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Antioxidants
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Antioxidants and Cancer
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Antioxidants and Cancer

A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Health Outcomes of Antioxidants and Oxidative Stress".

Deadline for manuscript submissions: closed (30 December 2020) | Viewed by 60444

Special Issue Editor

Prof. Dr. Jose Manuel Martinez-Martos

E-Mail Website
Guest Editor
Department of Health Sciences, School of Health Sciences, University of Jaén, Campus Universitario Las Lagunillas, E-23071 Jaén, Spain
Interests: natural antioxidants; glioma; glutathione; enzyme antioxidant defense systems; renin-angiotensin system

Special Issue Information

Dear Colleagues,

Antioxidants play important roles in the maintenance of cellular integrity and thus are critical in maintaining cell homeostasis. However, a delicate balance between the levels of pro-oxidants and antioxidants defines this cellular integrity, either maintaining the redox status or affecting normal cellular signaling pathways, resulting in uncontrolled proliferation of cells, leading to carcinogenesis. The use of antioxidants for the treatment of human cancers remains controversial, because cancer cells can also be killed by free radicals, which block key steps in the cell cycle and promote apoptosis. This Special Issue is focused on current knowledge about the use of pro-oxidants and antioxidants in cancer therapy, the enzyme and nonenzyme systems affected, and the intracellular signaling routes involved in their mechanisms of action with the aim to determine the true role of redox control on cancer cells.

Prof. Dr. Jose Manuel Martinez-Martos
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antioxidants is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Free radicals
  • Natural antioxidants
  • Cancer
  • Intracellular signalling
  • Adjuvant therapies
  • Apostosis/necrosis
  • Glutathione
  • Catalase
  • Superoxide dismutase
  • Glutathione peroxidase

Published Papers (16 papers)

