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Pleiotropic Action of Selenium in the Prevention and Treatment of Cancer, and Related Diseases

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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 November 2018) | Viewed by 49965

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Prof. Dr. Youcef M. Rustum

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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
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Dear Colleagues,

Gene cloning and sequence has provided the opportunity to identify and characterize the functional role of biomarkers expressed in and on tumor cells and the surrounding microenvironment. Molecular and immunologic heterogeneity of cells in the tumor microenvironment contribute to instability, enhanced angiogenesis and drug resistance of the tumor cell. Since tumor cells are the ultimate therapeutic targets for drugs and therapy development, the tumor microenvironment that regulates the growth and the delivery of effective drug concentrations to tumor cells is the gatekeeper. Thus, to have a significant impact on overall survival and cure of patients with advanced cancer, the stabilization of the tumor microenvironment should be the initial treatment, followed by treatment that targets and kills tumor cells.

Antiangeogenic therapies hold considerable promise in the treatment of a subset of cancer patients, and is reported to have significant impacts on the stabilization of the tumor microenvironment. More recently, selenium-containing molecules, such as Se-metylselenocysteine, seleno-L-methionine, and selenized yeast, among others, have been shown to target and modulate biomarkers associated with tumor cells and the tumor microenvironment. The effects are selenium type, dose, and schedule-dependent. The pleiotropic actions of selenium are necessary for tumor cells sensitization, and synergy with mechanism-based combinations. This Special Issue is devoted to highlighting evidence for the potential role of specific types, doses, and schedules of selenium alone and in combination with mechanism-based biologic and cytotoxic therapies for the prevention and treatment of cancer and related diseases. The collection of contributions should provide a comprehensive overview of the pharmacology, metabolism, and delineation of the pleiotropic action of different types of selenium molecules, relevant to the use of selenium as a potential modulator of the therapeutic efficacy and toxicity of biologic and cytotoxic therapies for cancer and related diseases. The pleiotropic action of specific types of selenium, doses and schedule, as selective and efficacious modulator of genetic, immunologic, and epigenetic biomarkers, should stimulate expanded preclinical research that could ultimately impact on the development of new and novel approaches for the treatment of cancer.

Prof. Dr. Youcef M. Rustum
Guest Editor

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Keywords

Selenium-containing molecules
Immunologic and epigenetic biomarkers
Tumor microenvironment
Mechanism-based biologic and cytotoxic therapies
Molecular, epigeneticand immunological targets (replacement)
Prevention and therapeutic potential
Pharmacology and metabolism
HIFs (Hypoxia-inducible factor), VEGF (Vascular endothelial growth factor)
VEGFR, PD-L1 and miRNAs targets

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Published Papers (9 papers)

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Research

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17 pages, 3804 KiB

Open AccessArticle

Identification of a Novel Quinoxaline-Isoselenourea Targeting the STAT3 Pathway as a Potential Melanoma Therapeutic

by Verónica Alcolea, Deepkamal N. Karelia, Manoj K. Pandey, Daniel Plano, Parvesh Singh, Juan Antonio Palop, Shantu Amin, Carmen Sanmartín and Arun K. Sharma

Int. J. Mol. Sci. 2019, 20(3), 521; https://doi.org/10.3390/ijms20030521 - 26 Jan 2019

Cited by 11 | Viewed by 4167

Abstract

The prognosis for patients with metastatic melanoma remains very poor. Constitutive signal transducer and activator of transcription 3 (STAT3) activation has been correlated to metastasis, poor patient survival, larger tumor size, and acquired resistance against vemurafenib (PLX-4032), suggesting its potential as a molecular target. We recently designed a series of isoseleno- and isothio-urea derivatives of several biologically active heterocyclic scaffolds. The cytotoxic effects of lead isoseleno- and isothio-urea derivatives (compounds 1 and 3) were studied in a panel of five melanoma cell lines, including B-RAF^V600E-mutant and wild-type (WT) cells. Compound 1 (IC₅₀ range 0.8–3.8 µM) showed lower IC₅₀ values than compound 3 (IC₅₀ range 8.1–38.7 µM) and the mutant B-RAF specific inhibitor PLX-4032 (IC₅₀ ranging from 0.4 to >50 µM), especially at a short treatment time (24 h). These effects were long-lasting, since melanoma cells did not recover their proliferative potential after 14 days of treatment. In addition, we confirmed that compound 1 induced cell death by apoptosis using Live-and-Dead, Annexin V, and Caspase3/7 apoptosis assays. Furthermore, compound 1 reduced the protein levels of STAT3 and its phosphorylation, as well as decreased the expression of STAT3-regulated genes involved in metastasis and survival, such as survivin and c-myc. Compound 1 also upregulated the cell cycle inhibitor p21. Docking studies further revealed the favorable binding of compound 1 with the SH2 domain of STAT3, suggesting it acts through STAT3 inhibition. Taken together, our results suggest that compound 1 induces apoptosis by means of the inhibition of the STAT3 pathway, non-specifically targeting both B-RAF-mutant and WT melanoma cells, with much higher cytotoxicity than the current therapeutic drug PLX-4032. Full article

