Sodium selenite (Na2SeO3) induces apoptosis through the mitochondrial pathway in CNE-2 nasopharyngeal carcinoma cells

  • Authors:
    • Zhongyi Cui
    • Caihong Li
    • Xiangyong Li
    • Qunzhou Zhang
    • Yuefei Zhang
    • Jingjing Shao
    • Keyuan Zhou
  • View Affiliations

  • Published online on: April 17, 2015
  • Pages: 2506-2514
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This study investigated the effect of sodium selenite (Na2SeO3) on proliferation, cell cycle, apoptosis as well as the underlying mechanism in CNE‑2 nasopharyngeal carcinoma (NPC) cells. The CNE‑2 cell line was treated with different concentrations of Na2SeO3, and the effects of Na2SeO3 on cell viability and proliferation were evaluated using Cell Counting kit‑8 (CCK‑8) assay. Cellular apoptosis and cell cycle were evaluated by flow cytomerty following Annexin V‑FITC/PI double staining and PI single staining respectively; nuclei morphology stained with DAPI and Hoechst 333258 was observed under a fluorescence microscope, while DNA fragmentation was detected by agarose gel electrophoresis. The mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) were analyzed using fluorescent staining assays. Expression of Bcl‑XL, Bax, Bak, and caspase‑3 activation were examined by western blotting. The results showed that Na2SeO3 inhibited proliferation and induced apoptosis of CNE‑2 cells in a dose‑ and time‑dependent manner. Na2SeO3 at low concentrations induced cell cycle arrest at S phase, while high concentrations of Na2SeO3 induced cell cycle arrest at G0/G1 phase. Furthermore, Na2SeO3 increased ROS level and decreased MMP, upregulated caspase‑3 activity and the expression of Bak and Bax but simultaneously downregulated Bcl‑XL. In conclusion, our studies demonstrated that Na2SeO3 had significant anti‑proliferative and apoptosis‑inducing effects via arresting cell cycle and regulating mitochondria‑mediated intrinsic caspase pathway in CNE‑2 NPC cells, suggesting that Na2SeO3 might have therapeutic potentials in the treatment of NPC.


Apoptotic cells are morphologically characterized by membrane blebbing, chromatin condensation, and the formation of apoptotic bodies. Apoptosis is a cell suicide mechanism that is regulated by two canonical programmed cellular signaling pathways; the death receptor-mediated pathway (extrinsic) and the mitochondrial pathway (intrinsic). Activation of caspases is important in both pathways (1,2). Interaction between ligands and death receptors initiates the extrinsic pathway at the plasma membrane, subsequently activating caspase-8, which is an initiator caspase. This protein, in turn, directly activates downstream effector caspases, including caspase-3 (3). Many physical and chemical stimuli induce mitochondrial dysfunction and changes in reactive oxygen species (ROS) production, triggering the intrinsic pathway. Mitochondrial dysfunction induces the activation of caspase-9 and subsequently activates effector caspases, such as caspase-3. Following the activation of caspase-3, several specific substrates are cleaved (4,5). Apoptosis is also associated with ROS, mitochondrial membrane potential (MMP) and other relevant factors. Apoptosis induction is a critical mechanism for numerous anti-cancer compounds (6).

Selenium (Se) is an essential trace element (7), and appropriate Se intake is necessary for the body to synthesize selenoproteins. Several studies have indicated that sodium selenite (Na2SeO3) inhibits growth of a series of cancer cell lines, including liver and prostate cancer, malignant melanoma and various hematologic malignancies, by inducing apoptosis via different mechanisms including mitochondria, oxidative stress, p53-dependent signaling, and thioredoxin reductase (811). Na2SeO3 in particular exerts antitumor effects by inducing apoptosis (1217).

Nasopharyngeal carcinoma (NPC) is the most common epithelial malignancy of the nasopharynx. The pathogenesis of NPC is yet not clear, and effective, low-toxicity therapies are not available so far. Thus, research and development of potential drug candidates for NPC are of utmost importance. In this study, we investigated the anti-cancer effects and mechanisms of Na2SeO3 in CNE-2 NPC cells. We found that Na2SeO3 can inhibit cell proliferation and induce cell apoptosis via cell cycle arresting and mitochondrial pathways.

