrol (3,4’,5-trihydroxy-trans-stilbene), a phytoalexin—or plant antibiotic—found in more than 70 plant species such as red grapes, berries, peanuts, and polygonum cuspidatum. It is most widely known as a constituent of red wine. In addition to cardioprotective, anti-inflammatory, antioxidant, anti-aging, and antiviral properties, resveratrol has been reported as an anticancer compound that regulates cell division and growth, apoptosis, inflammation, angiogenesis, and metastasis of cancer cells. Resveratrol also has preventative effects on cancer, particularly skin and mammal cancers in mice. This discovery was first introduced by Jang M. et al., 1997; who demonstrated the role of resveratrol in all three stages of carcinogenesis (initiation, promotion, and progression). However, despite the beneficial effects of resveratrol in cancer prevention and treatment, the translational steps from cell and animal studies toward humans are less than straightforward due to the poor bioavailability of resveratrol, and the fact that the targets of its mechanism of action are still not completely unraveled. Moreover, several reports suggest that resveratrol could be ineffective at inhibiting tumor growth in certain animal models, despite its in vitro antitumor action in related cells. Thus, further studies must address the tissue specificity of resveratrol, strategies to improve its bioavailability, and develop our understanding of the molecular mechanism of action as an anticancer and prevention compound.

This Special Issue aims to attract original research, systematic reviews, and meta-analysis articles reporting recent evidence and views on resveratrol that describe new potential mechanisms of action, strategies to enhance its bioavailability and delivery in the target organ, in vivo studies comparing resveratrol and its analogs, as well as its applications in chemotherapy and radiotherapy as a sensitizer and utility as a human cancer preventive.

Dr. José Díaz-Chávez
Dr. Giulia Malaguarnera
Guest Editors

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Published Papers (3 papers)

