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Pleiotropic Action of Selenium in the Treatment of Cancer and Related Diseases 2.0

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 (31 March 2023) | Viewed by 10361

Special Issue Editor

Prof. Dr. Youcef M. Rustum

E-Mail Website
Guest Editor
Department of Cancer Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA
Interests: HIFs; TGF-b; oncogenic microRNA-210 druggable targets; mechanism-based biologic and cytotoxic therapies; COVID-19 and selenium
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Targeted therapies alone and in combination with chemotherapy have made significant advances in the treatment of patients with advanced cancers. However, the majority of patients remain unresponsive, with de novo and/or acquired resistance with no cures. Although human tumors and their associated microenvironment are molecularly, histologically, and immunologically heterogeneous, microRNAs (miRs), hypoxia-inducible factor 1a and HIF2a (HIFs), and transforming growth factor-beta (TGF-b) are ubiquitously over expressed in the majority of advanced cancers. Collectively, oncogenic miRs, HIFs, and TGF-b regulate multiple target genes implicated in increased tumor angiogenesis, metastasis, and drug resistance. The altered expression of these specific biomarkers in the tumor microenvironment (TME) and associated tumor cells likely contributes to the unstable, permeable tumor vasculature limiting the delivery of therapeutically effective drug concentrations to tumor tissues, and thus to tumor cell resistance. The TME is therefore the gatekeeper and tumor cells are the ultimate therapeutic target. Thus, to further advance the quality and quantity of responses achieved with the present standard therapies, future combination treatment strategies should include molecules that contribute to the stabilization of the TME followed sequentially with drugs that target tumor cells. Selenium-containing molecules such as Se-methylselenocysteine (MSC), selene-l-methionine (SLM), and selenized yeast, among others, have been shown to target and modulate biomarkers expressed in tumor cells and their associated microenvironment. Pretreatment with a defined dose and schedule of MSC or SLM has resulted in the stabilization of tumor vasculature, selective increase in drug delivery to tumor cells, and the downregulation of miRs, HIFs, and TGF-b. Administration of anticancer therapeutics when the optimal effects of selenium were achieved resulted in therapeutic synergy. This new and novel strategy is being verified in patients with advanced clear cell renal cell carcinoma with very promising results. Recent data seems to associate baseline selenium concentrations with the incidence and recovery from of COVID-19. With the pleiotropic effects of selenium as a molecular and immunologic modulator, low-cost dietary selenium supplementation may be used to enhance the efficacy of drugs and vaccines in patients with COVID-19.

This Special Issue is devoted to soliciting contributions that preclinically or clinically document the therapeutic value that can be derived from agents that target specific miRs, HIFs, and TGF-β individually and/or collectively. The collection of contributions should provide a comprehensive overview of the biology, mechanism of action, and therapeutic potential of inhibitors that target miRs, HIFs, and TGF-b in vitro as well as translated and validated in vivo models. Contributions are also solicited that expand on the potential role of selenium alone and in combination with vaccine in the treatment of COVD-19.

Prof. Dr. Youcef M. Rustum
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • HIFs
  • TGF-b
  • oncogenic microRNA-210 druggable targets
  • mechanism-based biologic and cytotoxic therapies
  • COVID-19 and selenium

Published Papers (4 papers)