Materials and methods


Na2SeO3 was purchased from Food and Drug Administration of China (Beijing, China) (lot no. 110713-200911) and dissolved in Milli-Q water to get a stock concentration of 1 mM, then stored at −20°C until use. The Cell Counting kit-8 (CCK-8) (cat. C0038), MMP assay kit with 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolyl carbocyanine iodide (JC-1) (cat. C2006), ROS assay kit (cat. S0033), DNA Ladder assay kit (cat. C0007), DAPI staining kit (cat. C1005) and Hoechst 33258 staining kit (cat. C1018) were purchased from Beyotime Institute of Biotechnology (Jiangsu, China). Annexin V-FITC poptosis detection kit (cat. A211) and Cell Cycle assay kit (cat. A411) were purchased from Vazyme Biotech Co., Ltd. (Jiangsu, China). The primary antibodies for β-actin, Bcl-XL, Bax, Bak, caspase-3 as well as c-caspase-3 were purchased from Cell Signaling Technology, Inc. (Danvers, MA, USA). The horseradish peroxidase (HPR)-linked goat anti-rabbit IgG secondary antibodies were purchased from Bio-Rad (Hercules, CA, USA).

Cell culture

CNE-2 cell line (a human NPC cell line) was obtained from the Institute of Biochemistry and Molecular Biology, Guangdong Medical College (Guangdong, China). Cells were cultured in RPMI-1640 medium (Gibco-BRL, Carlsbad, CA, USA) supplemented with 10% fetal bovine serum (FBS) (Gibco-BRL) and 100 μg/ml penicillin-streptomycin (Beyotime Institute of Biotechnology), and maintained at 37°C in a humidified atmosphere of 5% CO2.

WST-8 conversion assay

The effect of Na2SeO3 on cell viability/proliferation was determined using the WST-8 assay. Briefly, CNE-2 cells were seeded into 96-well plates at a density of 5,000 cells/well and incubated for 24 h. Then the cells were treated with Na2SeO3 at different concentrations (0, 2, 5, 10, 20, 50 and 100 μM) for 0, 24, 48, 72 or 96 h. WST-8 conversion was then assessed using a one-step CCK-8, according to the manufacturer’s instructions. All tests were carried out in triplicate. The absorbance was measured at 450 nm by using a Synergy multifunctional microplate reader (Bio-Rad) with a reference at 650 nm serving as blank. The inhibiting ability of Na2SeO3-treated cells was calculated as the percentage of inhibition compared to untreated cells, which were arbitrarily assigned 100% viability. GraphPad Prism 4.0 was used to analyze the IC50 of Na2SeO3 in this case.

Cell cycle analysis

After treated with Na2SeO3 (0, 5, 10 and 20 μM) for 6 h, CNE-2 cells were collected and fixed overnight in 75% cold ethanol at −20°C. The cells were then washed twice with cold PBS (pH 7.4) and stained with Cell Cycle assay kit according to manufacturer’s instructions. Cell cycle distribution was determined using a flow cytometer (Beckman Coulter Epics xL-MCL; Beckman Coulter, Miami, FL, USA) and analyzed using CellQuest software (18).

DAPI staining

CNE-2 cells at a density of 1×105 were grown overnight in a cell culture dish. Then the cells were incubated with Na2SeO3 (0, 5, 10 and 20 μM) for 3 h. After incubation, cells were washed with ice-cold PBS and stained with DAPI staining fluid for 20 min in the dark at room temperature. After that, the cells were washed twice with PBS. Cell images were captured using a fluorescence microscope (Nikon Corp., Tokyo, Japan).

Hoechst 333258 staining

After treatment with Na2SeO3 at a series of concentration for 3 h, the CNE-2 cells were fixed and washed twice with PBS, then incubated with Hoechst 333258 for 30 min at room temperature. Then the cells were washed with PBS for three times, and the changes of nucleic morphologies were observed under fluorescence microscopy (Inverted Biological Binocular Microscope; Nikon Corp.).

DNA fragmentation analysis

CNE-2 cells (3×106 cells) were incubated with Na2SeO3 (0, 5, 10 and 20 μM) for 6 or 12 h and then harvested. The characteristic ladder pattern of DNA breakage was analyzed by agarose gel electrophoresis using an Apoptosis DNA Ladder detection kit (Beyotime Institute of Biotechnology) according to the manufacturer’s instructions. The DNA preparations were electrophoresed in 1% agarose gel, then stained with ethidium bromide and observed under UV transilluminator (ChemiDoc XRS Syngene; Bio-Rad).

