Introduction

Selenium is an essential micronutrient in vertebrates and is crucial for brain development and metabolism [1–4]. Although initially known for its toxic effects, selenium appeared also to be important in maintaining a number of vital functions in the body and current scientific interests in selenium raised mainly because of its health-promoting effects [5, 6]. These trials and in vitro studies led to the assumption that selenium not only can reduce the risk of cancer, but may also participate in many important processes relevant to tumor biology such as immunity, fertility, cell growth, reactive oxygen species signaling, and tumor microenvironmental modulation [7–10]. In humans, several clinical studies have been conducted to unravel the role of selenium supply as a chemopreventive agent (Table 1). These trials revealed that selenium in the clinical setting is a double-edged sword. The ‘Selenium and Vitamin E Cancer Prevention Trial’ (SELECT) sought to determine whether selenium supplements in combination with vitamin E could protect against the development of prostate cancer, but it was prematurely stopped due to futility analysis, not toxicity (of which there was very little) [11]. In a previous large skin cancer prevention trial, selenium was associated with a reduced risk for prostate cancer [12–14]. According to the National Cancer Institute, selenium acts an antioxidant that might directly help control cell damage as well as part of the catalytic domain of selenoenzymes with various essential cell functions with cancer prevention activity [12]. Furthermore, ongoing trials are proving the impact of selenium. This and other trials uncovered the difficulties of translating experimental selenium data into clinical settings (Table 1).

Table 1 Summary of conducted and ongoing clinical trials using selenium or Se-compounds
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Malignant gliomas or high-grade gliomas are common types of primary brain tumors (e.g., WHO grade III [anaplastic astrocytoma, oligodendroglioma, oligoastrocytoma, and ependymoma] and grade IV [glioblastoma multiforme, GBM] gliomas) and with a median survival time of approximately 1 year, belong to the most threatening tumor entities [15].

Especially, in this disease condition, there is urgent need for improving current medical practice for better outcome in terms of life expectancy and quality of life. Experimental and some clinical data suggested the efficacy of selenium application in malignant gliomas. Therefore, the aim of this paper is to investigate the current state-of-knowledge of selenium compounds in relation to malignant gliomas and the efficacy of selenium in current chemotherapy. For this, we performed a systematic literature search of PubMed (www.ncbi.nlm.nih.gov/pubmed) and Clinical Trials (www.clinicaltrials.org). English articles were primarily considered if not otherwise stated. Research articles and reviews were identified using the key words ‘glioma,’ ‘brain tumor,’ and ‘selenium,’ either alone or in combination. The relevant papers identified by this search were reviewed, and the references therein were further considered for other useful leads.

Selenium and its Biological Forms

The indispensable micronutrient selenium (Se) is available mainly in two forms, i.e. inorganic and organic. Inorganic Se forms include selenite (SeO 2 −3 ) and selenate (SeO 2 −4 ). The main organic forms are selenocysteine (SeC), selenomethionine (SeMet), and Se-methylselenocysteine (MSC). In addition to these compounds, experimental studies revealed the efficacy of the stable Se compound methylselenic acid which represents the simplest β–lyase version of Se-methylselenocysteine lacking the amino acid moiety [16, 17].

Selenium is metabolized dynamically and can be linked to in vivo combinatorial chemistry forming a wide array of products with different intracellular environment effects [18]. This may also explain why Se and Se compounds can have both beneficial as well as undesirable effects. A key metabolite of selenium in organisms is hydrogen selenide (H2Se) which is formed from inorganic sodium selenite (SSe) via selenodiglutathione (GSSeSG) through reduction by thiols and NADPH-dependent reductases, and released from SeC by lyase action [19, 20]. H2Se undergoes methylation by thiol S-methyltransferase as a major pathway for Se metabolism in microbes, plants, and animals and generate different methylated metabolic Se forms. At low Se doses, monomethylated forms of Se are excreted mainly into urine, while trimethylated forms are being predominant at high doses. When the level of trimethylselenonium ions reaches the metabolic plateau, dimethylselenide is exhaled by breath producing a characteristic garlic breath [21].