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Research

Jump to: Review

13 pages, 291 KiB  
Article
Polyphenol Intake and Epithelial Ovarian Cancer Risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study
by Catalina Londoño, Valerie Cayssials, Izar de Villasante, Marta Crous-Bou, Augustin Scalbert, Elisabete Weiderpass, Antonio Agudo, Anne Tjønneland, Anja Olsen, Kim Overvad, Verena Katzke, Matthias Schulze, Domenico Palli, Vittorio Krogh, Maria Santucci de Magistris, Rosario Tumino, Fulvio Ricceri, Inger T. Gram, Charlotta Rylander, Guri Skeie, Maria-Jose Sánchez, Pilar Amiano, José María Huerta, Aurelio Barricarte, Hanna Sartor, Emily Sonestedt, Anders Esberg, Annika Idahl, Yahya Mahamat-Saleh, Nasser Laouali, Marina Kvaskoff, Renée Turzanski-Fortner and Raul Zamora-Rosadd Show full author list remove Hide full author list
Antioxidants 2021, 10(8), 1249; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10081249 - 04 Aug 2021
Cited by 4 | Viewed by 2894
Abstract
Despite some epidemiological evidence on the protective effects of polyphenol intake on epithelial ovarian cancer (EOC) risk from case-control studies, the evidence is scarce from prospective studies and non-existent for several polyphenol classes. Therefore, we aimed to investigate the associations between the intake [...] Read more.
Despite some epidemiological evidence on the protective effects of polyphenol intake on epithelial ovarian cancer (EOC) risk from case-control studies, the evidence is scarce from prospective studies and non-existent for several polyphenol classes. Therefore, we aimed to investigate the associations between the intake of total, classes and subclasses of polyphenols and EOC risk in a large prospective study. The study was conducted in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, which included 309,129 adult women recruited mostly from the general population. Polyphenol intake was assessed through validated country-specific dietary questionnaires and the Phenol-Explorer database. During a mean follow-up of 14 years, 1469 first incident EOC cases (including 806 serous, 129 endometrioid, 102 mucinous, and 67 clear cell tumours) were identified. In multivariable-adjusted Cox regression models, the hazard ratio in the highest quartile of total polyphenol intake compared with the lowest quartile (HRQ4vsQ1) was 1.14 (95% CI 0.94–1.39; p-trend = 0.11). Similarly, the intake of most classes and subclasses of polyphenols were not related to either overall EOC risk or any EOC subtype. A borderline statistically significant positive association was observed between phenolic acid intake (HRQ4vsQ1 = 1.20, 95% CI 1.01–1.43; p-trend = 0.02) and EOC risk, especially for the serous subtype and in women with obesity, although these associations did not exceed the Bonferroni correction threshold. The current results do not support any association between polyphenol intake and EOC in our large European prospective study. Results regarding phenolic acid intake need further investigation Full article
(This article belongs to the Special Issue Antioxidants and Cancer)
14 pages, 2023 KiB  
Article
Novel N,N′-Disubstituted Selenoureas as Potential Antioxidant and Cytotoxic Agents
by Gorka Calvo-Martín, Daniel Plano, Ignacio Encío and Carmen Sanmartín
Antioxidants 2021, 10(5), 777; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10050777 - 14 May 2021
Cited by 8 | Viewed by 2178
Abstract
A series of 30 novel N,N disubstituted selenoureas were synthesized, characterized, and their antioxidant ability was tested using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid (ABTS) assays. Additionally, their cytotoxic activity was tested in vitro in a panel of three different cancer (breast, [...] Read more.
A series of 30 novel N,N disubstituted selenoureas were synthesized, characterized, and their antioxidant ability was tested using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid (ABTS) assays. Additionally, their cytotoxic activity was tested in vitro in a panel of three different cancer (breast, lung and colon) and two normal cell lines. Each selenourea entity contains a para-substituted phenyl ring with different electron-withdrawing and electron-donating groups, and different aliphatic and aromatic nuclei. All of the synthesized selenoureas present antioxidant capacity at high concentrations in the DPPH assay, and three of them (2b, 2c and 2d) showed greater radical scavenging capacity than ascorbic acid at lower concentrations. These results were confirmed by the ABTS assay, where these novel selenoureas present even higher antioxidant capacity than the reference compound Trolox. On the other hand, 10 selenoureas present IC50 values below 10 µM in at least one cancer cell line, resulting in the adamantyl nucleus (6a–6e), the most interesting in terms of activity and selectivity. Outstanding results were found for selenourea 6c, tested in the NCI60 cell line panel and showing an average GI50 of 1.49 µM for the 60 cell lines, and LC50 values ranging from 9.33 µM to 4.27 µM against 10 of these cancer cell lines. To gain insight into its anticancer activity mechanism, we investigated the cell cycle progression of the promising compound 6c, as well as the type of programmed-cell death in a colon cancer cell line it provokes (HT-29). Compound 6c provoked S phase cell cycle arrest and the induction of cell death was independent of caspase activation, suggesting autophagy, though this assertion requires additional studies. Overall, we envision that this compound can be further developed for the potential treatment of colon cancer. Full article