Annexin V-FITC apoptosis detection

Apoptosis was also analyzed by utilizing an Annexin V-FITC apoptosis detection kit (Vazyme Biotech Co., Ltd.). Briefly, cells were seeded in 100 mm-well plates and incubated for 24 h and then treated with Na2SeO3 (0, 5, 10 and 20 μM) for 24 h. After treatment, ~1×106 cells were harvested, washed twice with PBS, and stained with Annexin V-FITC and PI according to the manufacturer’s instructions. The resulting fluorescence was detected by flow cytometer (Beckman Coulter Epics xL-MCL, Beckman Coulter) with CellQuest analysis software.

Measurement of intracellular active oxygen

Formation of intracellular ROS was determined using a fluorescent probe 2′,7-dichlorofluorescein diacetate (Beyotime Institute of Biotechnology). DCFH-DA, a non-fluorescent substance, can cross to cell membranes and be hydrolyzed by intracellular esterase to DCFH, which can not cross the cell membranes, but change to green fluorescent DCF in the presence of peroxides. CNE-2 cells were incubated with Na2SeO3 for 3 h, followed by another 30-min incubation with 10 μM DCFH-DA. Then the cells were washed with PBS three times and the changes of fluorescence were observed using fluorescence microscopy.

Measurement of MMP

The MMP was determined using the mitochondria-specific lipophilic cationic fluorescence dye JC-1 detection kit according to the manufacturer’s instructions (Beyotime Institute of Biotechnology). In brief, CNE-2 cells, were seeded in 6-well culture plates at a density of 3×105 cells/well and cultured with or without Na2SeO3 (0, 5, 10 and 20 μM) for 3 h, followed by a 30-min incubation with 10 μM JC-1 in the dark, then the cells were washed twice with PBS, and the fluorescent intensity was examined by a fluorescence microscope. In healthy cells with high MMP, JC-1 gathers in mitochondrial matrix as J-aggregates, which emits red fluorescence (normal membrane potential). When the MMP collapses, the JC-1 cannot accumulate in mitochondria and are converted to monomer which can emit green fluorescence (declined membrane potential).

Western blotting

Cells were washed three times with ice-cold PBS. Cell lysates were prepared with RIPA buffer (Beyotime Institute of Biotechnology) containing 150 mM NaCl, 1% Triton X-100, 20 mM Tris (pH 7.5) and 1% of two kinds of protein inhibitors including protein phosphatase inhibitor and phenylmethanesulfonyl fluoride (PMSF). After a forced vortex, cell lysates were incubated on ice for 2 h, and centrifuged at 12,000 rpm for 15 min at 4°C to remove insoluble debris. Protein concentrations were determined using the BCA method (Beyotime Institute of Biotechnology). The whole cell lysates were treated by boiling in loading buffer containing SDS and electrophoresised in SDS-PAGE, then transferred onto membranes (Immobilon-P; Millipore, Billerica, MA, USA). After blocking with 5% skim milk for 1 h, the membranes were incubated with specific primary antibodies at 4°C overnight, followed by incubation with enzyme-linked secondary antibodies for 2 h at room temperature. The membranes were then visualized by enhanced chemiluminescence (ECL), and the result was analyzed by ChemiDoc XRS transilluminator (both from Bio-Rad). The gray analysis was carried out by ImageJ Gray Analysis software.

Statistical analysis

Results are reported as mean ± SD of triplicate independent experiments. Statistical analyses were performed with the SPSS v.19.0 software and performed by one-way analysis of variance (ANOVA). P<0.05 for each concentration versus control was considered to indicate significance.