Hence, in organisms inorganic selenium is not simply stored, instead it is utilized in selenoprotein synthesis into specific selenoproteins that have incorporated the twenty-first genetically coded amino acid SeC under a precise process requiring the UGA codon, a specified tRNA and the SeC insertion sequence (SECIS) element [22, 23]. There are at least 25 selenoproteins coded in the human genome [24, 25]. Within the 25 selenoproteins, there are essential proteins such as glutathione peroxidases (GPx1, 4), thioredoxin reductases (TRx), selenoprotein P, selenoenzymes R, and deiodinases. In particular, GPx isoenzymes are implicated in cellular protection against damage caused by oxygen free radicals and redox dysbalances, with each isoenzyme having a specific location and specificity [26–29]. TRx play an essential role in antioxidant processes but are also implicated in the regulation of certain transcription factors and in gene expression [30]. GPx and TRx catalyze the reduction of hydrogen peroxide to eliminate harmful reactive oxygen species from the tissues and protect biological membranes and large molecular structures from oxidative damage [31].

Non-specific incorporation of Se into proteins occurs through substitution of SeMet for methionine. SeMet is the major constituent of selenized yeast (selenium yeast) used in chemopreventive studies [32] (Table 1).

Selenoproteins in the Brain

Several selenoproteins and selenoprotein activities (mainly glutathionperoxidase (GPx)) are present in human and rodent brains [2, 33, 34]. However, detailed cellular brain mapping of selenoprotein localization in terms of neurons, ependymal cells, and glial cells throughout the brain remains to be conducted. For instance, GPx isoenzymes, with the exception of GPx4, cannot be distinguished solely on grounds of substrate specificity and immunocytochemistry revealed PhGPx/GPx4 exclusively in neurons, while GPx/GPx1 is ubiquitously expressed in both neurons and astrocytes [27].

The major selenium transport form in plasma is selenoprotein P (SePP). SePP is generated in the liver releasing plasma SePP. Deletion of SePP showed severe consequences for the brain, inducing selenium-deficiency with neurological dysfunction under suboptimal nutritional selenium supply [35, 36]. SePP mRNA has been detected in human, rat, mouse, and bovine brain. Controversy surrounds the function of SePP within the brain. Clear evidences for SePP expression in the brain come from initial in situ hybridization and immunohistochemical studies demonstrating SePP mRNA in cerebellar Purkinje cells of mice and cattles [2, 37]. Moreover, SePP has been identified as the essential component in bovine serum that is necessary for maintaining neurons in serum-free media [38].

More recent studies considered SePP as a physiological transporter of Se from liver to brain. Hence, SePP can be found in grey and white matter and in cerebrospinal fluid suggesting SePP as a Se storage form in the brain [39]. However, SePP cannot rapidly load and unload Se as a simple cargo since selenium is covalently incorporated as the amino acid selenocysteine (SeC) which requires degradation to release Se. SeC depends on the lysosome or proteasome to hydrolyze peptide bonds followed by liberation of Se from SeC, presumably by SeC lyase (SeCly). Recently, a study in mice suggests that SePP is more critical than SeCly for maintenance of brain Se and that recycling Se from SeC via SeCly is physiologically important during dietary Se deficiency [40]. As Se supply becomes limited, alternative routes of its hepatic metabolism decrease, allowing continued SePP synthesis for export into the plasma [41]. SePP in plasma provides Se to extra-hepatic tissues via ApoER2-mediated endocytosis and plays an important role for the protection against Se deficiency [42].

Consequences of Selenium Deficiency in Human Health

Selenium (Se) plays a vital part in many essential functions for humans. However, the functions of Se as an antioxidant trace element are considered to be carried out under physiological conditions by selenoproteins that possess antioxidant activities and the ability to promote neuronal cell survival. There selenium plays a pivotal role in the formation and function of selenocysteine-bearing selenoproteins, such as glutathione peroxidase (GPx) for antioxidant protection of cells [43]. Several studies indicated that sufficient Se intake could improve the human immune system and prevent tumor growth by enhancing immune cell activity and suppressing development of blood vessels to the tumor [12, 44, 45]. What is relevant is that the activity of these selenoproteins, and of others with as yet unidentified functions, depends on adequate selenium supply either via nutritional entry or by therapeutic interventions.