(This article belongs to the Special Issue Pleiotropic Action of Selenium in the Prevention and Treatment of Cancer, and Related Diseases)

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15 pages, 1396 KiB

Open AccessArticle

Methylseleninic Acid Induces Lipid Peroxidation and Radiation Sensitivity in Head and Neck Cancer Cells

by John T. Lafin, Ehab H. Sarsour, Amanda L. Kalen, Brett A. Wagner, Garry R. Buettner and Prabhat C. Goswami

Int. J. Mol. Sci. 2019, 20(1), 225; https://doi.org/10.3390/ijms20010225 - 8 Jan 2019

Cited by 15 | Viewed by 5596

Abstract

Combination radiation and chemotherapy are commonly used to treat locoregionally advanced head and neck squamous cell carcinoma (HNSCC). Aggressive dosing of these therapies is significantly hampered by side effects due to normal tissue toxicity. Selenium represents an adjuvant that selectively sensitizes cancer cells to these treatments modalities, potentially by inducing lipid peroxidation (LPO). This study investigated whether one such selenium compound, methylseleninic acid (MSA), induces LPO and radiation sensitivity in HNSCC cells. Results from 4,4-difluoro-4-bora-3a,4a-diaza-S-indacene (BODIPY) C11 oxidation and ferric thiocyanate assays revealed that MSA induced LPO in cells rapidly and persistently. Propidium iodide (PI) exclusion assay found that MSA was more toxic to cancer cells than other related selenium compounds; this toxicity was abrogated by treatment with α-tocopherol, an LPO inhibitor. MSA exhibited no toxicity to normal fibroblasts at similar doses. MSA also sensitized HNSCC cells to radiation as determined by clonogenic assay. Intracellular glutathione in cancer cells was depleted following MSA treatment, and supplementation of the intracellular glutathione pool with N-acetylcysteine sensitized cells to MSA. The addition of MSA to a cell-free solution of glutathione resulted in an increase in oxygen consumption, which was abrogated by catalase, suggesting the formation of H₂O₂. Results from this study identify MSA as an inducer of LPO, and reveal its capability to sensitize HNSCC to radiation. MSA may represent a potent adjuvant to radiation therapy in HNSCC. Full article

(This article belongs to the Special Issue Pleiotropic Action of Selenium in the Prevention and Treatment of Cancer, and Related Diseases)

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12 pages, 1983 KiB

Open AccessArticle

The Interaction of Selenium with Chemotherapy and Radiation on Normal and Malignant Human Mononuclear Blood Cells

by Richard J. Lobb, Gregory M. Jacobson, Ray T. Cursons and Michael B. Jameson

Int. J. Mol. Sci. 2018, 19(10), 3167; https://doi.org/10.3390/ijms19103167 - 15 Oct 2018

Cited by 26 | Viewed by 4229

Abstract

Selenium, a trace element with anticancer properties, can reduce harmful toxicities of chemotherapy and radiotherapy without compromising efficacy. However, the dose-response relationship in normal versus malignant human cells is unclear. We evaluated how methylseleninic acid (MSA) modulates the toxicity and efficacy of chemotherapy and radiation on malignant and non-malignant human mononuclear blood cells in vitro. We specifically investigated its effects on endoplasmic reticulum stress induction, intracellular glutathione concentration, DNA damage and viability of peripheral blood mononuclear cells and THP1 monocytic leukaemia cells in response to radiation, cytosine arabinoside or doxorubicin chemotherapy. MSA, at lower concentrations, induced protective responses in normal cells but cytotoxic effects in malignant cells, alone and in conjunction with chemotherapy or radiation. However, in normal cells higher concentrations of MSA were directly toxic and increased the cytotoxicity of radiation but not chemotherapy. In malignant cells higher MSA concentrations were generally more effective in combination with cancer treatments. Thus, optimal MSA concentrations differed between normal and malignant cells and treatments. This work supports clinical reports that selenium can significantly reduce dose-limiting toxicities of anticancer therapies and potentially improve efficacy of anticancer treatments. The optimal selenium compound and dose is not yet determined. Full article

(This article belongs to the Special Issue Pleiotropic Action of Selenium in the Prevention and Treatment of Cancer, and Related Diseases)

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17 pages, 2729 KiB

Open AccessArticle

Novel Methylselenoesters Induce Programed Cell Death via Entosis in Pancreatic Cancer Cells

by Prajakta Khalkar, Nuria Díaz-Argelich, Juan Antonio Palop, Carmen Sanmartín and Aristi P. Fernandes