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Research

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17 pages, 11202 KiB  
Article
Molecular Mechanisms of the Cytotoxic Effect of Recombinant Selenoprotein SELENOM on Human Glioblastoma Cells
by Vladimir V. Rogachev, Michael V. Goltyaev, Elena G. Varlamova and Egor A. Turovsky
Int. J. Mol. Sci. 2023, 24(7), 6469; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24076469 - 30 Mar 2023
Cited by 3 | Viewed by 1278
Abstract
Currently, selenobiology is an actively developing area, primarily due to the study of the role of the trace element selenium and its organic and inorganic compounds in the regulation of vital processes occurring in the cell. In particular, the study of the functions [...] Read more.
Currently, selenobiology is an actively developing area, primarily due to the study of the role of the trace element selenium and its organic and inorganic compounds in the regulation of vital processes occurring in the cell. In particular, the study of the functions of selenium nanoparticles has gained great popularity in recent years. However, a weak point in this area of biology is the study of the functions of selenoproteins, of which 25 have been identified in mammals to date. First of all, this is due to the difficulties in obtaining native forms of selenoproteins in preparative quantities, due to the fact that the amino acid selenocysteine is encoded by one of the three stop codons of the TGA universal genetic code. A complex system for recognizing a given codon as a selenocysteine codon has a number of features in pro- and eukaryotes. The selenoprotein SELENOM is one of the least studied mammalian selenoproteins. In this work, for the first time, studies of the molecular mechanisms of regulation of the cytotoxic effect of this protein on human glioblastoma cells were carried out. The cytotoxicity of cancer cells in our experiments was already observed when cells were exposed to 50 μg of SELENOM and increased in proportion to the increase in protein concentration. Apoptosis of human glioblastoma cells was accompanied by an increase in mRNA expression of a number of pro-apoptotic genes, an increase in endoplasmic reticulum stress, and activation of the UPR IRE1α signaling pathway. The results obtained also demonstrate a dose-dependent depletion of the Ca2+ pool under the action of SELENOM, which proves the important role of this protein in the regulation of calcium homeostasis in the cell. Full article
(This article belongs to the Special Issue Pleiotropic Action of Selenium in the Treatment of Cancer and Related Diseases 2.0)
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12 pages, 2611 KiB  
Article
MicroRNA Expression in Clear Cell Renal Cell Carcinoma Cell Lines and Tumor Biopsies: Potential Therapeutic Targets
by Samuel Swearson, Aseel O. Rataan, Steven Eliason, Brad A. Amendt, Yousef Zakharia, Aliasger K. Salem, Thai Ho and Youcef M. Rustum
Int. J. Mol. Sci. 2022, 23(10), 5604; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105604 - 17 May 2022
Cited by 1 | Viewed by 1931
Abstract
This study was carried out to quantitate the expression levels of microRNA-17, -19a, -34a, -155, and -210 (miRs) expressed in nine clear cell renal cell carcinoma (ccRCC) and one chromophobe renal cell carcinoma cell line with and without sarcomatoid differentiation, and in six [...] Read more.
This study was carried out to quantitate the expression levels of microRNA-17, -19a, -34a, -155, and -210 (miRs) expressed in nine clear cell renal cell carcinoma (ccRCC) and one chromophobe renal cell carcinoma cell line with and without sarcomatoid differentiation, and in six primary kidney tumors with matching normal kidney tissues. The data in the five non-sarcomatoid ccRCC cell lines—RC2, CAKI-1, 786-0, RCC4, and RCC4/VHL—and in the four ccRCC with sarcomatoid differentiation—RCJ41T1, RCJ41T2, RCJ41M, and UOK-127—indicated that miR-17 and -19a were expressed at lower levels relative to miR-34a, -155, and -210. Compared with RPTEC normal epithelial cells, miR-34a, miR-155, and miR-210 were expressed at higher levels, independent of the sarcomatoid differentiation status and hypoxia-inducible factors 1α and 2α (HIFs) isoform expression. In the one chromophobe renal cell carcinoma cell line, namely, UOK-276 with sarcomatoid differentiation, and expressing tumor suppressor gene TP53, miR-34a, which is a tumor suppressor gene, was expressed at higher levels than miR-210, -155, -17, and -19a. The pilot results generated in six tumor biopsies with matching normal kidney tissues indicated that while the expression of miR-17 and -19a were similar to the normal tissue expression profile, miR-210, -155, -and 34a were expressed at a higher level. To confirm that differences in the expression levels of the five miRs in the six tumor biopsies were statistically significant, the acquisition of a larger sample size is required. Data previously generated in ccRCC cell lines demonstrating that miR-210, miR-155, and HIFs are druggable targets using a defined dose and schedule of selenium-containing molecules support the concept that simultaneous and concurrent downregulation of miR-210, miR-155, and HIFs, which regulate target genes associated with increased tumor angiogenesis and drug resistance, may offer the potential for the development of a novel mechanism-based strategy for the treatment of patients with advanced ccRCC. Full article
(This article belongs to the Special Issue Pleiotropic Action of Selenium in the Treatment of Cancer and Related Diseases 2.0)
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Review