(This article belongs to the Special Issue Antioxidants and Cancer)
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17 pages, 779 KiB  
Article
Dietary Antioxidant Vitamins and Minerals and Breast Cancer Risk: Prospective Results from the SUN Cohort
by Cesar I. Fernandez-Lazaro, Miguel Ángel Martínez-González, Inmaculada Aguilera-Buenosvinos, Alfredo Gea, Miguel Ruiz-Canela, Andrea Romanos-Nanclares and Estefanía Toledo
Antioxidants 2021, 10(3), 340; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10030340 - 24 Feb 2021
Cited by 14 | Viewed by 2819
Abstract
There is growing interest in natural antioxidants and their potential effects on breast cancer (BC). Epidemiological evidence, however, is inconsistent. We prospectively evaluated the association between dietary intake of vitamins A, C, and E, selenium, and zinc and BC among 9983 female participants [...] Read more.
There is growing interest in natural antioxidants and their potential effects on breast cancer (BC). Epidemiological evidence, however, is inconsistent. We prospectively evaluated the association between dietary intake of vitamins A, C, and E, selenium, and zinc and BC among 9983 female participants from the SUN Project, a Mediterranean cohort of university graduates. Participants completed a food frequency questionnaire at baseline, and biennial follow-up information about incident BC diagnosis was collected. Cases were ascertained through revision of medical charts and consultation of the National Death Index. Cox proportional hazards models were used to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CI). During an average follow-up of 11.3 years, 107 incident BC cases were confirmed. The multivariable HRs (95% CI) for BC comparing extreme tertiles of energy-adjusted dietary intakes were 1.07 (0.64–1.77; Ptrend = 0.673) for vitamin A, 1.00 (0.58–1.71; Ptrend = 0.846) for vitamin C, 0.92 (0.55–1.54; Ptrend = 0.728) for vitamin E, 1.37 (0.85–2.20; Ptrend = 0.135) for selenium, and 1.01 (0.61–1.69; Ptrend = 0.939) for zinc. Stratified analyses showed an inverse association between vitamin E intake and postmenopausal BC (HRT3 vs. T1 = 0.35; 95% CI, 0.14–0.86; Ptrend = 0.027). Our results did not suggest significant protective associations between dietary vitamins A, C, and E, selenium, or zinc and BC risk. Full article
(This article belongs to the Special Issue Antioxidants and Cancer)
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18 pages, 3798 KiB  
Article
Radiation-Induced Bystander Effect: Loss of Radioprotective Capacity of Rosmarinic Acid In Vivo and In Vitro
by Amparo Olivares, Miguel Alcaraz-Saura, Daniel Gyingiri Achel, Juan de Dios Berná-Mestre and Miguel Alcaraz
Antioxidants 2021, 10(2), 231; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10020231 - 03 Feb 2021
Cited by 8 | Viewed by 2580
Abstract
In radiation oncology, the modulation of the bystander effect is a target both for the destruction of tumor cells and to protect healthy cells. With this objective, we determine whether the radioprotective capacity of rosmarinic acid (RA) can affect the intensity of these [...] Read more.
In radiation oncology, the modulation of the bystander effect is a target both for the destruction of tumor cells and to protect healthy cells. With this objective, we determine whether the radioprotective capacity of rosmarinic acid (RA) can affect the intensity of these effects. Genoprotective capacity was obtained by determining the micronuclei frequencies in in vivo and in vitro assays and the cell survival was determined by the (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay) (MTT) assay in three cell lines (PNT2, TRAMPC1 and B16F10), both in direct exposure to X-rays and after the production of radiation-induced bystander effect. The administration of RA in irradiated cells produced a decrease in the frequency of micronuclei both in vivo and in vitro, and an increase in cell survival, as expression of its radioprotective effect (p < 0.001) attributable to its ability to scavenge radio-induced free radicals (ROS). However, RA does not achieve any modification in the animals receiving serum or in the cultures treated with the irradiated medium, which expresses an absence of radioprotective capacity. The results suggest that ROS participates in the formation of signals in directly irradiated cells, but only certain subtypes of ROS, the cytotoxic products of lipid peroxidation, participate in the creation of lesions in recipient cells. Full article
(This article belongs to the Special Issue Antioxidants and Cancer)
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19 pages, 4466 KiB  
Article
Investigating the Thioredoxin and Glutathione Systems’ Response in Lymphoma Cells after Treatment with [Au(d2pype)2]Cl
by Sicong Wang, Yaoying Lu, Kyra Woods, Giovanna Di Trapani and Kathryn F. Tonissen