Selenium deficiency can lead to human diseases such as Keshan disease and Kashin-Beck disease. Although the etiology of Keshan disease (KD) is not fully understood, it has been recognized by most researchers that KD is strongly associated with selenium deficiency [46]. This statement is based on evidence that the Se levels in soil and food in the external environment of the endemic area are significantly lower than those in the non-endemic area. Blood and hair Se levels, the activity of GPx and the antioxidative capacity of patients with KD is also significantly lower than those in healthy individuals. In particular, the incidence of KD significantly decreased after Se supplementation.

Selenium in Primary Brain Tumors

The first clinical evidence for selenium in neuro-oncology came from one report on decreased serum concentrations of selenium in patients suffering from brain malignancies [47]. Gliomas are the most common primary brain tumor in the central nervous system derived from glial cells or glial progenitors, with WHO grade IV gliomas (glioblastoma, GBM) as the most malignant form with a median survival below 14 months from the time point of diagnosis [48]. Malignant gliomas demonstrate rapid progression and are highly resistant to standard treatment, resulting in a particularly poor prognosis in patients. These tumors are distinct from other cancer types by exhibiting profound vascularization, necrosis, brain swelling (edema), and microvascular hyperplasia. Pseudopalisades and microvascular hyperplasia are indicative of aggressive growth and are instrumental in malignant progression [49]. Pseudopalisading cells also produce proangiogenetic factors such as vascular endothelial growth factor (VEGF), which promote endothelial proliferation and angiogenesis. Furthermore, endothelial cells respond to the angiogenic signal by increasing the production of matrix metalloproteinases (MMPs), such as MMP-2. The increased MMP levels are associated with poor prognosis in malignant glioma patients. MMP-2 can cleave laminin 5 γ2 and release proteolytic fragments which are capable of leading to tumor cell invasion and prevention of tumor cell apoptosis via epidermal growth factor receptor (EGFR) [50]. EGFR contributes to cell proliferation, revival, motility, and invasion and is often overexpressed in gliomas. There is evidence that selenite can decrease the EGFR expression in vitro [51]. Using glioma cells A-172 to evaluate the anti-tumor activity of a mixture of nutrient compounds, which contained several antioxidants including Se, Roomi et al. demonstrated that the nutrient mixture significantly reduced the invasion of glioma cells and the secretion of MMP-2 in a dose-dependent manner [52].

In biopsy specimens of an anaplastic astrocytoma, Rooprai et al. showed that selenite induced apoptosis and extensive changes in the expression of MMPs [51]. Most MMPs (except MMP-25) were reduced and their natural inhibitor tissue inhibitor of metalloproteinase (TIMP) increased [51]. In line with this are the findings of Yoon et al. reporting that selenium prevents migration of endothelial cells through the extracellular matrix (ECM) and blocks MMP expression and tumor invasion [53]. Future studies are required to decipher the anti-tumor effect of selenium on malignant gliomas. In principle, two mechanisms need to be considered: Selenium action could be directly mediated through apoptosis induction or by specific alteration of the MMP expression profiles which affects glioma cell survival secondarily.

Selenium and Chemotherapy

Cancer chemotherapy has been shown to play an important role in the treatment of most solid tumors, although this therapeutic approach has also been associated with substantial short- and long-term side effects (Fig. 1). These side effects impact significantly on the quality-of-life in cancer patients. A growing body of evidence suggests that a combinatorial treatment of chemotherapy and chemo-preventive agents with anti-carcinogenic activity may enhance the efficacy of chemotherapeutics and reduce the systemic toxicity induced by chemotherapy [54–56]. Selenium (Se) is essential to human health, but its role as a chemopreventive agent was for a long-time controversial. However, recent studies are in support of chemo-preventive and cancer-preventive properties of selenium according to clinical, epidemiologic, and experimental studies [57–59]. Although most research efforts on Se have focused on prevention of tumor initiation and promotion [60], there are a number of studies indicating the ability of Se compounds to enhance the efficacy of standard chemotherapeutic drugs [61–63], such as cyclophosphamide, cisplatin, and temozolamide (Fig. 1).

