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The study is aimed at elucidating the effect of selenium nanoparticles (SeNPs) on the death of cells in the primary culture of mouse cerebral cortex during oxygen and glucose deprivation (OGD). A primary cell culture of the cerebral cortex containing neurons and astrocytes was subjected to OGD and reoxygenation to simulate cerebral ischemia-like conditions in vitro. To evaluate the neuroprotective effect of SeNPs, cortical astrocytes and neurons were incubated for 24 h with SeNPs, and then subjected to 2-h OGD, followed by 24-h reoxygenation. Vitality tests, fluorescence microscopy, and real-time PCR have shown that incubation of primary cultured neurons and astrocytes with SeNPs at concentrations of 2.5-10 µg/ml under physiological conditions has its own characteristics depending on the type of cells (astrocytes or neurons) and leads to a dose-dependent increase in apoptosis. At low concentration SeNPs (0.5 µg/ml), on the contrary, almost completely suppressed the processes of basic necrosis and apoptosis. Both high (5 µg/ml) and low (0.5 µg/ml) concentrations of SeNPs, added for 24 h to the cells of cerebral cortex, led to an increase in the expression level of genes Bcl-2, Bcl-xL, Socs3, while the expression of Bax was suppressed. Incubation of the cells with 0.5 µg/ml SeNPs led to a decrease in the expression of SelK and SelT. On the contrary, 5 µg/ml SeNPs caused an increase in the expression of SelK, SelN, SelT, SelP. In the ischemic model, after OGD/R, there was a significant death of brain cells by the type of necrosis and apoptosis. OGD/R also led to an increase in mRNA expression of the Bax, SelK, SelN, and SelT genes and suppression of the Bcl-2, Bcl-xL, Socs3, SelP genes. Pre-incubation of cell cultures with 0.5 and 2.5 µg/ml SeNPs led to almost complete inhibition of OGD/R-induced necrosis and greatly reduced apoptosis. Simultaneously with these processes we observed suppression of caspase-3 activation. We hypothesize that the mechanisms of the protective action of SeNPs involve the activation of signaling cascades recruiting nuclear factors Nrf2 and SOCS3/STAT3, as well as the activation of adaptive pathways of ESR signaling of stress arising during OGD and involving selenoproteins SelK and SelT, proteins of the Bcl-2 family ultimately leading to inactivation of caspase-3 and inhibition of apoptosis. Thus, our results demonstrate that SeNPs can act as neuroprotective agents in the treatment of ischemic brain injuries., (© 2022. The Author(s).)

Aim to study the molecular mechanisms of apoptotic death of mouse testicular teratocarcinoma cells (line F-9) under exposure to the widely used selenium-containing compounds with antitumor activity, sodium selenite and methylseleninic acid. Methods fluorescence microscopy, MTT assay, Western blotting. Results It was shown that sodium selenite at a concentration of 10 μM and methylseleninic acid at concentrations of 1 and 10 μM cause apoptosis-dependent death of F-9 cells, excluding necrotic death. Western blotting showed an increase in the expression of XBP1s when treating F-9 cells with 1 μM methylseleninic acid. Conclusions 10 μM methylseleninic acid leads to cell apoptosis, most likely by activation of the IRE1 signaling pathway under prolonged stress of the endoplasmic reticulum.