Antioxidants 2021, 10(1), 104; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10010104 - 13 Jan 2021
Cited by 10 | Viewed by 2977
Abstract
Lymphoma is a blood cancer comprising various subtypes. Although effective therapies are available, some patients fail to respond to treatment and can suffer from side effects. Antioxidant systems, especially the thioredoxin (Trx) and glutathione (GSH) systems, are known to enhance cancer cell survival, [...] Read more.
Lymphoma is a blood cancer comprising various subtypes. Although effective therapies are available, some patients fail to respond to treatment and can suffer from side effects. Antioxidant systems, especially the thioredoxin (Trx) and glutathione (GSH) systems, are known to enhance cancer cell survival, with thioredoxin reductase (TrxR) recently reported as a potential anticancer target. Since the GSH system can compensate for some Trx system functions, we investigated its response in three lymphoma cell lines after inhibiting TrxR activity with [Au(d2pype)2]Cl, a known TrxR inhibitor. [Au(d2pype)2]Cl increased intracellular reactive oxygen species (ROS) levels and induced caspase-3 activity leading to cell apoptosis through inhibiting both TrxR and glutathione peroxidase (Gpx) activity. Expression of the tumour suppresser gene TXNIP increased, while GPX1 and GPX4 expression, which are related to poor prognosis of lymphoma patients, decreased. Unlike SUDHL2 and SUDHL4 cells, which exhibited a decreased GSH/GSSG ratio after treatment, in KMH2 cells the ratio remained unchanged, while glutathione reductase and glutaredoxin expression increased. Since KMH2 cells were less sensitive to treatment with [Au(d2pype)2]Cl, the GSH system may play a role in protecting cells from apoptosis after TrxR inhibition. Overall, our study demonstrates that inhibition of TrxR represents a valid therapeutic approach for lymphoma. Full article
(This article belongs to the Special Issue Antioxidants and Cancer)
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16 pages, 4075 KiB  
Article
The Effect of Glutathione Peroxidase-1 Knockout on Anticancer Drug Sensitivities and Reactive Oxygen Species in Haploid HAP-1 Cells
by Steven Behnisch-Cornwell, Lisa Wolff and Patrick J. Bednarski
Antioxidants 2020, 9(12), 1300; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox9121300 - 18 Dec 2020
Cited by 9 | Viewed by 3253
Abstract
The role of glutathione peroxidases (GPx) in cancer and their influence on tumor prognosis and the development of anticancer drug resistance has been extensively and controversially discussed. The aim of this study was to evaluate the influence of GPx1 expression on anticancer drug [...] Read more.
The role of glutathione peroxidases (GPx) in cancer and their influence on tumor prognosis and the development of anticancer drug resistance has been extensively and controversially discussed. The aim of this study was to evaluate the influence of GPx1 expression on anticancer drug cytotoxicity. For this purpose, a GPx1 knockout of the near-haploid human cancer cell line HAP-1 was generated and compared to the native cell line with regards to morphology, growth and metabolic rates, and oxidative stress defenses. Furthermore, the IC50 values of two peroxides and 16 widely used anticancer drugs were determined in both cell lines. Here we report that the knockout of GPx1 in HAP-1 cells has no significant effect on cell size, viability, growth and metabolic rates. Significant increases in the cytotoxic potency of hydrogen peroxide and tert-butylhydroperoxide, the anticancer drugs cisplatin and carboplatin as well as the alkylating agents lomustine and temozolomide were found. While a concentration dependent increases in intracellular reactive oxygen species (ROS) levels were observed for both HAP-1 cell lines treated with either cisplatin, lomustine or temozolamide, no significant enhancement in ROS levels was observed in the GPx1 knockout compared to the native cell line except at the highest concentration of temozolamide. On the other hand, a ca. 50% decrease in glutathione levels was noted in the GPx1 knockout relative to the native line, suggesting that factors other than ROS levels alone play a role in the increased cytotoxic activity of these drugs in the GPx1 knockout cells. Full article
(This article belongs to the Special Issue Antioxidants and Cancer)
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13 pages, 1359 KiB  
Article
Effect of Rosmarinic Acid and Ionizing Radiation on Glutathione in Melanoma B16F10 Cells: A Translational Opportunity
by Amparo Olivares, Miguel Alcaraz-Saura, Daniel Gyingiri Achel and Miguel Alcaraz
Antioxidants 2020, 9(12), 1291; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox9121291 - 16 Dec 2020
Cited by 13 | Viewed by 2612
Abstract
To explain a paradoxical radiosensitizing effect of rosmarinic acid (RA) on the melanoma B16F10 cells, we analyzed the glutathione (GSH) intracellular production on this cell (traditionally considered radioresistant) in comparison with human prostate epithelial cells (PNT2) (considered to be radiosensitive). In PNT2 cells, [...] Read more.