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Research

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23 pages, 7847 KiB  
Article
Glycolysis Inhibition of Autophagy Drives Malignancy in Ovarian Cancer: Exacerbation by IL-6 and Attenuation by Resveratrol
by Chiara Vidoni, Alessandra Ferraresi, Letizia Vallino, Amreen Salwa, Ji Hee Ha, Christian Seca, Beatrice Garavaglia, Danny N. Dhanasekaran and Ciro Isidoro
Int. J. Mol. Sci. 2023, 24(2), 1723; https://doi.org/10.3390/ijms24021723 - 15 Jan 2023
Cited by 9 | Viewed by 2409
Abstract
Cancer cells drive the glycolytic process towards the fermentation of pyruvate into lactate even in the presence of oxygen and functioning mitochondria, a phenomenon known as the “Warburg effect”. Although not energetically efficient, glycolysis allows the cancer cell to synthesize the metabolites needed [...] Read more.
Cancer cells drive the glycolytic process towards the fermentation of pyruvate into lactate even in the presence of oxygen and functioning mitochondria, a phenomenon known as the “Warburg effect”. Although not energetically efficient, glycolysis allows the cancer cell to synthesize the metabolites needed for cell duplication. Autophagy, a macromolecular degradation process, limits cell mass accumulation and opposes to cell proliferation as well as to cell migration. Cancer cells corrupt cancer-associated fibroblasts to release pro-inflammatory cytokines, which in turn promote glycolysis and support the metastatic dissemination of cancer cells. In mimicking in vitro this condition, we show that IL-6 promotes ovarian cancer cell migration only in the presence of glycolysis. The nutraceutical resveratrol (RV) counteracts glucose uptake and metabolism, reduces the production of reactive oxygen species consequent to excessive glycolysis, rescues the mitochondrial functional activity, and stimulates autophagy. Consistently, the lack of glucose as well as its metabolically inert analogue 2-deoxy-D-glucose (2-DG), which inhibits hexokinase 2 (HK2), trigger autophagy through mTOR inhibition, and prevents IL-6-induced cell migration. Of clinical relevance, bioinformatic analysis of The Cancer Genome Atlas dataset revealed that ovarian cancer patients bearing mutated TP53 with low expression of glycolytic markers and IL-6 receptor, together with markers of active autophagy, display a longer overall survival and are more responsive to platinum therapy. Taken together, our findings demonstrate that RV can counteract IL-6-promoted ovarian cancer progression by rescuing glycolysis-mediated inhibition of autophagy and support the view that targeting Warburg metabolism can be an effective strategy to limit the risk for cancer metastasis. Full article
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19 pages, 3028 KiB  
Article
Main Determinants Affecting the Antiproliferative Activity of Stilbenes and Their Gut Microbiota Metabolites in Colon Cancer Cells: A Structure–Activity Relationship Study
by Antonio González-Sarrías, Juan Carlos Espín-Aguilar, Salvador Romero-Reyes, Julio Puigcerver, Mateo Alajarín, José Berná, María Victoria Selma and Juan Carlos Espín
Int. J. Mol. Sci. 2022, 23(23), 15102; https://doi.org/10.3390/ijms232315102 - 1 Dec 2022
Cited by 12 | Viewed by 1598
Abstract
trans-Resveratrol can be catabolized by the gut microbiota to dihydroresveratrol, 3,4′-dihydroxy-trans-stilbene, lunularin, and 4-hydroxydibenzyl. These metabolites can reach relevant concentrations in the colon. However, not all individuals metabolize RSV equally, as it depends on their RSV gut microbiota metabotype (i.e., lunularin producers [...] Read more.
trans-Resveratrol can be catabolized by the gut microbiota to dihydroresveratrol, 3,4′-dihydroxy-trans-stilbene, lunularin, and 4-hydroxydibenzyl. These metabolites can reach relevant concentrations in the colon. However, not all individuals metabolize RSV equally, as it depends on their RSV gut microbiota metabotype (i.e., lunularin producers vs. non-producers). However, how this microbial metabolism affects the cancer chemopreventive activity of stilbenes and their microbial metabolites is poorly known. We investigated the structure–antiproliferative activity relationship of dietary stilbenes, their gut microbial metabolites, and various analogs in human cancer (Caco-2 and HT-29) and non-tumorigenic (CCD18-Co) colon cells. The antiproliferative IC50 values of pterostilbene, oxy-resveratrol, piceatannol, resveratrol, dihydroresveratrol, lunularin, 3,4′-dihydroxy-trans-stilbene, pinosylvin, dihydropinosylvin, 4-hydroxy-trans-stilbene, 4-hydroxydibenzyl, 3-hydroxydibenzyl, and 4-trans-stilbenemethanol were calculated. IC50 values were correlated with 34 molecular characteristics by bi- and multivariate analysis. Little or no activity on CCD18-Co was observed, while Caco-2 was more sensitive than HT-29, which was explained by their different capacities to metabolize the compounds. Caco-2 IC50 values ranged from 11.4 ± 10.1 μM (4-hydroxy-trans-stilbene) to 73.9 ± 13.8 μM (dihydropinosylvin). In HT-29, the values ranged from 24.4 ± 11.3 μM (4-hydroxy-trans-stilbene) to 96.7 ± 6.7 μM (4-hydroxydibenzyl). At their IC50, most compounds induced apoptosis and arrested the cell cycle at the S phase, pterostilbene at G2/M, while 4-hydroxy-trans-stilbene and 3,4′-dihydroxy-trans-stilbene arrested at both phases. Higher Connolly values (larger size) hindered the antiproliferative activity, while a lower pKa1 enhanced the activity in Caco-2, and higher LogP values (more hydrophobicity) increased the activity in HT-29. Reducing the styrene double bond in stilbenes was the most critical feature in decreasing the antiproliferative activity. These results (i) suggest that gut microbiota metabolism determines the antiproliferative effects of dietary stilbenes. Therefore, RSV consumption might exert different effects in individuals depending on their gut microbiota metabotypes associated with RSV metabolism, and (ii) could help design customized drugs with a stilbenoid and (or) dibenzyl core against colorectal cancer. Full article
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Review

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14 pages, 1364 KiB  
Review
Focus on the Use of Resveratrol in Bladder Cancer
by Alessandro Zucchi, Francesco Claps, Antonio Luigi Pastore, Alessandro Perotti, Andrea Biagini, Luana Sallicandro, Rosaria Gentile, Concetta Caglioti, Federico Palazzetti and Bernard Fioretti
Int. J. Mol. Sci. 2023, 24(5), 4562; https://doi.org/10.3390/ijms24054562 - 26 Feb 2023
Cited by 8 | Viewed by 4725
Abstract
Bladder cancer is the most common tumor of the urinary system, with a high incidence in the male population. Surgery and intravesical instillations can eradicate it, although recurrences are very common, with possible progression. For this reason, adjuvant therapy should be considered in [...] Read more.
Bladder cancer is the most common tumor of the urinary system, with a high incidence in the male population. Surgery and intravesical instillations can eradicate it, although recurrences are very common, with possible progression. For this reason, adjuvant therapy should be considered in all patients. Resveratrol displays a biphasic dose response both in vitro and in vivo (intravesical application) with an antiproliferative effect at high concentrations and antiangiogenic action in vivo (intraperitoneal application) at a low concentration, suggesting a potential role for it in clinical management as an adjuvant to conventional therapy. In this review, we examine the standard therapeutical approach to bladder cancer and the preclinical studies that have investigated resveratrol in xenotransplantation models of bladder cancer. Molecular signals are also discussed, with a particular focus on the STAT3 pathway and angiogenic growth factor modulation. Full article
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