Lead (Pb) is a toxic heavy metal and can harm organisms by inducing apoptosis. Selenium (Se), an essential trace element for humans and animals, can alleviate heavy metal toxicity. The aim of our study is to investigate alleviative effect of Se on Pb-induced apoptosis via endoplasmic reticulum (ER) stress in chicken kidneys. One hundred and eighty male chickens were randomly divided into four groups at 7 days of age and were fed with commercial diet (containing 0.49 mg/kg Se) and drinking water, Na 2 SeO 3 -added commercial diet (containing 1 mg/kg Se) and drinking water, the commercial diet and (CH 3 OO) 2 Pb-added drinking water (containing 350 mg/L Pb), and Na 2 SeO 3 -added commercial diet (containing 1 mg/kg Se) and (CH 3 OO) 2 Pb-added drinking water (containing 350 mg/L Pb), respectively. On the 30th, 60th, and 90th days of the experiment period, 15 chickens in each group were euthanized and the kidneys were collected. Following contents were performed: kidney ultrastructure; nitric oxide (NO) content; inducible nitric oxide synthase (iNOS) activity; relative messenger RNA (mRNA) and protein expression of iNOS, ER-related genes (glucose-regulated protein (GRP)78, GRP94, activating transcription factor (ATF)4, ATF6, and iron-responsive element (IRE)), and apoptosis-related genes (caspase-3 and B cell lymphoma-2 (Bcl-2)); and caspase-12 protein expression. The results indicated that Pb changed kidney ultrastructural structure; decreased Bcl-2 mRNA and protein expression; and increased NO content, iNOS activity, relative mRNA and protein expression of iNOS, ER-related genes, and caspase-3 and caspase-12 protein expression. Se attenuated above changes caused by Pb. Pb had time-dependent manners on NO content, GRP78, GRP94, ATF4, IRE, and caspase-3 mRNA expression. Se attenuated Pb-induced apoptosis via ER stress in the chicken kidneys.

We herein examined the effects of different doses, forms, and compatibilities of selenium on a canine mammary gland tumor cell line, CTM1211, and explored the related mechanisms. Three selenium compounds, sodium selenite (SSE), methylseleninic acid (MSA), and methylselenocysteine (MSC), were selected for these experiments, and cyclophosphamide (CTX) served as a positive control. In the cell viability assay, the cell viability of each group at 48/72 h decreased significantly compared with the control group (p < 0.05), and the cell viability of the CTX + MSA group was lower than that of CTX and MSA groups (p < 0.05). Moreover, the inhibitory effect of selenium on cell proliferation was time-dependent but not concentration-dependent. In the cell apoptosis assay, the apoptosis values of each group increased significantly compared with the control group, and the apoptosis values of the CTX + MSA group increased the most significantly (p < 0.01). The protein and mRNA expression levels of vascular endothelial growth factor-alpha (VEGF-alpha), angiopoietin-2 (Ang-2), and hypoxia inducible factor-1 alpha (HIF-1 alpha) were downregulated in each group, while that of phosphatase and tensin homolog (PTEN) were upregulated (p < 0.05). In conclusion, these three selenium compounds, especially MSA, could significantly inhibit the viability and growth of the CTM1211 cell line, which is partly due to the induction of apoptosis and regulation of tumor angiogenesis.

The aim of the study was to investigate the competency of selenium (Se) in counteracting the adverse effects of aflatoxin B1 (AFB1) on apoptosis, cell cycle, and proliferation of nephritic cells. Two hundred forty 1-day-old healthy male avian broilers were randomly divided into four groups and fed basal diet (control group), 0.3 mg/kg AFB1 diet (AFB1 group), 0.4 mg/kg Se diet (+Se group), and 0.3 mg/kg AFB1 + 0.4 mg/kg Se diet (AFB1 + Se group), respectively. Compared to the control group, the number of apoptotic renal cells and expressions of Bax and caspase-3 messenger RNA (mRNA) were significantly increased, while the expression of Bcl-2 was significantly decreased in the AFB1 and the +Se groups (p < 0.01). A significantly decreased proliferating cell nuclear antigen (PCNA) expression and arrested G0/G1 phases of the cell cycle were also seen in the AFB1 and the +Se groups when compared with those of the control group. Moreover, these parameters were restored to the control group levels in the AFB1 + Se group. These results suggested that sodium selenite supplied in the diet could effectively inhibit AFB1-induced apoptosis and cell cycle blockage in renal cells of broiler.

Several authors have demonstrated the chemoprotective and anti-carcinogenic role of selenium. However, the therapeutic potential of selenium in myelodysplastic syndrome (MDS) as single agent and as co-adjuvant of the current therapies has not been previously studied. Sodium selenite and selenomethionine, alone and in combination with cytarabine, induce a decrease in cell viability in a time-, dose- and administration-dependent manner inducing cell death by apoptosis in F36P cells (MDS cell line). These compounds increased superoxide production and induced mitochondrial membrane depolarization. The increase in BAX/BCL-2 ratio and in the activated caspase 3 expression levels, the decrease in mitochondria membrane potential, as well as the increase in superoxide production, supports the mitochondria contribution on selenium-induced apoptosis. These findings suggest that selenium may offer a new therapeutic approach in myelodysplastic syndrome in monotherapy and/or as co-adjuvant therapy to conventional anti-carcinogenic.