Na2SeO3 inhibits proliferation of CNE-2 cells

We first observed the effect of Na2SeO3 on proliferation of CNE-2 cells. As shown in Fig. 1A, Na2SeO3 significantly inhibited proliferation of CNE-2 cells in a time- and dose-dependent manner. At 20 μM, Na2SeO3 inhibited proliferation of CNE-2 cells by 5.55, 29.50, 46.11 and 53.19% after treatment for 24, 48, 72 and 96 h, respectively. When the concentration of Na2SeO3 increased to 100 μM, the inhibition rate reached 77.20% after treatment for 96 h. The IC50 of Na2SeO3 for treating CNE-2 cells for different time periods were analyzed by the curve fitting (Fig. 1B). As compared with the 24 and 72 h, the fitting degree of 48 and 96 h were more accurate, and the IC50 was 19.86 and 11.9 μM, respectively. Based on these results, Na2SeO3 was used at 5, 10 and 20 μM in the following experiments. In addition, after treatment with Na2SeO3, the cell morphology was observed under a microscope. As shown in Fig. 1C, after 24 h treatment with Na2SeO3, the cell density was significantly decreased in a dose-dependent manner. The cells shrunk, retracted from neighboring cells, lost their flat and polygonal shape, and ultimately detached from the culture dish, indicative of a cell death induced by Na2SeO3.

Na2SeO3 induces cell cycle arrest in CNE-2 cells

We next observed the effect of Na2SeO3 on cell cycle of CNE-2 cells. CNE-2 cells were treated with Na2SeO3 at a series of concentrations for 6 h followed by PI staining and analyzed by a flow cytometer. As shown in Fig. 2A and B, treatment of CNE-2 cells with Na2SeO3 at relatively higher concentrations (10 and 20 μM) resulted in a significant accumulation of cells at G0/G1 phase (p<0.05); a sub-G1 apoptotic peak was also observed, while at a relatively lower concentration (5 μM), Na2SeO3 induced S phase arrest (p<0.05). Together, these findings suggest that Na2SeO3 could induce cell cycle arrest in CNE-2 cells.

Na2SeO3 induces apoptosis in CNE-2 cells

The cell cycle arrest as well as the apoptotic peak induced by Na2SeO3 led us to further determine if Na2SeO3 could induce apoptosis of CNE-2 cells using an Annexin V-FITC apoptosis detection kit. Na2SeO3 treated or untreated cells were analyzed by flow cytometry using Annexin V-FITC/PI double staining assay. The apoptotic cells could be divided into early-stage apoptosis (Annexin V+ and PI) and late-stage apoptosis (Annexin V+ and PI+), which are shown in the lower right (LR) and upper right (UR) quadrants of the FACS histograms, respectively (Fig. 3A, left panel). As shown in Fig. 3B, the percentage of total apoptotic cells in CNE-2 cells was 5.2% in control cells (early-stage: 1.3% and late-stage: 3.9%), 9.3% in cells treated with 5 μM Na2SeO3 (early-stage: 6.0% and late-stage: 3.3%), 51.2% in cells treated with 10 μM Na2SeO3 (early-stage: 50.3% and late-stage: 0.9%) and 60.6% in cells treated with 20 μM Na2SeO3 (early-stage: 60.0% and late-stage: 0.6%). These results indicate that Na2SeO3 significantly induced apoptosis (including early- and late-stage apoptosis, p<0.01) in CNE-2 cells.

To further confirm Na2SeO3-induced apoptosis, we next observed the morphological change of cell nuclei induced by Na2SeO3 via staining cell nuclei with DAPI and Hoechst 333258. As shown in Fig. 3C, chromatic agglutination and karyopyknosis were observed after treatment with Na2SeO3 (5, 10 and 20 μM) for 3 h, and fragmented nuclei were observed after treatment for 6 and 12 h. In contrast, cells in control group exhibited normal intact nuclei. Furthermore, after treatment with Na2SeO3, a series of DNA ladders were observed (Fig. 3D), indicative of late-stage apoptosis in CNE-2 cells. These results further demonstrated that Na2SeO3 can induce significant apoptosis in CNE-2 cells.

Na2SeO3 downregulates Bcl-XL and upregulates Bak and Bax

The Bcl-XL, Bak and Bax proteins play crucial roles in the regulation of apoptosis (19,20). We examined the changes in the expression of Bcl-XL, Bak and Bax by western blotting in CNE-2 cells in response to Na2SeO3 treatment. The representative blots for CNE-2 cells are shown in Fig. 4A, and the relative expression of these proteins was also calculated through normalization to β-actin expression and is summarized in Fig. 4B. The results showed that after treatment with Na2SeO3 (5, 10 and 20 μM) for 6 h, the expression of Bak and Bax was increased and the expression of Bcl-XL was decreased in a dose-dependent manner in CNE-2 cells (Fig. 4). These data suggest that Na2SeO3 might induce CNE-2 cell apoptosis through downregulation of Bcl-XL and upregulation of Bak and Bax.