Int. J. Mol. Sci. 2018, 19(10), 2849; https://doi.org/10.3390/ijms19102849 - 20 Sep 2018

Cited by 27 | Viewed by 4013

Abstract

Redox active selenium (Se) compounds have gained substantial attention in the last decade as potential cancer therapeutic agents. Several Se compounds have shown high selectivity and sensitivity against malignant cells. The cytotoxic effects are exerted by their biologically active metabolites, with methylselenol (CH₃SeH) being one of the key executors. In search of novel CH₃SeH precursors, we previously synthesized a series of methylselenoesters that were active (GI₅₀ < 10 µM at 72 h) against a panel of cancer cell lines. Herein, we refined the mechanism of action of the two lead compounds with the additional synthesis of new analogs (ethyl, pentyl, and benzyl derivatives). A novel mechanism for the programmed cell death mechanism for Se-compounds was identified. Both methylseleninic acid and the novel CH₃SeH precursors induced entosis by cell detachment through downregulation of cell division control protein 42 homolog (CDC42) and its downstream effector β1-integrin (CD29). To our knowledge, this is the first time that Se compounds have been reported to induce this type of cell death and is of importance in the characterization of the anticancerogenic properties of these compounds. Full article

(This article belongs to the Special Issue Pleiotropic Action of Selenium in the Prevention and Treatment of Cancer, and Related Diseases)

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Review

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26 pages, 607 KiB

Open AccessReview

Selenium Species: Current Status and Potentials in Cancer Prevention and Therapy

by Heng Wee Tan, Hai-Ying Mo, Andy T. Y. Lau and Yan-Ming Xu

Int. J. Mol. Sci. 2019, 20(1), 75; https://doi.org/10.3390/ijms20010075 - 25 Dec 2018

Cited by 158 | Viewed by 9088

Abstract

Selenium (Se) acts as an essential trace element in the human body due to its unique biological functions, particularly in the oxidation-reduction system. Although several clinical trials indicated no significant benefit of Se in preventing cancer, researchers reported that some Se species exhibit superior anticancer properties. Therefore, a reassessment of the status of Se and Se compounds is necessary in order to provide clearer insights into the potentiality of Se in cancer prevention and therapy. In this review, we organize relevant forms of Se species based on the three main categories of Se—inorganic, organic, and Se-containing nanoparticles (SeNPs)—and overview their potential functions and applications in oncology. Here, we specifically focus on the SeNPs as they have tremendous potential in oncology and other fields. In general, to make better use of Se compounds in cancer prevention and therapy, extensive further study is still required to understand the underlying mechanisms of the Se compounds. Full article

(This article belongs to the Special Issue Pleiotropic Action of Selenium in the Prevention and Treatment of Cancer, and Related Diseases)

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14 pages, 780 KiB

Open AccessReview

Current Landscape and the Potential Role of Hypoxia-Inducible Factors and Selenium in Clear Cell Renal Cell Carcinoma Treatment

by Rohan Garje, Josiah J. An, Kevin Sanchez, Austin Greco, Jeffrey Stolwijk, Eric Devor, Youcef Rustum and Yousef Zakharia

Int. J. Mol. Sci. 2018, 19(12), 3834; https://doi.org/10.3390/ijms19123834 - 1 Dec 2018

Cited by 27 | Viewed by 6004

Abstract

In the last two decades, the discovery of various pathways involved in renal cell carcinoma (RCC) has led to the development of biologically-driven targeted therapies. Hypoxia-inducible factors (HIFs), angiogenic growth factors, von Hippel–Lindau (VHL) gene mutations, and oncogenic microRNAs (miRNAs) play essential roles in the pathogenesis and drug resistance of clear cell renal cell carcinoma. These insights have led to the development of vascular endothelial growth factor (VEGF) inhibitors, Mechanistic target of rapamycin (mTOR) inhibitors, and immunotherapeutic agents, which have significantly improved the outcomes of patients with advanced RCC. HIF inhibitors will be a valuable asset in the growing therapeutic armamentarium of RCC. Various histone deacetylase (HDAC) inhibitors, selenium, and agents like PT2385 and PT2977 are being explored in various clinical trials as potential HIF inhibitors, to ameliorate the outcomes of RCC patients. In this article, we will review the current treatment options and highlight the potential role of selenium in the modulation of drug resistance biomarkers expressed in clear cell RCC (ccRCC) tumors. Full article

(This article belongs to the Special Issue Pleiotropic Action of Selenium in the Prevention and Treatment of Cancer, and Related Diseases)

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14 pages, 870 KiB

Open AccessReview

Selenium-Binding Protein 1 in Human Health and Disease

by Mostafa Elhodaky and Alan M. Diamond

Int. J. Mol. Sci. 2018, 19(11), 3437; https://doi.org/10.3390/ijms19113437 - 2 Nov 2018