Aims: To investigate the effects and study the underlying cell death mechanisms of diaryl diselenides, including: diphenyl diselenide (C(6)H(5)Se)(2); 4-chlorodiphenyl diselenide (4-ClC(6)H(4)Se)(2); 3-(trifluoromethyl)-diphenyl diselenide (3-CF(3)C(6)H(4)Se)(2) and 4-methoxydiphenyl diselenide (4-MeOC(6)H(4)Se)(2), on the human colon adenocarcinoma cell line HT-29., Main Methods: The viability of HT-29 cells after exposure to the diaryl diselenides and its substituted structures was based on the MTT assay. To verify if cell death was mediated throughout apoptosis mechanisms, flow cytometry and real-time PCR (qPCR) analyses were conducted., Key Findings: The MTT assay and flow cytometry analyses showed that (3-CF(3)C(6)H(4)Se)(2) and (4-MeOC(6)H(4)Se)(2) induced cytotoxicity through apoptosis mechanisms in HT-29 cells. qPCR revealed there was an up-regulation of pro-apoptotic (Bax, casapase-9, caspase-8, apoptosis-inducing factor (AIF) and Endonuclease G (EndoG)) and cell-cycle arrest genes (p53 and p21) and down-regulation of anti-apoptotic (Bcl-2 and survivin) and Myc genes., Significance: These results demonstrate that (3-CF(3)C(6)H(4)Se)₂ and (4-MeOC(6)H(4)Se)(2) have the potential to induce apoptosis in HT-29 cells through the activation of caspase-dependent and independent pathways and through cell-cycle arrest., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The purpose of this study was to investigate the antitumor effects and mechanism of the selenium heteropoly compound (NH₄)₄H₄[Se₂Mo₂V₄O₂₄]·7H₂O (SeMoV) in K562 cells. The results showed that 0.313-10 mg/l SeMoV significantly inhibited the proliferation of K562 cells in vitro in a time- and concentration-dependent manner as determined by a micro-culture tetrazolium assay; the IC50 values were 7.69 and 4.06 mg/l following 48 and 72 h of treatment with SeMoV, respectively. Analysis of the cell cycle indicated that the proportion of cells in the G0/G1 phase was decreased at 48 h whereas the proportion of cells in the S phase was increased following treatment for 24 and 48 h. A significant sub-G1 peak was observed at 5 mg/l for 24 h. Morphological observation revealed typical apoptotic features. SeMoV signifi-cantly caused the accumulation of Ca²⁺, Mg²⁺ and ROS, and a reduction in the pH value and the mitochondrial membrane potential (MMP) in the K562 cells compared with the control (p<0.01), as shown by confocal laser scanning microscopy. Experiments also showed that the expression of Bcl-2 was significantly inhibited by 20 mg/l SeMoV, while Bax expression increased. Meanwhile, the amount of cytochrome C and IκB in K562 cells was increased, while NF-κB expression was significantly decreased, following treatment with SeMoV for 24 h. The experiment implied that SeMoV had antitumor activity and its mechanism was attributed partially to apoptosis, which was induced by the elevation of the intracellular Ca²⁺, Mg²⁺ and ROS concentration, a reduction in the pH value and MMP, and the NF-κB/IκB signaling pathway.