Na2SeO3 induces disruption of MMP in CNE-2 cells

Mitochondria play a key role in cell apoptosis and depletion of MMP is one of the early and key events that occur following induction of cellular apoptosis. To determine the changes of MMP in CNE-2 cells after Na2SeO3 treatment, JC-1 staining was carried out. The fluorescence microscopy observation confirmed that Na2SeO3 (5, 10 and 20 μM)-treated cells showed a progressive loss of red J-aggregates fluorescence and appearance of green monomer fluorescence in the cytoplasm, and this decrease obviously occurred in a dose-dependent manner (Fig. 5). These data suggest that the intrinsic mitochondrial pathway of apoptosis might be one of the mechanisms involved in cell death of CNE-2 cells induced by Na2SeO3.

Na2SeO3 increases caspase-3 activity in CNE-2 cells

It is well known that the intracellular translocation of Bak and Bax can induce the loss of MMP, which is linked to the initiation and activation of the apoptotic process in cells (21,22). Due to the loss of MMP, cytochrome c is released into the cytosol from mitochondria, which activates pro-caspase-9 in the apoptosome and leads to the cleavage of caspase-3 (1). Subsequently, active cleaved caspase-3 can cleave a broad spectrum of target proteins and finally result in apoptotic cell death. To examine whether apoptosis induced by Na2SeO3 involves caspase activation, the total and cleaved caspase-3 were examined by western blotting. The results showed that treatment with Na2SeO3 for 6 h resulted in significant increase in caspase-3 activity in a dose-dependent manner (Fig. 6) as indicated by increase of cleaved caspase-3 and decrease of total PARP, a substrate of caspase-3, suggesting that apoptosis of CNE-2 cells induced by Na2SeO3 might involve the activation of caspase-3 pathway.

Na2SeO3 induces ROS production in CNE-2 cells

Previous reports have shown that ROS generation plays a critical role in apoptosis induction (2325). Therefore, we next investigated the changes of ROS level in Na2SeO3-treated CNE-2 cells. As shown in Fig. 7, Na2SeO3 (5, 10 and 20 μM) enhanced the levels of ROS in CNE-2 cells in a dose-dependent manner, which might also contribute to Na2SeO3-induced apoptosis in CNE-2 cells.


Compared to other types of head and neck cancer, NPC is a highly metastatic disease. Despite advances in diagnosis and treatment, the 5-year survival of this malignant disease remains disappointing due to the local recurrence/metastasis and resistance to chemo- and radiotherapies. Therefore, an increasing understanding of the complex metastases/recurrence mechanisms of NPC is imperative to the development of more effective mechanism-based therapeutic modalities for this malignancy.

Se is an essential trace element because of its role in glutathione peroxidase (GSH-Px), the daily dietary supply of Se in human body must reach 50 μg according to the Chinese Nutrition Society, a standard that has been adopted by the World Health Organization (Geneva, Switzerland) (26). In addition to its nutritional functions, accumulating evidence has shown that super-nutritional selenite intake has antitumor activity both in vitro and in vivo (14,2732). Mechanistically, Na2SeO3 can induce cell apoptosis through mitochondrial apoptotic pathway in a variety of cancer cell lines including ovarian carcinoma, lung carcinoma, colon cancer and breast cancer cells (15,3336). In the present study, we demonstrated for the first time to our knowledge that Na2SeO3 can inhibit proliferation and induce cell cycle arrest in CNE-2 NPC cells. Interestingly, treatment of CNE-2 cells with higher concentrations of Na2SeO3 resulted in a significant accumulation of cells at G 0/G1 phase, while treatment with the agent at lower concentrations arrested the cell cycle at S phase. Therefore, further studies are warranted to elucidate the detailed underlying mechanisms.