To explain a paradoxical radiosensitizing effect of rosmarinic acid (RA) on the melanoma B16F10 cells, we analyzed the glutathione (GSH) intracellular production on this cell (traditionally considered radioresistant) in comparison with human prostate epithelial cells (PNT2) (considered to be radiosensitive). In PNT2 cells, the administration of RA increased the total GSH content during the first 3 h (p < 0.01) as well as increased the GSH/oxidized glutathione (GSSG) ratio in all irradiated cultures during all periods studied (1h and 3h) (p < 0.001), portraying an increase in the radioprotective capacity. However, in B16F10 cells, administration of RA had no effect on the total intracellular GSH levels, decreasing the GSH/GSSG ratio (p < 0.01); in addition, it caused a significant reduction in the GSH/GSSG ratio in irradiated cells (p < 0.001), an expression of radioinduced cell damage. In B16F10 cells, the administration of RA possibly activates the metabolic pathway of eumelanin synthesis that would consume intracellular GSH, thereby reducing its possible use as a protector against oxidative stress. The administration of this type of substance during radiotherapy could potentially protect healthy cells for which RA is a powerful radioprotector, and at the same time, cause significant damage to melanoma cells for which it could act as a radiosensitive agent. Full article
(This article belongs to the Special Issue Antioxidants and Cancer)
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13 pages, 1999 KiB  
Article
Paraoxonase-2 Silencing Enhances Sensitivity of A375 Melanoma Cells to Treatment with Cisplatin
by Roberto Campagna, Tiziana Bacchetti, Eleonora Salvolini, Valentina Pozzi, Elisa Molinelli, Valerio Brisigotti, Davide Sartini, Anna Campanati, Gianna Ferretti, Annamaria Offidani and Monica Emanuelli
Antioxidants 2020, 9(12), 1238; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox9121238 - 07 Dec 2020
Cited by 37 | Viewed by 2486
Abstract
Melanoma represents the most aggressive skin cancer, being responsible for the majority of deaths related with these neoplasms. Despite chemotherapy represents a frontline approach for management of the advanced stages of the disease, it displayed poor response rates and short-term efficacy due to [...] Read more.
Melanoma represents the most aggressive skin cancer, being responsible for the majority of deaths related with these neoplasms. Despite chemotherapy represents a frontline approach for management of the advanced stages of the disease, it displayed poor response rates and short-term efficacy due to melanoma cell resistance. Therefore, the discovery of molecules that can be used for effective targeted therapy of melanoma is crucial. In this study, we evaluated the impact of paraoxonase-2 (PON2) silencing on proliferation, viability, and resistance to treatment of the A375 melanoma cell line with chemotherapeutic drugs dacarbazine (DTIC) and cisplatin (CDDP). Due to the enzymes ability to counteract oxidative stress, we also evaluated the effect of enzyme knockdown on reactive oxygen species (ROS) production in cells treated with CDDP. The data reported clearly demonstrated that PON2 knockdown led to a significant reduction of cell proliferation and viability, as well as to an enhancement of A375 sensitivity to CDDP treatment. Moreover, enzyme downregulation was associated with an increase of ROS production in CDDP-treated cells. Although further analyses will be necessary to understand how PON2 could influence melanoma cell metabolism and phenotype, our results seem to suggest that the enzyme may serve as an interesting molecular target for effective melanoma treatment. Full article
(This article belongs to the Special Issue Antioxidants and Cancer)
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21 pages, 3778 KiB  
Article
Hemin Prevents Increased Glycolysis in Macrophages upon Activation: Protection by Microbiota-Derived Metabolites of Polyphenols
by Catalina Carrasco-Pozo, Kah Ni Tan and Vicky M. Avery
Antioxidants 2020, 9(11), 1109; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox9111109 - 11 Nov 2020
Cited by 10 | Viewed by 2722
Abstract
Meat consumption plays a critical role in the development of several types of cancer. Hemin, a metabolite of myoglobin produced after meat intake, has been demonstrated to be involved in the cancer initiation phase. Macrophages are key components of the innate immunity, which, [...] Read more.
Meat consumption plays a critical role in the development of several types of cancer. Hemin, a metabolite of myoglobin produced after meat intake, has been demonstrated to be involved in the cancer initiation phase. Macrophages are key components of the innate immunity, which, upon activation, can prevent cancer development by eliminating neoplastic cells. Metabolic reprogramming, characterized by high glycolysis and low oxidative phosphorylation, is critical for macrophage activation. 