The present study was designed to evaluate the possible protective effects of 3,3'-diselenodipropionic acid (DSePA), a potent radioprotector, against oxidative organ damage induced by whole body γ-irradiation and explore its mechanistic effects. The mice were subjected to whole body γ-irradiation at 5 Gy for the detection of oxidative stress, apoptosis, and proliferation in the intestinal (jejunum) tissue and at 7 Gy for the examination of intestinal inflammation and immune imbalance. Groups of mice received intraperitoneal injections of DSePA (2 mg/kg/day) or vehicle (phosphate-buffered saline) for 5 consecutive days prior to irradiation. The whole body γ-irradiation of mice led to the induction of oxidative stress and apoptosis in the intestinal tissue, and pretreatment with DSePA significantly reduced both these parameters. It was also found to abrogate the radiation-induced intestinal inflammatory response and augment the proliferation of intestinal cells. Additionally, irradiation-induced polarization of Th1/Th2 immune balance toward the Th2-dominant direction and pretreatment with DSePA ameliorated this shift, which may be beneficial for the recovery from radiation injury. In conclusion, pretreatment with DSePA prevented radiation-induced oxidative damage in small intestine and the underlying mechanisms responsible for this could be attributed to inhibition of oxidative stress, apoptosis, and inflammation.

Melanoma incidence and mortality rates continue to increase despite the use of sunscreen as well as screening programs for early surgical excision of premalignant lesions. The steady increase in melanoma incidence suggests that additional preventive approaches are needed to augment these existing strategies. One unexplored area involves targeting genes whose deregulation promotes disease development to prevent melanoma. The Akt3 signaling pathway is one key signaling cascade that plays a central role by deregulating apoptosis to promote development of approximately 70% of melanomas. Isoselenocyanate-4 (ISC-4), derived from isothiocyanates by increasing the alkyl chain length and replacing sulfur with selenium, has been developed to target this important signaling pathway in melanomas; however, its chemopreventive potential is unknown. In this study, the chemopreventive efficacy of topical ISC-4 was evaluated in a laboratory-generated human skin melanoma model containing early melanocytic lesion or advanced stage melanoma cell lines and in animals containing invasive xenografted human melanoma. Repeated topical application of ISC-4 reduced tumor cell expansion in the skin model by 80% to 90% and decreased tumor development in animals by approximately 80%. Histologic examination of ISC-4-treated skin showed no obvious damage to skin cells or skin morphology, and treated animals did not exhibit markers indicative of major organ-related toxicity. Mechanistically, ISC-4 prevented melanoma by decreasing Akt3 signaling that lead to a 3-fold increase in apoptosis rates. Thus, topical ISC-4 can delay or slow down melanocytic lesion or melanoma development in preclinical models and could impact melanoma incidence rates if similar results are observed in humans., (©2010 AACR.)

The novel polysaccharide SeGLP-2B-1 isolated from Se-enriched Ganoderma lucidum, showed anti-proliferative activity towards several cancer cell lines in vitro. To investigate the antitumor mechanisms, the apoptotic effects of SeGLP-2B-1 in human breast cancer cells were studied, and the mechanism of this action was further elucidated. Cell apoptosis was detected by Annexin V/PI staining. Caspase activity was assayed using a caspase apoptosis detection kit. Western blot analysis was used to evaluate the levels of pro-caspase-3, -8, -9, PARP and cytochrome c expression. The results showed that SeGLP-2B-1 inhibited the growth of MCF-7 cells in a time- and dose-dependent manner. Typical characteristics of apoptosis were observed, including morphological changes, sub-G1 cells and DNA ladder formation. Further analysis showed that SeGLP-2B-1 treatment disrupted the mitochondrial membrane potential followed by an increase in the cytochrome c cytosolic levels. Sequentially, SeGLP-2B-1 increased the activities of caspase-9, -3 and poly (ADP-ribose) polymerase in a time-dependent manner, however, no obvious activation of caspase-8 was observed. Caspase-9 and caspase-3 inhibitor prevented SeGLP-2B-1-induced apoptosis, and the activities of caspases-3, -9 were significantly up-regulated by SeGLP-2B-1. Our studies suggest that SeGLP-2B-1 induces apoptosis via a mitochondria-mediated pathway.