Cited by 65 | Viewed by 5635

Abstract

Selenium-binding protein 1 (SBP1) is a highly conserved protein that covalently binds selenium. SBP1 may play important roles in several fundamental physiological functions, including protein degradation, intra-Golgi transport, cell differentiation, cellular motility, redox modulation, and the metabolism of sulfur-containing molecules. SBP1 expression is often reduced in many cancer types compared to the corresponding normal tissues and low levels of SBP1 are frequently associated with poor clinical outcome. In this review, the transcriptional regulation of SBP1, the different physiological roles reported for SBP1, as well as the implications of SBP1 function in cancer and other diseases are presented. Full article

(This article belongs to the Special Issue Pleiotropic Action of Selenium in the Prevention and Treatment of Cancer, and Related Diseases)

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20 pages, 7275 KiB

Open AccessReview

Non-Coding Micro RNAs and Hypoxia-Inducible Factors Are Selenium Targets for Development of a Mechanism-Based Combination Strategy in Clear-Cell Renal Cell Carcinoma—Bench-to-Bedside Therapy

by Youcef M. Rustum, Sreenivasulu Chintala, Farukh A. Durrani and Arup Bhattacharya

Int. J. Mol. Sci. 2018, 19(11), 3378; https://doi.org/10.3390/ijms19113378 - 29 Oct 2018

Cited by 18 | Viewed by 3836

Abstract

Durable response, inherent or acquired resistance, and dose-limiting toxicities continue to represent major barriers in the treatment of patients with advanced clear-cell renal cell carcinoma (ccRCC). The majority of ccRCC tumors are characterized by the loss of Von Hippel–Lindau tumor suppressor gene function, a stable expression of hypoxia-inducible factors 1α and 2α (HIFs), an altered expression of tumor-specific oncogenic microRNAs (miRNAs), a clear cytoplasm with dense lipid content, and overexpression of thymidine phosphorylase. The aim of this manuscript was to confirm that the downregulation of specific drug-resistant biomarkers deregulated in tumor cells by a defined dose and schedule of methylselenocysteine (MSC) or seleno-l-methionine (SLM) sensitizes tumor cells to mechanism-based drug combination. The inhibition of HIFs by selenium was necessary for optimal therapeutic benefit. Durable responses were achieved only when MSC was combined with sunitinib (a vascular endothelial growth factor receptor (VEGFR)-targeted biologic), topotecan (a topoisomerase 1 poison and HIF synthesis inhibitor), and S-1 (a 5-fluorouracil prodrug). The documented synergy was selenium dose- and schedule-dependent and associated with enhanced prolyl hydroxylase-dependent HIF degradation, stabilization of tumor vasculature, downregulation of 28 oncogenic miRNAs, as well as the upregulation of 12 tumor suppressor miRNAs. The preclinical results generated provided the rationale for the development of phase 1/2 clinical trials of SLM in sequential combination with axitinib in ccRCC patients refractory to standard therapies. Full article

(This article belongs to the Special Issue Pleiotropic Action of Selenium in the Prevention and Treatment of Cancer, and Related Diseases)

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19 pages, 871 KiB

Open AccessReview

Role of Hypoxic Stress in Regulating Tumor Immunogenicity, Resistance and Plasticity

by Stéphane Terry, Rania Faouzi Zaarour, Goutham Hassan Venkatesh, Amirtharaj Francis, Walid El-Sayed, Stéphanie Buart, Pamela Bravo, Jérome Thiery and Salem Chouaib

Int. J. Mol. Sci. 2018, 19(10), 3044; https://doi.org/10.3390/ijms19103044 - 6 Oct 2018

Cited by 67 | Viewed by 6436

Abstract

Hypoxia, or gradients of hypoxia, occurs in most growing solid tumors and may result in pleotropic effects contributing significantly to tumor aggressiveness and therapy resistance. Indeed, the generated hypoxic stress has a strong impact on tumor cell biology. For example, it may contribute to increasing tumor heterogeneity, help cells gain new functional properties and/or select certain cell subpopulations, facilitating the emergence of therapeutic resistant cancer clones, including cancer stem cells coincident with tumor relapse and progression. It controls tumor immunogenicity, immune plasticity, and promotes the differentiation and expansion of immune-suppressive stromal cells. In this context, manipulation of the hypoxic microenvironment may be considered for preventing or reverting the malignant transformation. Here, we review the current knowledge on how hypoxic stress in tumor microenvironments impacts on tumor heterogeneity, plasticity and resistance, with a special interest in the impact on immune resistance and tumor immunogenicity. Full article

(This article belongs to the Special Issue Pleiotropic Action of Selenium in the Prevention and Treatment of Cancer, and Related Diseases)

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