Selenium is generally known as an antioxidant due to its presence in selenoproteins as selenocysteine, but it is also toxic. The toxic effects of selenium are, however, strictly concentration and ...chemical species dependent. One class of selenium compounds is a potent inhibitor of cell growth with remarkable tumor specificity. These redox active compounds are pro-oxidative and highly cytotoxic to tumor cells and are promising candidates to be used in chemotherapy against cancer. Herein we elaborate upon the major forms of dietary selenium compounds, their metabolic pathways, and their antioxidant and pro-oxidant potentials with emphasis on cytotoxic mechanisms. Relative cytotoxicity of inorganic selenite and organic selenocystine compounds to different cancer cells are presented as evidence to our perspective. Furthermore, new novel classes of selenium compounds specifically designed to target tumor cells are presented and the potential of selenium in modern oncology is extensively discussed.
Selenium Cytotoxicity in Cancer Wallenberg, Marita; Misra, Sougat; Björnstedt, Mikael
Basic & clinical pharmacology & toxicology,
20/May , Letnik:
114, Številka:
5
Journal Article
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Selenium is an essential trace element with growth‐modulating properties. Decades of research clearly demonstrate that selenium compounds inhibit the growth of malignant cells in diverse experimental ...model systems. However, the growth‐modulating and cytotoxic mechanisms are diverse and far from clear. Lately, a remarkable tumour selective cytotoxicity of selenium compounds has been shown, indicating the potential of selenium in the treatment of cancer. Of particular interest are the redox‐active selenium compounds exhibiting cytotoxic potential to tumour cells. These selenium compounds elicit complex patterns of pharmacodynamics and pharmacokinetics, leading to cell death pathways that differ among compounds. Modern oncology often focuses on targeted ligand‐based therapeutic strategies that are specific to their molecular targets. These drugs are initially efficient, but the tumour cells often rapidly develop resistance against these drugs. In contrast, certain redox‐active selenium compounds induce complex cascades of pro‐death signalling at pharmacological concentrations with superior tumour specificity. The target molecules are often the ones that are important for the survival of cancer cells and often implicated in drug resistance. Therefore, the chemotherapeutic applications of selenium offer great possibilities of multi‐target attacks on tumour cells. This MiniReview focuses on the tumour‐specific cytotoxic effects of selenium, with special emphasis on cascades of cellular events induced by the major groups of pharmacologically active selenium compounds. Furthermore, the great pharmacological potential of selenium in the treatment of resistant cancers is discussed.
Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, which is mainly due to late diagnosis and profound resistance to treatment. The latter is to a large extent attributed to the tumor ...stroma that is exceedingly prominent in PDAC and engages in complex interactions with the cancer cells. Hence, relevant preclinical models of PDAC should also include the tumor stroma. We herein describe the establishment and functional validation of an ex vivo organotypic culture of human PDAC that is based on precision-cut tissue slices from surgical specimens and reproducibly recapitulates the complex cellular and acellular composition of PDAC, including its microenvironment. The cancer cells, tumor microenvironment and interspersed remnants of nonneoplastic pancreas contained in these 350 µm thick slices maintained their structural integrity, phenotypic characteristics and functional activity when in culture for at least 4 days. In particular, tumor cell proliferation persisted and the grade of differentiation and morphological phenotype remained unaltered. Cultured tissue slices were metabolically active and responsive to rapamycin, an mTOR inhibitor. This culture system is to date the closest surrogate to the parent carcinoma and harbors great potential as a drug sensitivity testing system for the personalized treatment of PDAC.
Evolutionarily conserved RFX transcription factors (TFs) regulate their target genes through a DNA sequence motif called the X-box. Thereby they regulate cellular specialization and terminal ...differentiation. Here, we provide a comprehensive analysis of all the eight human RFX genes (RFX1-8), their spatial and temporal expression profiles, potential upstream regulators and target genes.
We extracted all known human RFX1-8 gene expression profiles from the FANTOM5 database derived from transcription start site (TSS) activity as captured by Cap Analysis of Gene Expression (CAGE) technology. RFX genes are broadly (RFX1-3, RFX5, RFX7) and specifically (RFX4, RFX6) expressed in different cell types, with high expression in four organ systems: immune system, gastrointestinal tract, reproductive system and nervous system. Tissue type specific expression profiles link defined RFX family members with the target gene batteries they regulate. We experimentally confirmed novel TSS locations and characterized the previously undescribed RFX8 to be lowly expressed. RFX tissue and cell type specificity arises mainly from differences in TSS architecture. RFX transcript isoforms lacking a DNA binding domain (DBD) open up new possibilities for combinatorial target gene regulation. Our results favor a new grouping of the RFX family based on protein domain composition. We uncovered and experimentally confirmed the TFs SP2 and ESR1 as upstream regulators of specific RFX genes. Using TF binding profiles from the JASPAR database, we determined relevant patterns of X-box motif positioning with respect to gene TSS locations of human RFX target genes.