Mitochondrial pathway is critical in cell apoptosis. Mitochondrial dysfunction can induce the activation of caspase-9 and the subsequent caspase-3, followed by cleavage of its substrates such as PARP, eventually inducing cell apoptosis (4,5). Increase of ROS production could induce mitochondrial dysfunction. Our studies show that Na2SeO3 could increase ROS production, induce disruption of MMP and activate the caspase-3 pathway. All these data suggest that Na2SeO3-induced apoptosis in CNE-2 cells might be associated with the mitochondrial apoptotic pathway. This was further confirmed by the results that Na2SeO3 could downregulate Bcl-XL and upregulate Bak and Bax, which are apoptosis-related proteins located in mitochondria. Therefore, we speculated that Na2SeO3 inhibited CNE-2 cell growth through its effects on mitochondria.

In summary, our studies demonstrate that Na2SeO3 has significant anti-proliferation- and apoptosis-induction effects in CNE-2 cells by cell cycle arresting and regulation of mitochondria-mediated intrinsic caspase pathway, suggesting that Na2SeO3 might have potent therapeutic potentials in the treatment of NPC.


This study was financially supported by grants from the National Natural Science Foundation of China (no. 81272434), the Science and Technological Program of Dongguan’s Higher Education, Science and Research, and Health Care Institutions (no. 2011108102044), the Doctor Initial Funding of Guangdong Medical College (no. B2011022), and the Science and Technology Innovation Fund of Guangdong Medical College (no. STIF201105).



Wolf BB and Green DR: Suicidal tendencies: Apoptotic cell death by caspase family proteinases. J Biol Chem. 274:20049–20052. 1999. View Article : Google Scholar : PubMed/NCBI


Susin SA, Daugas E, Ravagnan L, Samejima K, Zamzami N, Loeffler M, Costantini P, Ferri KF, Irinopoulou T, Prévost MC, et al: Two distinct pathways leading to nuclear apoptosis. J Exp Med. 192:571–580. 2000. View Article : Google Scholar : PubMed/NCBI


Elrod HA and Sun SY: Modulation of death receptors by cancer therapeutic agents. Cancer Biol Ther. 7:163–173. 2008. View Article : Google Scholar


Kim BG, Kwon HY, Sohn EJ, Hwang S, Kwon OS and Kim SH: Activation of caspases and inhibition of ribosome biogenesis mediate antitumor activity of Chijongdan in A549 non-small lung cancer cells. BMC Complement Altern Med. 14:4202014. View Article : Google Scholar : PubMed/NCBI


Zorofchian Moghadamtousi S, Karimian H, Rouhollahi E, Paydar M, Fadaeinasab M and Abdul Kadir H: Annona muricata leaves induce G1 cell cycle arrest and apoptosis through mitochondria-mediated pathway in human HCT-116 and HT-29 colon cancer cells. J Ethnopharmacol. 156:277–289. 2014. View Article : Google Scholar : PubMed/NCBI


Qu L, Liu FX, Cao XC, Xiao Q, Yang X and Ren KQ: Activation of the apoptosis signal-regulating kinase 1/c-Jun N-terminal kinase pathway is involved in the casticin-induced apoptosis of colon cancer cells. Exp Ther Med. 8:1494–1500. 2014.PubMed/NCBI


Chen Y, Mo HZ, Hu LB, Li YQ, Chen J and Yang LF: The endogenous nitric oxide mediates selenium-induced phytotoxicity by promoting ROS generation in Brassica rapa. PLoS One. 9:e1109012014. View Article : Google Scholar : PubMed/NCBI


Li Z, Meng J, Xu TJ, Qin XY and Zhou XD: Sodium selenite induces apoptosis in colon cancer cells via Bax-dependent mitochondrial pathway. Eur Rev Med Pharmacol Sci. 17:2166–2171. 2013.PubMed/NCBI


Li XL, Wong YS, Xu G and Chan JC: Selenium-enriched Spirulina protects INS-1E pancreatic beta cells from human islet amyloid polypeptide-induced apoptosis through suppression of ROS-mediated mitochondrial dysfunction and PI3/AKT pathway. Eur J Nutr. Aug 12–2014.(Epub ahead of print).