3,4-dihydroxyphenylacetic acid (3,4DHPAA) and 4-hydroxyphenylacetic acid (4HPAA), both microbiota-derived metabolites of flavonoids, have not been extensively studied although they exert antioxidant properties. The aim of this study was to determine the effect of hemin on the anticancer properties of macrophages and the role of 3,4DHPAA and 4HPAA in metabolic reprogramming and activation of macrophages leading to the elimination of cancer cells. The results showed that hemin inhibited glycolysis, glycolytic, and pentose phosphate pathway (PPP) enzyme activities and hypoxia-inducible factor-1 alpha (HIF-1α) stabilization, which interferes with macrophage activation (evidenced by decreased interferon-γ-inducible protein 10 (IP-10) release) and their ability to eliminate cancer cells (via cytotoxic mediators and phagocytosis). Hemin also reduced the mitochondrial membrane potential (MMP) and mitochondrial mass in macrophages. 3,4DHPAA and 4HPAA, by stimulating glycolysis and PPP, prevented the impairment of the macrophage anticancer activity induced by hemin. In conclusion, 3,4HPAA and 4HPAA administration could represent a promising strategy for preventing the reduction of macrophage activation induced by hemin. Full article
(This article belongs to the Special Issue Antioxidants and Cancer)
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13 pages, 2265 KiB  
Article
In Silico Identification and Biological Evaluation of Antioxidant Food Components Endowed with Human Carbonic Anhydrase IX and XII Inhibition
by Giosuè Costa, Annalisa Maruca, Roberta Rocca, Francesca Alessandra Ambrosio, Emanuela Berrino, Fabrizio Carta, Francesco Mesiti, Alessandro Salatino, Delia Lanzillotta, Francesco Trapasso, Anna Artese, Stefano Alcaro and Claudiu T. Supuran
Antioxidants 2020, 9(9), 775; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox9090775 - 21 Aug 2020
Cited by 6 | Viewed by 2409
Abstract
The tumor-associated isoenzymes hCA IX and hCA XII catalyze the hydration of carbon dioxide to bicarbonate and protons. These isoforms are highly overexpressed in many types of cancer, where they contribute to the acidification of the tumor environment, promoting tumor cell [...] Read more.
The tumor-associated isoenzymes hCA IX and hCA XII catalyze the hydration of carbon dioxide to bicarbonate and protons. These isoforms are highly overexpressed in many types of cancer, where they contribute to the acidification of the tumor environment, promoting tumor cell invasion and metastasis. In this work, in order to identify novel dual hCA IX and XII inhibitors, virtual screening techniques and biological assays were combined. A structure-based virtual screening towards hCA IX and XII was performed using a database of approximately 26,000 natural compounds. The best shared hits were submitted to a thermodynamic analysis and three promising best hits were identified and evaluated in terms of their hCA IX and XII inhibitor activity. In vitro biological assays were in line with the theoretical studies and revealed that syringin, lithospermic acid, and (-)-dehydrodiconiferyl alcohol behave as good hCA IX and hCA XII dual inhibitors. Full article
(This article belongs to the Special Issue Antioxidants and Cancer)
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22 pages, 4491 KiB  
Article
The Catalytic Cycle of the Antioxidant and Cancer-Associated Human NQO1 Enzyme: Hydride Transfer, Conformational Dynamics and Functional Cooperativity
by Ernesto Anoz-Carbonell, David J. Timson, Angel L. Pey and Milagros Medina
Antioxidants 2020, 9(9), 772; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox9090772 - 20 Aug 2020
Cited by 22 | Viewed by 3536
Abstract
Human NQO1 [NAD(H):quinone oxidoreductase 1] is a multi-functional and stress-inducible dimeric protein involved in the antioxidant defense, the activation of cancer prodrugs and the stabilization of oncosuppressors. Despite its roles in human diseases, such as cancer and neurological disorders, a detailed characterization of [...] Read more.
Human NQO1 [NAD(H):quinone oxidoreductase 1] is a multi-functional and stress-inducible dimeric protein involved in the antioxidant defense, the activation of cancer prodrugs and the stabilization of oncosuppressors. Despite its roles in human diseases, such as cancer and neurological disorders, a detailed characterization of its enzymatic cycle is still lacking. In this work, we provide a comprehensive analysis of the NQO1 catalytic cycle using rapid mixing techniques, including multiwavelength and spectral deconvolution studies, kinetic modeling and temperature-dependent kinetic isotope effects (KIEs). Our results systematically support the existence of two pathways for hydride transfer throughout the NQO1 catalytic cycle, likely reflecting that the two active sites in the dimer catalyze two-electron reduction with different rates, consistent with the cooperative binding of inhibitors such as dicoumarol. This negative cooperativity in NQO1 redox activity represents a sort of half-of-sites activity. Analysis of KIEs and their temperature dependence also show significantly different contributions from quantum tunneling, structural dynamics and reorganizations to catalysis at the two active sites. Our work will improve our understanding of the effects of cancer-associated single amino acid variants and post-translational modifications in this protein of high relevance in cancer progression and treatment. Full article
(This article belongs to the Special Issue Antioxidants and Cancer)
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Review