The essential trace element selenium and polyunsaturated fatty acids (PUFA) have been used for the prevention of cancer. Both nutrients enhance the apoptosis of malignant cells and provide health benefits. However, an increased dietary intake of PUFA augments the susceptibility of lipid peroxidation and oxidative damage in many cells. So far, relatively few data are available about the interaction of selenium and PUFA in testis and thus a possible effect of both dietary components on the prevention of testicular cancer or on the apoptosis of testicular germ cells. Male germ cells in the rat contain most of the testicular phospholipid hydroperoxide glutathione peroxidase (PHGPx), mainly as the mitochondrial isoform of this selenoprotein (m-PHGPx). An experiment was therefore carried out to determine the action of fish oil, a nutrient rich in PUFA, on the testicular expression of PHGPx. Because the PHGPx formation remains nearly unchanged in the animals fed the PUFA-enriched diet, we conclude that no apoptosis of testicular germ cells is induced by an increased intake of this nutrient. The intake of fish oil in the selenium-deficient animal led to a markedly altered formation of several selenium-containing proteins, including sperm nuclei glutathione peroxidase (snGPx), also designated as the nuclear form of PHGPx (n-PHGPx), and a 10-kDa selenium-containing protein.

Selenium is an essential element incorporated into selenoproteins. Selenium deficiency may predispose to immune deficiency, mood disorders, and cancer. On the other hand, excessive environmental exposure to selenite may cause a variety of disorders including anemia. At least in theory, the anemia could result from accelerated suicidal erythrocyte death or eryptosis, characterized by cell shrinkage and phosphatidylserine exposure at the erythrocyte surface. Eryptosis is triggered by an increase in the cytosolic Ca(2+) concentration and by ceramide. The present experiments explored, whether high concentrations of selenite stimulate eryptosis. According to Fluo3 fluorescence, selenite (>or=200 microg/l sodium selenite) within 48 hours significantly increased the cytosolic Ca(2+) concentration in human erythrocytes. According to binding of selective fluorescent antibodies, selenite (>or= 200 microg/l) significantly increased ceramide formation. Annexin V-binding demonstrated that selenite (>or=200 microg/l) significantly increased phosphatidylserine exposure of erythrocytes. Forward scatter analysis further revealed that selenite (>or=200 microg/l) significantly decreased cell volume. In contrast to selenite, selenate failed to trigger eryptosis. In conclusion, selenite triggers suicidal erythrocyte death at least partially by increasing the cytosolic Ca(2+) concentration and by stimulating the formation of ceramide. The present study discloses novel cellular effects of this essential nutrient., (Copyright 2008 S. Karger AG, Basel.)

Converging data from epidemiological, ecological, and clinical studies have shown that selenium (Se) can decrease the risk for some types of human cancers. Induction of apoptosis is considered an important cellular event that can account for the cancer preventive effects of Se. Prior to occurrence of apoptosis, Se compounds alter the expression and/or activities of signaling molecules, mitochondria-associated factors, transcriptional factors, tumor suppressor genes, and cellular reduced glutathione. Mechanistic studies have demonstrated that the methylselenol metabolite pool has many desirable attributes of chemoprevention, whereas the hydrogen selenide pool with excess of selenoprotein synthesis can lead to DNA single-strand breaks. To elucidate the effects of Se on cytotoxic events, it should be remembered that the chemical forms and the dose of Se, and the experimental system used, are determinants of its biological activities. This mini-review focuses on elucidation of the molecular mechanisms of cancer prevention by Se with the apoptotic approach.

Selenium (Se) is a very effective anti-cancer agent. We studied the effects of inorganic Se compounds on induction of apoptosis by which Se compounds exert cancer chemopreventive activity. With the use of HSC-3 human oral squamous cell carcinoma cells, the present study showed that treatment with Se for 72 h, in the form of SeO2 and Na2SeO3, but not Na2SeO4, markedly induced apoptosis in a dose-dependent manner. Treatment of HSC-3 cells with 100 microM SeO2 resulted in the caspase-3-like and -9-like activation. Se compounds induced a loss of mitochondrial membrane potential (DeltaPsim), but did not induce the generation of reactive oxygen species. Treatment with SeO2 for 18 h resulted in 80% loss of reduced glutathione (GSH), which is known to be involved in the metabolism of Se. Treatment with N-acetyl-L-cysteine, or exogenous GSH, prevented the SeO2-induced apoptosis. Treatment with GSH led to the partial reverse in reduction of DeltaPsim caused by SeO2, while buthionine sulfoximine augmented the SeO2- or Na2SeO3-induced apoptosis. These results suggest that modulation of the mitochondrial redox equilibrium by Se contributes to the mitochondrial pathway, regulating caspase-9-mediated apoptosis without a concurrent increase in ROS.