The wealth of data we provide will serve as the basis for precisely determining the roles RFX TFs play in human development and disease.
Selenoprotein P (SELENOP) is an established biomarker of selenium (Se) status. Serum SELENOP becomes saturated with increasing Se intake, reaching maximal concentrations of 5-7 mg SELENOP/L at ...intakes of ca. 100-150 µg Se/d. A biomarker for higher Se intake is missing. We hypothesized that SELENOP may also reflect Se status in clinical applications of therapeutic dosages of selenite. To this end, blood samples from two supplementation studies employing intravenous application of selenite at dosages >1 mg/d were analyzed. Total Se was quantified by spectroscopy, and SELENOP by a validated ELISA. The high dosage selenite infusions increased SELENOP in parallel to elevated Se concentrations relatively fast to final values partly exceeding 10 mg SELENOP/L. Age or sex were not related to the SELENOP increase. Western blot analyses of SELENOP verified the results obtained by ELISA, and indicated an unchanged pattern of immunoreactive protein isoforms. We conclude that the saturation of SELENOP concentrations observed in prior studies with moderate Se dosages (<400 µg/d) may reflect an intermediate plateau of expression, rather than an absolute upper limit. Circulating SELENOP seems to be a suitable biomarker for therapeutic applications of selenite exceeding the recommended upper intake levels. Whether SELENOP is also capable of reflecting other supplemental selenocompounds in high dosage therapeutic applications remains to be investigated.
Selenium compounds inhibit neoplastic growth. Redox active selenium compounds are evolving as promising chemotherapeutic agents through tumour selectivity and multi‐target response, which are of ...great benefit in preventing development of drug resistance. Generation of reactive oxygen species is implicated in selenium‐mediated cytotoxic effects on cancer cells. Recent findings indicate that activation of diverse intracellular signalling leading to cell death depends on the chemical form of selenium applied and/or cell line investigated. In the present study, we aimed at deciphering different modes of cell death in a single cell line (HeLa) upon treatment with three redox active selenium compounds (selenite, selenodiglutathione and seleno‐DL‐cystine). Both selenite and selenodiglutathione exhibited equipotent toxicity (IC50 5 μM) in these cells with striking differences in toxicity mechanisms. Morphological and molecular alterations provided evidence of necroptosis‐like cell death in selenite treatment, whereas selenodiglutathione induced apoptosis‐like cell death. We demonstrate that selenodiglutathione efficiently glutathionylated free protein thiols, which might explain the early differences in cytotoxic effects induced by selenite and selenodiglutathione. In contrast, seleno‐DL‐cystine treatment at an IC50 concentration of 100 μM induced morphologically two distinct different types of cell death, one with apoptosis‐like phenotype, while the other was reminiscent of paraptosis‐like cell death, characterized by induction of unfolded protein response, ER‐stress and occurrence of large cytoplasmic vacuoles. Collectively, the current results underline the diverse cytotoxic effects and variable potential of redox active selenium compounds on the survival of HeLa cells and thereby substantiate the potential of chemical species‐specific usage of selenium in the treatment of cancers.
Sodium selenite at high dose exerts antitumor effects and increases efficacy of cytostatic drugs in multiple preclinical malignancy models. We assessed the safety and efficacy of intravenous ...administered sodium selenite in cancer patients' refractory to cytostatic drugs in a phase I trial. Patients received first line of chemotherapy following selenite treatment to investigate altered sensitivity to these drugs and preliminary assessment of any clinical benefits.
Thirty-four patients with different therapy resistant tumors received iv sodium selenite daily for consecutive five days either for two weeks or four weeks. Each cohort consisted of at least three patients who received the same daily dose of selenite throughout the whole treatment. If 0/3 patients had dose-limiting toxicities (DLTs), the study proceeded to the next dose-level. If 2/3 had DLT, the dose was considered too high and if 1/3 had DLT, three more patients were included. Dose-escalation continued until the maximum tolerated dose (MTD) was reached. MTD was defined as the highest dose-level on which 0/3 or 1/6 patients experienced DLT. The primary endpoint was safety, dose-limiting toxic effects and the MTD of sodium selenite. The secondary endpoint was primary response evaluation.
MTD was defined as 10.2 mg/m(2), with a calculated median plasma half-life of 18.25 h. The maximum plasma concentration of selenium from a single dose of selenite increased in a nonlinear pattern. The most common adverse events were fatigue, nausea, and cramps in fingers and legs. DLTs were acute, of short duration and reversible. Biomarkers for organ functions indicated no major systemic toxicity. In conclusion, sodium selenite is safe and tolerable when administered up to 10.2 mg/m(2) under current protocol. Further development of the study is underway to determine if prolonged infusions might be a more effective treatment strategy.