Jump to: Research

17 pages, 552 KiB  
Review
Pterostilbene in Cancer Therapy
by Elena Obrador, Rosario Salvador-Palmer, Ali Jihad-Jebbar, Rafael López-Blanch, Thanh H. Dellinger, Ryan W. Dellinger and José M. Estrela
Antioxidants 2021, 10(3), 492; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10030492 - 21 Mar 2021
Cited by 49 | Viewed by 5152
Abstract
Natural polyphenols are organic chemicals which contain phenol units in their structures and possess antitumor properties. However, a key problem is their short half-life and low bioavailability under in vivo conditions. Pterostilbene (3,5-dimethoxy-4′-hydroxystilbene; PT) is a phytoalexin originally isolated from the heartwood of [...] Read more.
Natural polyphenols are organic chemicals which contain phenol units in their structures and possess antitumor properties. However, a key problem is their short half-life and low bioavailability under in vivo conditions. Pterostilbene (3,5-dimethoxy-4′-hydroxystilbene; PT) is a phytoalexin originally isolated from the heartwood of red sandalwood. As recently reported by our group, PT was shown to be effective in the treatment of melanoma. Counterintuitively, PT is not effective (cytotoxic) against melanoma in vitro, and only under in vivo conditions does PT display its anticancer activity. This study elucidated that PT can be effective against melanoma through the inhibition of adrenocorticotropic hormone production in the brain of a mouse, which weakens the Nrf2-dependent antioxidant defenses of melanoma and also pancreatic cancers. This results in both the inhibition of tumor growth and sensitization of the tumor to oxidative stress. Moreover, PT can promote cancer cell death via a mechanism involving lysosomal membrane permeabilization. Different grades of susceptibility were observed among the different cancer cells depending on their lysosomal heat shock protein 70 content, a known stabilizer of lysosomal membranes. In addition, the safety of PT administered i.v. has been evaluated in mice. PT was found to be pharmacologically safe because it showed no organ-specific or systemic toxicity (including tissue histopathologic examination and regular hematology and clinical chemistry data) even when administered i.v. at a high dose (30 mg/kg per day × 23 days). Moreover, new pharmacological advances are being developed to increase its bioavailability and, thereby, its bioefficacy. Therefore, although applications of PT in cancer therapy are just beginning to be explored, it represents a potential (and effective) adjuvant/sensitizing therapy which may improve the results of various oncotherapies. The aim of this review is to present and discuss the results that in our opinion best support the usefulness of PT in cancer therapy, making special emphasis on the in vivo evidence. Full article
(This article belongs to the Special Issue Antioxidants and Cancer)
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42 pages, 3766 KiB  
Review
Melatonin and Cancer: A Polyhedral Network Where the Source Matters
by Maria-Angeles Bonmati-Carrion and Antonia Tomas-Loba
Antioxidants 2021, 10(2), 210; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10020210 - 01 Feb 2021
Cited by 30 | Viewed by 7070
Abstract
Melatonin is one of the most phylogenetically conserved signals in biology. Although its original function was probably related to its antioxidant capacity, this indoleamine has been “adopted” by multicellular organisms as the “darkness signal” when secreted in a circadian manner and is acutely [...] Read more.
Melatonin is one of the most phylogenetically conserved signals in biology. Although its original function was probably related to its antioxidant capacity, this indoleamine has been “adopted” by multicellular organisms as the “darkness signal” when secreted in a circadian manner and is acutely suppressed by light at night by the pineal gland. However, melatonin is also produced by other tissues, which constitute its extrapineal sources. Apart from its undisputed chronobiotic function, melatonin exerts antioxidant, immunomodulatory, pro-apoptotic, antiproliferative, and anti-angiogenic effects, with all these properties making it a powerful antitumor agent. Indeed, this activity has been demonstrated to be mediated by interfering with various cancer hallmarks, and different epidemiological studies have also linked light at night (melatonin suppression) with a higher incidence of different types of cancer. In 2007, the World Health Organization classified night shift work as a probable carcinogen due to circadian disruption, where melatonin plays a central role. Our aim is to review, from a global perspective, the role of melatonin both from pineal and extrapineal origin, as well as their possible interplay, as an intrinsic factor in the incidence, development, and progression of cancer. Particular emphasis will be placed not only on those mechanisms related to melatonin’s antioxidant nature but also on the recently described novel roles of melatonin in microbiota and epigenetic regulation. Full article
(This article belongs to the Special Issue Antioxidants and Cancer)
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15 pages, 915 KiB  
Review
Antioxidants and Therapeutic Targets in Ovarian Clear Cell Carcinoma
by Tsukuru Amano, Atsushi Murakami, Takashi Murakami and Tokuhiro Chano
Antioxidants 2021, 10(2), 187; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10020187 - 28 Jan 2021
Cited by 11 | Viewed by 2964
Abstract
Ovarian clear cell carcinomas (OCCCs) are resistant to conventional anti-cancer drugs; moreover, the prognoses of advanced or recurrent patients are extremely poor. OCCCs often arise from endometriosis associated with strong oxidative stress. Of note, the stress involved in OCCCs can be divided into [...] Read more.