Fig. 1
figure 1

Selenium, brain tumor microenvironment, and chemotherapeutic therapies. Current chemotherapeutics in neuro-oncology are depicted in the scheme. Unintended side effects with serious consequences are given (boxes at the right) which are common in neuro-oncology. Also, the impact of therapeutics on the tumor microenvironment is indicated, such as brain edema, neuronal cell death, and angiogenesis. Brain tumor is depicted in black, peritumoral zone and tumor microenvironment is shown in red. Abbreviations: CP cyclophosphamide; TMZ temozolomide, Se selenium

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Cyclophosphamide (CP), an agent frequently employed for its chemotherapeutic effects in cancer treatment, is a cytostatic and immunosuppressive drug. The efficacy of CP in treating brain tumors has been limited by the fact that although CP crosses the blood–brain barrier, its active metabolites are only poorly transported across this barrier [64]. CP is a pro-drug that undergoes bioactivation mainly by CYP-3A4 and CYP-2B6 to produce reactive metabolites such as acrolein and phosphoramide mustard [65]. The active form of CP is an alkylating agent and causes disruption of cell growth, mitotic activity, differentiation, and function by cross-linking of DNA strands. In addition to carcinogenic potential, CP has a wide spectrum of toxicities [66]. However, numerous studies have shown that CP exposure enhances intracellular reactive oxygen species (ROS) production, suggesting that biochemical and physiological disturbances may result from oxidative stress [67–70]. These reactive oxygen species damage DNA, proteins, and cellular lipids leading to cell death [71]. Antioxidants are known to be responsible for enzyme reduction, molecular repair (superoxide dismutase, catalase, and glutathione peroxidase), and protection against ROS [72]. The combination of CP together with a potent antioxidant may be the appropriate approach to reduce the toxicity effects of CP [73]. However, among those antioxidants, selenium is involved in several key metabolic activities via selenoproteins, enzymes that are essential for protection against oxidative damage, and the regulation of immune function. Depending on the dose, selenium attenuates the toxic effect of CP, and it also attenuates CP-induced oxidation stress and DNA damage [74]. More recently, Bhattacharjee et al. reported that nano-Se protects against hepatotoxicity and genotoxicity induced by CP. These data suggest that the mechanisms of hepatoprotection by nano-Se against CP-induced toxicity and hepatic damage involve suppression of oxidative stress by preventing glutathione depletion [75]. We suggest that at the appropriate concentration, selenium could be a potentially effective modulator of CP toxicity (Fig. 1). However, additional experiments are required to explore the underlying mechanism of selenium protection against CP toxicity and the therapeutic window.

The platinum compounds cisplatin and carboplatin are cell cycle nonspecific, bi-functional alkylating agents with demonstrated efficacy in adult and pediatric malignancies including brain tumors [76–78]. Cisplatin is a potent toxin for cells. It enters into cells, gets hydrolyzed, and then binds to DNA leading to cellular toxicity (Fig. 1). However, this goes along with increased risks for renal toxicity which is dose-dependent, and thus limits its usage [79, 80]. The use of carboplatin as an alternative to cisplatin in several adult and pediatric solid tumors has increased in the last 20 years in view of emerging evidence for its efficacy and lower nephrotoxic potential [81]. Moreover, preclinical and early clinical studies in adults suggested that carboplatin causes much less renal damage than cisplatin [82, 83].

Many strategies have attempted to prevent or reduce the nephrotoxicity side effects of chemotherapeutics [84, 85]. Animal studies also suggest that cisplatin nephrotoxicity may be reduced by a variety of antioxidants including capsaicin, glutamine, melatonin, and N-acetylcysteine [86]. Furthermore, a survey of the literature reveals in particular the protective effects of Se against cisplatin-induced renal damage [20, 87].

