Selenoprotein P (SELENOP) acts as a crucial mediator, distributing selenium from the liver to other tissues within the body. Despite its established role in selenium metabolism, the specific ...functions of SELENOP in the development of liver cancer remain enigmatic. This study aims to unravel SELENOP’s associations in hepatocellular carcinoma (HCC) by scrutinizing its expression in correlation with disease characteristics and investigating links to hormonal and lipid/triglyceride metabolism biomarkers as well as its potential as a prognosticator for overall survival and predictor of hypoxia. SELENOP mRNA expression was analyzed in 372 HCC patients sourced from The Cancer Genome Atlas (TCGA), utilizing statistical methodologies in R programming and machine learning techniques in Python. SELENOP expression significantly varied across HCC grades (p < 0.000001) and among racial groups (p = 0.0246), with lower levels in higher grades and Asian individuals, respectively. Gender significantly influenced SELENOP expression (p < 0.000001), with females showing lower altered expression compared to males. Notably, the Spearman correlation revealed strong positive connections of SELENOP with hormonal markers (AR, ESR1, THRB) and key lipid/triglyceride metabolism markers (PPARA, APOC3, APOA5). Regarding prognosis, SELENOP showed a significant association with overall survival (p = 0.0142) but explained only a limited proportion of variability (~10%). Machine learning suggested its potential as a predictive biomarker for hypoxia, explaining approximately 18.89% of the variance in hypoxia scores. Future directions include validating SELENOP’s prognostic and diagnostic value in serum for personalized HCC treatment. Large-scale prospective studies correlating serum SELENOP levels with patient outcomes are essential, along with integrating them with clinical parameters for enhanced prognostic accuracy and tailored therapeutic strategies.
Selenium is an essential trace element for regulating immune functions through redox-regulating activity of selenoproteins (e.g. glutathione peroxidase), protecting immune cells from oxidative ...stress. However, in cancer, selenium has biological bimodal action depending on the concentration. At nutritional low doses, selenium, depending on its form, may act as an antioxidant, protecting against oxidative stress, supporting cell survival and growth, thus, plays a chemo-preventive role; while, at supra-nutritional higher pharmacological doses, selenium acts as pro-oxidant inducing redox signalling and cell death. To date, many studies have been conducted on the benefits of selenium intake in reducing the risk of cancer incidence at the nutritional level, indicating that likely selenium functions as an immunostimulator, i.e. reversing the immunosuppression in tumour microenvironment towards antitumour immunity by activating immune cells (e.g. M1 macrophages and CD8+ T-lymphocytes) and releasing pro-inflammatory cytokines such as interferon-gamma; whereas, fewer studies have explored the effects of supra-nutritional or pharmacological doses of selenium in cancer immunity. This review, thus, systematically analyses the current knowledge about how selenium stimulates the immune system against cancer and lay the groundwork for future research. Such knowledge can be promising to design combinatorial therapies with Selenium-based compounds and other modalities like immunotherapy to lower the adverse effects and increase the efficacy of treatments.
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•Se is an essential element for regulating immune functions.•Se reverses immunosuppression in the tumour microenvironment.•Effects of Se on cancer immunity are neglected and require more detailed studies.
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.
Abstract Background Selenium and coenzyme Q10 are essential for the cell. Low cardiac contents of selenium and coenzyme Q10 have been shown in patients with cardiomyopathy, but inconsistent results ...are published on the effect of supplementation of the two components separately. A vital relationship exists between the two substances to obtain optimal function of the cell. However, reports on combined supplements are lacking. Methods A 5-year prospective randomized double-blind placebo-controlled trial among Swedish citizens aged 70 to 88 was performed in 443 participants given combined supplementation of selenium and coenzyme Q10 or a placebo. Clinical examinations, echocardiography and biomarker measurements were performed. Participants were monitored every 6th month throughout the intervention. The cardiac biomarker N-terminal proBNP (NT-proBNP) and echocardiographic changes were monitored and mortalities were registered. End-points of mortality were evaluated by Kaplan–Meier plots and Cox proportional hazard ratios were adjusted for potential confounding factors. Intention-to-treat and per-protocol analyses were applied. Results During a follow up time of 5.2 years a significant reduction of cardiovascular mortality was found in the active treatment group vs. the placebo group (5.9% vs. 12.6%; P = 0.015). NT-proBNP levels were significantly lower in the active group compared with the placebo group (mean values: 214 ng/L vs. 302 ng/L at 48 months; P = 0.014). In echocardiography a significant better cardiac function score was found in the active supplementation compared to the placebo group ( P = 0.03). Conclusion Long-term supplementation of selenium/coenzyme Q10 reduces cardiovascular mortality. The positive effects could also be seen in NT-proBNP levels and on echocardiography.
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.
Interferon (IFN) therapy has been the standard of care for a variety of cancers for decades due to the pleiotropic actions of IFNs against malignancies. However, little is known about the role of ...copy number alteration (CNA) of the IFN gene cluster, located at the 9p21.3, in cancer. This large individual patient data meta-analysis using 9937 patients obtained from cBioportal indicates that CNA of the IFN gene cluster is prevalent among 24 cancer types. Two statistical approaches showed that notably deletion of this cluster is significantly associated with increased mortality in many cancer types particularly uterus (OR = 2.71), kidney (OR = 2.26), and brain (OR = 2.08) cancers. The Cancer Genome Atlas PanCancer analysis also showed that CNA of the IFN gene cluster is significantly associated with decreased overall survival. For instance, the overall survival of patients with brain glioma reduced from 93m (diploidy) to 24m (with the CNA of the IFN gene). In conclusion, the CNA of the IFN gene cluster is associated with increased mortality and decreased overall survival in cancer. Thus, in the prospect of immunotherapy, CNA of IFN gene may be a useful biomarker to predict the prognosis of patients and also as a potential companion diagnostic test to prescribe IFN α/β therapy.
PD-1 and PD-L1 are crucial regulators of immunity expressed on the surface of T cells and tumour cells, respectively. Cancer cells frequently use PD-1/PD-L1 to evade immune detection; hence, blocking ...them exposes tumours to be attacked by activated T cells. The synergy of PD-1/PD-L1 blockade with type I interferon (IFN) can improve cancer treatment efficacy. Type I IFN activates immune cells boosts antigen presentation and controls proliferation. In addition, type I IFN increases tumour cell sensitivity to the blockade. Combining the two therapies increases tumoral T cell infiltration and activation within tumours, and stimulate the generation of memory T cells, leading to prolonged patient survival. However, limitations include heterogeneous responses, the need for biomarkers to predict and monitor outcomes, and adverse effects and toxicity. Although treatment resistance remains an obstacle, the combined therapeutic efficacy of IFNα/β and PD-1/PD-L1 blockade demonstrated considerable benefits across a spectrum of cancer types, notably in melanoma. Overall, the phases I and II clinical trials have demonstrated safety and efficiency. In future, further investigations in clinical trials phases III and IV are essential to compare this combinatorial treatment with standard treatment and assess long-term side effects in patients.
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.
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