Ovarian clear cell carcinomas (OCCCs) are resistant to conventional anti-cancer drugs; moreover, the prognoses of advanced or recurrent patients are extremely poor. OCCCs often arise from endometriosis associated with strong oxidative stress. Of note, the stress involved in OCCCs can be divided into the following two categories: (a) carcinogenesis from endometriosis to OCCC and (b) factors related to treatment after carcinogenesis. Antioxidants can reduce the risk of OCCC formation by quenching reactive oxygen species (ROS); however, the oxidant stress-tolerant properties assist in the survival of OCCC cells when the malignant transformation has already occurred. Moreover, the acquisition of oxidative stress resistance is also involved in the cancer stemness of OCCC. This review summarizes the recent advances in the process and prevention of carcinogenesis, the characteristic nature of tumors, and the treatment of post-refractory OCCCs, which are highly linked to oxidative stress. Although therapeutic approaches should still be improved against OCCCs, multi-combinatorial treatments including nucleic acid-based drugs directed to the transcriptional profile of each OCCC are expected to improve the outcomes of patients. Full article
(This article belongs to the Special Issue Antioxidants and Cancer)
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35 pages, 1395 KiB  
Review
Comprehensive Review of Methodology to Detect Reactive Oxygen Species (ROS) in Mammalian Species and Establish Its Relationship with Antioxidants and Cancer
by Shivkanya Fuloria, Vetriselvan Subramaniyan, Sundram Karupiah, Usha Kumari, Kathiresan Sathasivam, Dhanalekshmi Unnikrishnan Meenakshi, Yuan Seng Wu, Mahendran Sekar, Nitin Chitranshi, Rishabha Malviya, Kalvatala Sudhakar, Sakshi Bajaj and Neeraj Kumar Fuloria
Antioxidants 2021, 10(1), 128; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10010128 - 18 Jan 2021
Cited by 31 | Viewed by 6475
Abstract
Evidence suggests that reactive oxygen species (ROS) mediate tissue homeostasis, cellular signaling, differentiation, and survival. ROS and antioxidants exert both beneficial and harmful effects on cancer. ROS at different concentrations exhibit different functions. This creates necessity to understand the relation between ROS, antioxidants, [...] Read more.
Evidence suggests that reactive oxygen species (ROS) mediate tissue homeostasis, cellular signaling, differentiation, and survival. ROS and antioxidants exert both beneficial and harmful effects on cancer. ROS at different concentrations exhibit different functions. This creates necessity to understand the relation between ROS, antioxidants, and cancer, and methods for detection of ROS. This review highlights various sources and types of ROS, their tumorigenic and tumor prevention effects; types of antioxidants, their tumorigenic and tumor prevention effects; and abnormal ROS detoxification in cancer; and methods to measure ROS. We conclude that improving genetic screening methods and bringing higher clarity in determination of enzymatic pathways and scale-up in cancer models profiling, using omics technology, would support in-depth understanding of antioxidant pathways and ROS complexities. Although numerous methods for ROS detection are developing very rapidly, yet further modifications are required to minimize the limitations associated with currently available methods. Full article
(This article belongs to the Special Issue Antioxidants and Cancer)
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15 pages, 1186 KiB  
Review
Miracle Berry as a Potential Supplement in the Control of Metabolic Risk Factors in Cancer
by Marta Gómez de Cedrón, Sonia Wagner, Marina Reguero, Adrián Menéndez-Rey and Ana Ramírez de Molina
Antioxidants 2020, 9(12), 1282; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox9121282 - 15 Dec 2020
Cited by 8 | Viewed by 6842
Abstract
The increased incidence of chronic diseases related to altered metabolism has become a social and medical concern worldwide. Cancer is a chronic and multifactorial disease for which, together with genetic factors, environmental factors are crucial. According to the World Health Organization (WHO), up [...] Read more.
The increased incidence of chronic diseases related to altered metabolism has become a social and medical concern worldwide. Cancer is a chronic and multifactorial disease for which, together with genetic factors, environmental factors are crucial. According to the World Health Organization (WHO), up to one third of cancer-related deaths could be prevented by modifying risk factors associated with lifestyle, including diet and exercise. Obesity increases the risk of cancer due to the promotion of low-grade chronic inflammation and systemic metabolic oxidative stress. The effective control of metabolic parameters, for example, controlling glucose, lipid levels, and blood pressure, and maintaining a low grade of chronic inflammation and oxidative stress might represent a specific and mechanistic approach against cancer initiation and progression. Miracle berry (MB) (Synsepalum dulcificum) is an indigenous fruit whose small, ellipsoid, and bright red berries have been described to transform a sour taste into a sweet one. MB is rich in terpenoids, phenolic compounds, and flavonoids, which are responsible for their described antioxidant activities. Moreover, MB has been reported to ameliorate insulin resistance and inhibit cancer cell proliferation and malignant transformation in vitro. Herein, we briefly summarize the current knowledge of MB to provide a scientific basis for its potential use as a supplement in the management of chronic diseases related to altered metabolism, including obesity and insulin resistance, which are well-known risk factors in cancer. First, we introduce cancer as a metabolic disease, highlighting the impact of systemic metabolic alterations, such as obesity and insulin resistance, in cancer initiation and progression. Next, as oxidative stress is closely associated with metabolic stress, we also evaluate the effect of phytochemicals in managing oxidative stress and its relationship with cancer. Finally, we summarize the main biological activities described for MB-derived extracts with a special focus on the ability of miraculin to transform a sour taste into a sweet one through its interaction with the sweet taste receptors. The identification of sweet taste receptors at the gastrointestinal level, with effects on the secretion of enterohormones, may provide an additional tool for managing chronic diseases, including cancer. Full article
(This article belongs to the Special Issue Antioxidants and Cancer)
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