Temozolomide (TMZ) is currently used as an upfront treatment for newly diagnosed and recurrent glioblastoma multiforme (GBM), and is also utilized for treating patients with metastatic melanoma due to its ability to penetrate through the blood–brain barrier and does not require hepatic metabolism for activation [88, 89]. TMZ is known to enhance the responsiveness of GBM to radiation in preclinical testing, and the action of concurrent TMZ at the time of radiotherapy is likely to be responsible for most of the treatment effects [90]. Furthermore, TMZ is an imidazotetrazine derivate and a novel oral alkylating agent with enhanced cytotoxicity for fast growing cells. DNA replication disruption is the principal mechanism responsible for the cytotoxic activity of TMZ, resulting in the fragmentation of DNA and defects in DNA replication, and in consequence to cell growth suppression and apoptotic cell death [91, 92]. A relevant number of malignant brain tumors are TMZ-resistant or acquire resistance via O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, as evidenced by therapeutic failure in some malignant glioma patients who still die within 2 years under therapy. Cheng et al. tested incorporating Se into TMZ (TMZ-Se) demonstrating superior anti-tumor activity. Researchers reported the effectiveness of this compound even against TMZ-resistant tumor cells. The comparison between TMZ and TMZ-Se showed in vitro a greater inhibitory effect on proliferating glioma cells with TMZ-Se and growth suppression of tumors in xenograft animal models. These reports indicate that TMZ-Se triggers cell-death more rapidly, possesses stronger apoptosis-inducing activity and induced stronger autophagic response than solely TMZ (Fig. 2). Notably, there are potentially two roles of Se in current chemotherapy: First, Se and Se compounds can reduce toxicity in multimodal tumor therapy. Second, Se and Se compounds can act as a sensitizer and enhancer/multiplier for conventional chemotherapeutic treatment regiments (Fig. 2). Both aspects need to be evaluated further in clinical trials. Obviously, simply reducing chemotherapeutic toxicity with simultaneous reducing efficacy is not a desirable outcome.

Fig. 2
figure 2

Dual actions of selenium in neuro-oncology. Summary of Se actions on glioma cells. First, Se can act directly as a reducing agent against ROS formation induced by chemotherapeutics thereby restricting collateral damages. Second, Se is incorporated into selenoproteins such as GPx, SePP, and TRx. These selenoenzymes are known to balance ROS levels and execute cell protective functions. Abbreviations: GPx glutathione peroxidase; Se selenium; SePP selenoprotein P; SOD superoxiddismutase; TRx thioredoxin reductase

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Taken together, the mechanism of action of Se compounds has an effective chemo-protective impact that should be taken into account especially in the case of TMZ-resistant tumors [93].

However, selenium at high concentrations (serum Se levels above 200 μg/l) has also negative impact on cellular functions. This fact should be kept in mind when supplementing Se with inorganic or novel Se-coupled pharmacological agents in clinical settings. High Se intake can be toxic and have adversely effect on the integrity of genomic DNA in various tissues and organs [94]. Although the mechanisms responsible for the adverse effects of high doses of Se are not completely understood, the effects can be severe with DNA damage, oxidative stress, and cell death induction [95–97]. On the other side, balanced levels of Se are required for cell survival and growth (Fig. 2). Due to the prospective use of Se in clinical practice, further studies are necessary to elucidate the mechanisms of toxicity and the therapeutic window for selenium compounds.

Conclusion

Taking into account the outcome of this current literature and clinical trial research paper, we can conclude that selenium is largely implicated in antioxidant defense mechanisms, redox signaling, and immune function. Investigations show so far that insufficient selenium levels are associated with disadvantageous health effects and in the context of disease, with tumor progression. Notwithstanding that epidemiological data and clinical trials do not give an unambiguous picture for selenium supplementation many studies suggest that selenium, and its compounds are promising chemo-preventive and anti-cancer agents. The unambiguous results of clinical trials surrounding selenium do not only foster our knowledge of chemo-preventive efficacy, but also increase the efforts to understand its molecular mechanisms and interactions with conventional therapeutics. Investigations on the efficacy of selenium in malignant gliomas are further required. So far, data support the notion that the investigation of selenium and selenium compounds shows considerable properties, which places selenium at the center for future research on preventive or therapeutic agents in neurological conditions.