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Antioxidants
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Redox-Active Selenium Compounds in Cancer
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Redox-Active Selenium Compounds in 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 (31 December 2019) | Viewed by 22086

Special Issue Editor

Prof. Dr. Mikael Björnstedt

E-Mail Website
Guest Editor
Department of Laboratory Medicine, Division of Pathology F46, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden
Interests: clinical and mechanistic studies of redox-active selenium compounds in cancer; primary cells, human ex vivo models, and clinical trials applied with special focus on liver cancer and pancreas cancer

Special Issue Information

Dear Colleagues,

For decades, the highly interesting growth modulatory properties of redox-active selenium compounds have been reported in various model systems. Despite this, there are very few clinical trials on selenium in cancer, and selenium has not been introduced in modern oncology. The reasons for this can only be speculated, but the simplicity and beauty of selenium compounds as cytostatic/cytotoxic agents really deserves much wider attention. Maybe the simplicity of it, that is, the fact that an element and the simple compounds of such an element could have similar or even better effects compared to novel, expensive so-called targeted therapies is the reason selenium formulations have not been extensively explored in clinical trials and are thus not part of any pharmacopeia for the treatment of cancer. The focus of this Special Issue is the therapeutic potential of redox-active selenium compounds and their potential use in combating highly drug-resistant cancers for which currently no efficient therapy exists. In the literature, prevention and therapy are often mixed. It is important to separate these two fundamentally different effects, since the former is mostly explained by antioxidant and the latter by pro-oxidant mechanisms of selenium. The Special Issue welcomes original research papers or reviews that deal with the cytotoxic and antineoplastic effects of redox-active selenium compounds. Both clinically oriented papers and mechanistic basic science contributions are welcome. The main focus is therapy and not prevention, but the Special Issue is also open to prevention studies as long as redox-active selenium compounds are applied.

Prof. Dr. Mikael Bjornstedt
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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

  • Selenium
  • Cancer
  • Therapy
  • Mechanisms
  • Redox
  • Oxidative stress

Published Papers (5 papers)