Zika virus (ZIKV) remains a public health concern, with epidemics in endemic regions and sporadic outbreaks in new areas posing significant threats. Several mosquito-borne flaviviruses that can cause ...human illness, including West Nile, Usutu, and St. Louis encephalitis, have associations with birds. However, the susceptibility of chickens to ZIKV and their role in viral epidemiology is not currently known. We investigated the susceptibility of chickens to experimental ZIKV infection using chickens ranging from 1-day-old chicks to 6-week-old birds. ZIKV caused no clinical signs in chickens of all age groups tested. Viral RNA was detected in the blood and tissues during the first 5 days post-inoculation in 1-day and 4-day-old chicks inoculated with a high viral dose, but ZIKV was undetectable in 6-week-old birds at all timepoints. Minimal antibody responses were observed in 6-week-old birds, and while present in younger chicks, they waned by 28 days post-infection. Innate immune responses varied significantly between age groups. Robust type I interferon and inflammasome responses were measured in older chickens, while limited innate immune activation was observed in younger chicks. Signal transducer and activator of transcription 2 (STAT2) is a major driver of host restriction to ZIKV, and chicken STAT2 is distinct from human STAT2, potentially contributing to the observed resistance to ZIKV infection. The rapid clearance of the virus in older chickens coincided with an effective innate immune response, highlighting age-dependent susceptibility. Our study indicates that chickens are not susceptible to productive ZIKV infection and are unlikely to play a role in the ZIKV epidemiology.
Macrophages play a pivotal role in mediating inflammation and subsequent resolution of inflammation. The availability of selenium as a micronutrient and the subsequent biosynthesis of selenoproteins, ...containing the 21st amino acid selenocysteine (Sec), are important for the physiological functions of macrophages. Selenoproteins regulate the redox tone in macrophages during inflammation, the early onset of which involves oxidative burst of reactive oxygen and nitrogen species. SELENOW is a highly expressed selenoprotein in bone marrow-derived macrophages (BMDMs). Beyond its described general role as a thiol and peroxide reductase and as an interacting partner for 14-3-3 proteins, its cellular functions, particularly in macrophages, remain largely unknown. In this study, we utilized Selenow knock-out (KO) murine bone marrow-derived macrophages (BMDMs) to address the role of SELENOW in inflammation following stimulation with bacterial endotoxin lipopolysaccharide (LPS). RNAseq-based temporal analyses of expression of selenoproteins and the Sec incorporation machinery genes suggested no major differences in the selenium utilization pathway in the Selenow KO BMDMs compared to their wild-type counterparts. However, selective enrichment of oxidative stress-related selenoproteins and increased ROS in Selenow−/− BMDMs indicated anomalies in redox homeostasis associated with hierarchical expression of selenoproteins. Selenow−/− BMDMs also exhibited reduced expression of arginase-1, a key enzyme associated with anti-inflammatory (M2) phenotype necessary to resolve inflammation, along with a significant decrease in efferocytosis of neutrophils that triggers pathways of resolution. Parallel targeted metabolomics analysis also confirmed an impairment in arginine metabolism in Selenow−/− BMDMs. Furthermore, Selenow−/− BMDMs lacked the ability to enhance characteristic glycolytic metabolism during inflammation. Instead, these macrophages atypically relied on oxidative phosphorylation for energy production when glucose was used as an energy source. These findings suggest that SELENOW expression in macrophages may have important implications on cellular redox processes and bioenergetics during inflammation and its resolution.
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•Loss of Selenow alters the hierarchy of selenoprotein expression in inflamed murine macrophages.•SELENOW regulates pathways of resolution of inflammation, including arginine metabolism, in macrophages.•Inflamed macrophages lacking SELENOW exhibit changes in energy metabolism characterized by altered TCA cycle and glycolysis.•SELENOW is localized to the mitochondria in addition to being a cytosolic protein.
Naturally occurring selenium compounds like selenite and selenodiglutathione are metabolized to selenide in plants and animals. This highly reactive form of selenium can undergo methylation and form ...monomethylated and multimethylated species. These redox active selenium metabolites are of particular biological and pharmacological interest since they are potent inducers of apoptosis in cancer cells. The mammalian thioredoxin and glutaredoxin systems efficiently reduce selenite and selenodiglutathione to selenide. The reactions are non-stoichiometric aerobically due to redox cycling of selenide with oxygen and thiols. Using LDI-MS, we identified that the addition of S-adenosylmethionine (SAM) to the reactions formed methylselenol. This metabolite was a superior substrate to both the thioredoxin and glutaredoxin systems increasing the velocities of the nonstoichiometric redox cycles three-fold. In vitro cell experiments demonstrated that the presence of SAM increased the cytotoxicity of selenite and selenodiglutathione, which could neither be explained by altered selenium uptake nor impaired extra-cellular redox environment, previously shown to be highly important to selenite uptake and cytotoxicity. Our data suggest that selenide and SAM react spontaneously forming methylselenol, a highly nucleophilic and cytotoxic agent, with important physiological and pharmacological implications for the highly interesting anticancer effects of selenium.
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