Objective: To investigate the mechanisms underlying the effect of selenium dioxide (SeO(2)) on the proliferation, apoptosis, and apoptosis-related gene expressions of Bcl-2 and p53 in 3 leukemia cell lines NB4, K562 and HL-60., Methods: The three leukemia cell lines were treated with 3, 10 and 30 mmol/L SeO(2) and apoptosis detected by flow cytometry and analysis of p53 and Bcl-2 expressions., Results: SeO(2) at 10 and 30 mmol/L could inhibit the proliferation of three leukemia cell lines. SeO(2) treatment at 30 mmol/L for 48 h induced an apoptosis rate of 54.0 %, 46.5 %, 49.6 % in NB4, K562, and HL-60 cells respectively, and down-regulated Bcl-2 expression in NB4 and K562 but not in HL-60 cells., Conclusion: SeO(2) can induce apoptosis in NB4, K562 and HL-60 leukemia cells, involving the down-regulation of Bcl-2 and up-regulation of p53.

Background & Objective: It was reported that selenium could induce apoptosis of cancer cells; moreover, apoptosis of cancer cells and telomerase activity were closely related to the development of cancer. This study was designed to investigate the effect of selenium dioxide on human pulmonary adenocarcinoma GLC-82 cell to reveal its probable mechanism and the relationship between apoptosis and telomerase activity., Methods: Methyl thiazolyl tetrazolium(MTT) method was used to determine the growth inhibition rates of lung cancer GLC-82 cells by various concentrations of selenium dioxide at different time. TRAP-PCR-ELISA assay was used to examine the changes of GLC-82 cells treated with selenium dioxide. The cell apoptotic rate was measured by flow cytometry (FCM). DNA ladder was showed by DNA agarose gel electrophoresis. The morphological changes of the cancer cells were examined under light and electron microscope., Results: After being treated with 3, 10, 30 micromol/L selenium dioxide, the proliferation and telomerase activity of GLC-82 cells were markedly inhibited. The growth inhibition rates in GLC-82 cells for 24 hours were 0.7%, 12.8%, and 31.8%; for 72 hours were 15.1%, 51.2%, and 61.1%, respectively. Telomerase activity of GLC-82 cells for 24 hours were 1.173+/-0.029,1.127+/-0.067, and 1.050+/-0.098(P< 0.05); for 48 hours were 1.150+/-0.026, 1.047+/-0.060, and 0.950+/-0.036(P< 0.05), respectively (control group: 1.227+/-0.032 and 1.167+/-0.023, respectively). An apoptosis peak appeared before diploid peak in FCM. Agarose gel electrophoresis showed overt ladder-shape band of cell apoptosis. GLC-82 cells treated by selenium dioxide showed morphological characteristics of apoptotic cells., Conclusion: Selenium dioxide could significantly inhibit the growth of lung cancer GLC-82 cells through inducing apoptosis and inhibiting the telomerase activity. Selenium dioxide has strong growth inhibitory effect in a dose-and time-dependent manner.

Marine mammals are known for their low susceptibility to mercury toxicity, and selenium may play a role in this protection against mercury intoxication. To gain insight into mechanisms by which selenium might inhibit mercury toxicity in cetacean cells, we investigated the effects of sodium selenite on cell proliferation and cell death (including apoptosis, oncosis, and necrosis) of control and mercuric chloride-treated Atlantic spotted dolphin renal cells (Sp1K cells). Concurrent exposure to 80 microM Na2SeO3 provided full protection against the decrease in cell proliferation induced by 20 microM HgCl2. Pretreatment with Na2SeO3 increased the protective effects of selenium administered later in conjunction with mercury, but pretreatment alone did not provide protection against mercury given alone. Furthermore, Na2SeO3 administered after the exposure to HgCl2 did not protect cells. These data suggest that the coexistence of Na2SeO3 and HgCl2 was essential for the protective effects of Na2SeO3 against the toxicity of HgCl2 in Sp1K cells, and may involve selenium-mercury binding. This is supported by the results of an experiment in which earlier premixed mercury and selenium solutions were less cytotoxic than freshly mixed solutions. Furthermore, HgCl2 induced apoptosis in Sp1K cells, as revealed by nuclear specific dye (7-AAD) incorporation and cell flow cytometry, and this was prevented by the concurrent exposure to Na2SeO3. Inhibition of mercury-induced apoptosis in marine mammal cells, provided by selenium, may contribute to the in vivo protection. This study is the first report that addresses the mechanism of mercury-selenium antagonism in cultured cetacean cells at the cellular level.