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Research

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14 pages, 1513 KiB  
Article
A Novel Assay Method to Determine the β-Elimination of Se-Methylselenocysteine to Monomethylselenol by Kynurenine Aminotransferase 1
by Arun Kumar Selvam and Mikael Björnstedt
Antioxidants 2020, 9(2), 139; https://doi.org/10.3390/antiox9020139 - 05 Feb 2020
Cited by 8 | Viewed by 2613
Abstract
Kynurenine aminotransferase 1 (KYAT1 or CCBL1) plays a major role in Se-methylselenocysteine (MSC) metabolism. It is a bi-functional enzyme that catalyzes transamination and beta-elimination activity with a single substrate. KYAT1 produces methylselenol (CH3SeH) via β-elimination activities with MSC as a substrate. [...] Read more.
Kynurenine aminotransferase 1 (KYAT1 or CCBL1) plays a major role in Se-methylselenocysteine (MSC) metabolism. It is a bi-functional enzyme that catalyzes transamination and beta-elimination activity with a single substrate. KYAT1 produces methylselenol (CH3SeH) via β-elimination activities with MSC as a substrate. This methylated selenium compound is a major cytotoxic selenium metabolite, causing apoptosis in a wide variety of cancer cells. Methylselenol is volatile and possesses extraordinary nucleophilic properties. We herein describe a simple spectrophotometric assay by combining KYAT1 and thioredoxin reductase (TrxR) to detect CH3SeH in a coupled activity assay. The metabolite methylselenol and its oxidized form from MSC metabolism is utilized as a substrate for TrxR1 and this can be monitored spectroscopically at 340 nm. Our results show the feasibility of monitoring the β-elimination of KYAT1 by our assay and the results were compared to the previously described β-elimination assays measuring pyruvate. By using known inhibitors of KYAT1 and TrxR1, we further validated the respective reaction. Our data provide a simple but accurate method to determine the β-elimination activity of KYAT1, which is of importance for mechanistic studies of a highly interesting selenium compound. Full article
(This article belongs to the Special Issue Redox-Active Selenium Compounds in Cancer)
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22 pages, 6177 KiB  
Article
Investigating the Potential of Conjugated Selenium Redox Folic Acid as a Treatment for Triple Negative Breast Cancer
by Soni Khandelwal, Mallory Boylan, Gilbert Kirsch, Julian E. Spallholz and Lauren S. Gollahon
Antioxidants 2020, 9(2), 138; https://doi.org/10.3390/antiox9020138 - 05 Feb 2020
Cited by 10 | Viewed by 3080
Abstract
Previous studies have demonstrated that redox selenium compounds arrest cancer cell viability in vitro through their pro-oxidative activity by generating superoxide (O2•−). Currently, there are no efficacious treatment options for women with Triple Negative Breast Cancer (TNBC). However, the association [...] Read more.
Previous studies have demonstrated that redox selenium compounds arrest cancer cell viability in vitro through their pro-oxidative activity by generating superoxide (O2•−). Currently, there are no efficacious treatment options for women with Triple Negative Breast Cancer (TNBC). However, the association between the over-expression of the Folate Receptor Alpha (FRA) in TNBC and other cancer cells, has led to the possibility that TNBCs might be treated by targeting the FRA with redox selenium covalent Folic Acid conjugates. The present study reports the synthesis of the redox active vitamer, Selenofolate, generating superoxide. Superoxide (O2•−) catalytic generation by Selenofolate was assessed by an in vitro chemiluminescence (CL) assay and by a Dihydroethidium (DHE) in vivo assay. Cytotoxicity of Selenofolate was assessed against the TNBC cell line MDA-MB-468 and an immortalized, mammary epithelial cell line, HME50-5E. Cytotoxicity of Selenofolate was compared to Folic Acid and sodium selenite, in a time and dose dependent manner. Selenofolate and selenite treatments resulted in greater inhibition of MDA-MB-468 cell proliferation than HME50-5E as evaluated by Trypan Blue exclusion, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) metabolic assay and Annexin V apoptosis assays. Folate receptor alpha (FRA) protein expression was assessed by Western blotting, with the experimental results showing that redox active Selenofolate and selenite, but not Folic Acid, was cytotoxic to MDA-MB-468 cells in vitro, suggesting a possible clinical option for treating TNBC and other cancers over-expressing FRA. Full article
(This article belongs to the Special Issue Redox-Active Selenium Compounds in Cancer)
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16 pages, 3022 KiB  
Article
Novel N,N′-Disubstituted Acylselenoureas as Potential Antioxidant and Cytotoxic Agents
by Ana Carolina Ruberte, Sandra Ramos-Inza, Carlos Aydillo, Irene Talavera, Ignacio Encío, Daniel Plano and Carmen Sanmartín
Antioxidants 2020, 9(1), 55; https://doi.org/10.3390/antiox9010055 - 08 Jan 2020
Cited by 24 | Viewed by 2939
Abstract
Selenium compounds are pivotal in medicinal chemistry for their antitumoral and antioxidant properties. Forty seven acylselenoureas have been designed and synthesized following a fragment-based approach. Different scaffolds, including carbo- and hetero-cycles, along with mono- and bi-cyclic moieties, have been linked to the selenium [...] Read more.
Selenium compounds are pivotal in medicinal chemistry for their antitumoral and antioxidant properties. Forty seven acylselenoureas have been designed and synthesized following a fragment-based approach. Different scaffolds, including carbo- and hetero-cycles, along with mono- and bi-cyclic moieties, have been linked to the selenium containing skeleton. The dose- and time-dependent radical scavenging activity for all of the compounds were assessed using the in vitro 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) assays. Some of them showed a greater radical scavenging capacity at low doses and shorter times than ascorbic acid. Therefore, four compounds were evaluated to test their protective effects against H2O2-induced oxidative stress. One derivative protected cells against H2O2-induced damage, increasing cell survival by up to 3.6-fold. Additionally, in vitro cytotoxic activity of all compounds was screened against several cancer cells. Eight compounds were selected to determine their half maximal inhibitory concentration (IC50) values towards breast and lung cancer cells, along with their selectivity indexes. The breast cancer cells turned out to be much more sensitive than the lung. Two compounds (5d and 10a) stood out with IC50 values between 4.2 μM and 8.0 μM towards MCF-7 and T47D cells, with selectivity indexes greater than 22.9. In addition, compound 10b exhibited dual antioxidant and cytotoxic activities. Although further evidence is needed, the acylselenourea scaffold could be a feasible frame to develop new dual agents. Full article
(This article belongs to the Special Issue Redox-Active Selenium Compounds in Cancer)
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Review