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18 pages, 1256 KiB  
Review
Druggable Biomarkers Altered in Clear Cell Renal Cell Carcinoma: Strategy for the Development of Mechanism-Based Combination Therapy
by Youcef M. Rustum, Ryan Reis and Tara M. Rustum
Int. J. Mol. Sci. 2023, 24(2), 902; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24020902 - 04 Jan 2023
Cited by 1 | Viewed by 2507
Abstract
Targeted therapeutics made significant advances in the treatment of patients with advanced clear cell renal cell carcinoma (ccRCC). Resistance and serious adverse events associated with standard therapy of patients with advanced ccRCC highlight the need to identify alternative ‘druggable’ targets to those currently [...] Read more.
Targeted therapeutics made significant advances in the treatment of patients with advanced clear cell renal cell carcinoma (ccRCC). Resistance and serious adverse events associated with standard therapy of patients with advanced ccRCC highlight the need to identify alternative ‘druggable’ targets to those currently under clinical development. Although the Von Hippel-Lindau (VHL) and Polybromo1 (PBRM1) tumor-suppressor genes are the two most frequently mutated genes and represent the hallmark of the ccRCC phenotype, stable expression of hypoxia-inducible factor-1α/2α (HIFs), microRNAs-210 and -155 (miRS), transforming growth factor-beta (TGF-ß), nuclear factor erythroid 2-related factor 2 (Nrf2), and thymidine phosphorylase (TP) are targets overexpressed in the majority of ccRCC tumors. Collectively, these altered biomarkers are highly interactive and are considered master regulators of processes implicated in increased tumor angiogenesis, metastasis, drug resistance, and immune evasion. In recognition of the therapeutic potential of the indicated biomarkers, considerable efforts are underway to develop therapeutically effective and selective inhibitors of individual targets. It was demonstrated that HIFS, miRS, Nrf2, and TGF-ß are targeted by a defined dose and schedule of a specific type of selenium-containing molecules, seleno-L-methionine (SLM) and methylselenocystein (MSC). Collectively, the demonstrated pleiotropic effects of selenium were associated with the normalization of tumor vasculature, and enhanced drug delivery and distribution to tumor tissue, resulting in enhanced efficacy of multiple chemotherapeutic drugs and biologically targeted molecules. Higher selenium doses than those used in clinical prevention trials inhibit multiple targets altered in ccRCC tumors, which could offer the potential for the development of a new and novel therapeutic modality for cancer patients with similar selenium target expression. Better understanding of the underlying mechanisms of selenium modulation of specific targets altered in ccRCC could potentially have a significant impact on the development of a more efficacious and selective mechanism-based combination for the treatment of patients with cancer. Full article
(This article belongs to the Special Issue Pleiotropic Action of Selenium in the Treatment of Cancer and Related Diseases 2.0)
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16 pages, 4841 KiB  
Review
Can Selenium Reduce the Susceptibility and Severity of SARS-CoV-2?—A Comprehensive Review
by Muhammed Majeed, Kalyanam Nagabhushanam, Priji Prakasan and Lakshmi Mundkur
Int. J. Mol. Sci. 2022, 23(9), 4809; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23094809 - 27 Apr 2022
Cited by 10 | Viewed by 3749
Abstract
The SARS-CoV-2 infection is a highly contagious viral infection, which has claimed millions of lives in the last two years. The infection can cause acute respiratory distress, myocarditis, and systemic inflammatory response in severe cases. The interaction of the viral spike protein with [...] Read more.
The SARS-CoV-2 infection is a highly contagious viral infection, which has claimed millions of lives in the last two years. The infection can cause acute respiratory distress, myocarditis, and systemic inflammatory response in severe cases. The interaction of the viral spike protein with the angiotensin-converting enzyme in various tissues causes damage to vital organs and tissues, leading to complications in the post-infection period. Vaccines and antiviral drugs have improved patient response to the infection, but the long-term effect on vital organs is still unknown. Investigations are now focused on supportive nutrient therapies, which can mitigate the susceptibility as well as the long-term complications of COVID-19. Selenium is one such micronutrient that plays a vital role in preventing oxidative stress induced by the virus. Further, selenium is important for effective immune response, controlling systemic inflammation, and maintain overall health of humans. We examine the role of selenium in various aspects of SARS-CoV-2 infection and address the importance of selenium supplementation in reducing the susceptibility and severity of infection in this review. Full article
(This article belongs to the Special Issue Pleiotropic Action of Selenium in the Treatment of Cancer and Related Diseases 2.0)
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