An immortal human hepatic cell line HL-7702 and human hepatoma cell line SMMC-7721 were treated with 3-30 microM SeO(2). SeO(2) at 30 microM markedly inhibited cell proliferation and viability, and prompted apoptosis of both normal hepatic and hepatoma cells after 48h treatment. SeO(2) could also down-regulate the Bcl-2 level, greatly in HL-7702 and slightly in SMMC-7721 cells, but up-regulate wild type P53 level a little in HL-7702 and significantly in SMMC-7721 cells. The Bcl-2/P53 value was closely correlated with the apoptotic rate as well as SeO(2) concentrations.

Selenium compounds that are chemopreventive in animal models inhibit cell growth and induce apoptosis in vitro, and this could explain how they reduce the outgrowth of tumor cells in vivo. Our recent work has shown that primary cultures of oral carcinoma biopsies are significantly more sensitive than normal oral mucosa cultures to induction of apoptosis by a natural selenium metabolite [selenodiglutathione (SDG)], and this is associated with induction of Fas ligand, a well-known mediator of apoptosis in other contexts, and activation of so-called stress kinase signaling pathways, particularly the Jun NH2-terminal kinase (JNK). Heme oxygenase, another marker of stress responses, is also induced by selenite and SDG. The selective activation of the Fas pathway in carcinomas could be responsible directly for their destruction by apoptosis or target them for attack by immunologic responses. In contrast, although the potent pharmacological selenium chemopreventive agent 1,4-phenylenebis(methylene)selenocyanate (p-XSC) also induces Fas ligand, heme oxygenase, and stress kinase pathways, apoptosis/Fas induction is not so strongly JNK-dependent and p-XSC does not show tumor selectivity. These differences in mechanism between SDG and p-XSC may be due to the manner in which they induce redox changes in the cells, since although the effects of SDG and p-XSC are prevented by antioxidants such as glutathione or N-acetylcysteine, hydroxyl radical scavengers such as mannitol or pyrrolidine dithiocarbamate only protect against the effects of p-XSC.

Selenium-dependent glutathione peroxidase (GPx) plays a protective role in oxidative stress-induced apoptosis. In this study, we demonstrated that MDBK cells, a bovine renal epithelial cell line, exhibited internucleosomal DNA fragmentation characteristic of apoptotic cell death under selenium-deficient conditions with lower doses of hydrogen peroxide (H2O2) than under selenium-supplemented ones. This was due to a decreased amount of GPx in the cells under selenium-deficient conditions, because other antioxidative enzyme activities were not affected by the selenium supplementation. Cumene hydroperoxide also induced DNA fragmentation in selenium-deficient cells but no ladder formation was observed. Flow cytometric analysis showed that selenium-deficient cells were less capable of scavenging intracellular peroxides after exposure to exogenous H2O2 than selenium-supplemented ones. In contrast, there was no difference in viability between selenium-supplemented and non-supplemented cells in cell survival after exposure to menadione, which activates the electron transport system and increases intracellular superoxide radicals. Clofibrate, a peroxisomal proliferator and an inducer of catalase (CAT), partially protected both Se-deficient and Se-supplemented cells from exogenous H202. We concluded that selenium-deficient cells were more easily brought to apoptotic cell death by peroxides, but not by superoxide radicals, than selenium-supplemented ones and that CAT could compensate for the depletion of GPx to a certain degree by scavenging H2O2.