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25 pages, 1767 KiB  
Review
Understanding the Redox Biology of Selenium in the Search of Targeted Cancer Therapies
by Jeffrey M. Stolwijk, Rohan Garje, Jessica C. Sieren, Garry R. Buettner and Yousef Zakharia
Antioxidants 2020, 9(5), 420; https://doi.org/10.3390/antiox9050420 - 13 May 2020
Cited by 32 | Viewed by 4541
Abstract
Selenium (Se) is an essential trace nutrient required for optimal human health. It has long been suggested that selenium has anti-cancer properties. However, clinical trials have shown inconclusive results on the potential of Se to prevent cancer. The suggested role of Se in [...] Read more.
Selenium (Se) is an essential trace nutrient required for optimal human health. It has long been suggested that selenium has anti-cancer properties. However, clinical trials have shown inconclusive results on the potential of Se to prevent cancer. The suggested role of Se in the prevention of cancer is centered around its role as an antioxidant. Recently, the potential of selenium as a drug rather than a supplement has been uncovered. Selenium compounds can generate reactive oxygen species that could enhance the treatment of cancer. Transformed cells have high oxidative distress. As normal cells have a greater capacity to meet oxidative challenges than tumor cells, increasing the flux of oxidants with high dose selenium treatment could result in cancer-specific cell killing. If the availability of Se is limited, supplementation of Se can increase the expression and activities of Se-dependent proteins and enzymes. In cell culture, selenium deficiency is often overlooked. We review the importance of achieving normal selenium biology and how Se deficiency can lead to adverse effects. We examine the vital role of selenium in the prevention and treatment of cancer. Finally, we examine the properties of Se-compounds to better understand how each can be used to address different research questions. Full article
(This article belongs to the Special Issue Redox-Active Selenium Compounds in Cancer)
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11 pages, 641 KiB  
Review
Selenium Anticancer Properties and Impact on Cellular Redox Status
by Lolita Kuršvietienė, Aušra Mongirdienė, Jurga Bernatonienė, Jurgita Šulinskienė and Inga Stanevičienė
Antioxidants 2020, 9(1), 80; https://doi.org/10.3390/antiox9010080 - 17 Jan 2020
Cited by 120 | Viewed by 8451
Abstract
(1) Background: In this review, we provide information published in recent years on the chemical forms, main biological functions and especially on antioxidant and prooxidant activities of selenium. The main focus is put on the impact of selenoproteins on maintaining cellular redox balance [...] Read more.
(1) Background: In this review, we provide information published in recent years on the chemical forms, main biological functions and especially on antioxidant and prooxidant activities of selenium. The main focus is put on the impact of selenoproteins on maintaining cellular redox balance and anticancerogenic function. Moreover, we summarize data on chemotherapeutic application of redox active selenium compounds. (2) Methods: In the first section, main aspects of metabolism and redox activity of selenium compounds is reviewed. The second outlines multiple biological functions, asserted when selenium is incorporated into the structure of selenoproteins. The final section focuses on anticancer activity of selenium and chemotherapeutic application of redox active selenium compounds as well. (3) Results: optimal dietary level of selenium ensures its proper antioxidant and anticancer activity. We pay special attention to antioxidant activities of selenium compounds, especially selenoproteins, and their importance in antioxidant defence. It is worth noting, that data on selenium anticancer properties is still contraversive. Moreover, selenium compounds as chemotherapeutic agents usually are used at supranutritional doses. (4) Conclusions: Selenium play a vital role for many organism systems due to its incorporation into selenoproteins structure. Selenium possesses antioxidant activity at optimal doses, while at supranutritional doses, it displays prooxidant activity. Redox active selenium compounds can be used for cancer treatment; recently special attention is put to selenium containing nanoparticles. Full article
(This article belongs to the Special Issue Redox-Active Selenium Compounds in Cancer)
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