Sarveswaran S, Liroff J, Zhou Z, Nikitin AY and Ghosh J: Selenite triggers rapid transcriptional activation of p53, and p53-mediated apoptosis in prostate cancer cells: Implication for the treatment of early-stage prostate cancer. Int J Oncol. 36:1419–1428. 2010.PubMed/NCBI


Huang F, Huang J, Lv Q, Yang Y, Wu G and Xu C: Selenite induces apoptosis in colorectal cancer cells through interaction with thioredoxin reductase. BMB Rep. pii: 2370. 2013.


Cherukuri DP and Nelson MA: Role of reactive oxygen species (ROS) and JNKs in selenite-induced apoptosis in HepG2 cells. Cancer Biol Ther. 7:697–698. 2008. View Article : Google Scholar : PubMed/NCBI


Chen XJ, Duan FD, Zhang HH, Xiong Y and Wang J: Sodium selenite-induced apoptosis mediated by ROS attack in human osteosarcoma U2OS cells. Biol Trace Elem Res. 145:1–9. 2012. View Article : Google Scholar


Huang F, Nie C, Yang Y, Yue W, Ren Y, Shang Y, Wang X, Jin H, Xu C and Chen Q: Selenite induces redox-dependent Bax activation and apoptosis in colorectal cancer cells. Free Radic Biol Med. 46:1186–1196. 2009. View Article : Google Scholar : PubMed/NCBI


Zhang W, Xiao H and Parkin KL: Apoptosis in MCF-7 breast cancer cells induced by S-alkenylmercaptocysteine (CySSR) species derived from Allium tissues in combination with sodium selenite. Food Chem Toxicol. 68:1–10. 2014. View Article : Google Scholar : PubMed/NCBI


Wu S, Bao Y, Ma D, Zi Y, Yang C, Yang M, Xing M and Yang W: Sodium selenite inhibits leukemia HL-60 cell proliferation and induces cell apoptosis by enhancing the phosphorylation of JNK1 and increasing the expression of p21 and p27. Int J Mol Med. 34:1175–1179. 2014.PubMed/NCBI


Suzuki M, Endo M, Shinohara F, Echigo S and Rikiishi H: Rapamycin suppresses ROS-dependent apoptosis caused by selenomethionine in A549 lung carcinoma cells. Cancer Chemother Pharmacol. 67:1129–1136. 2011. View Article : Google Scholar


Shi X, Jin Y, Cheng C, Zhang H, Zou W, Zheng Q, Lu Z, Chen Q, Lai Y and Pan J: Triptolide inhibits Bcr-Abl transcription and induces apoptosis in STI571-resistant chronic myelogenous leukemia cells harboring T315I mutation. Clin Cancer Res. 15:1686–1697. 2009. View Article : Google Scholar : PubMed/NCBI


Oltvai ZN, Milliman CL and Korsmeyer SJ: Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell. 74:609–619. 1993. View Article : Google Scholar : PubMed/NCBI


Kitamura Y, Shimohama S, Kamoshima W, Ota T, Matsuoka Y, Nomura Y, Smith MA, Perry G, Whitehouse PJ and Taniguchi T: Alteration of proteins regulating apoptosis, Bcl-2, Bcl-x, Bax, Bak, Bad, ICH-1 and CPP32, in Alzheimer’s disease. Brain Res. 780:260–269. 1998. View Article : Google Scholar : PubMed/NCBI


Hockenbery D, Nuñez G, Milliman C, Schreiber RD and Korsmeyer SJ: Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature. 348:334–336. 1990. View Article : Google Scholar : PubMed/NCBI


Gross A, McDonnell JM and Korsmeyer SJ: BCL-2 family members and the mitochondria in apoptosis. Genes Dev. 13:1899–1911. 1999. View Article : Google Scholar : PubMed/NCBI


Ma Q, Fang H, Shang W, Liu L, Xu Z, Ye T, Wang X, Zheng M, Chen Q and Cheng H: Superoxide flashes: Early mitochondrial signals for oxidative stress-induced apoptosis. J Biol Chem. 286:27573–27581. 2011. View Article : Google Scholar : PubMed/NCBI


Said RS, Badr AM, Nada AS and El-Demerdash E: Sodium selenite treatment restores long-lasting ovarian damage induced by irradiation in rats: Impact on oxidative stress and apoptosis. Reprod Toxicol. 43:85–93. 2014. View Article : Google Scholar


Weekley CM, Jeong G, Tierney ME, Hossain F, Maw AM, Shanu A, Harris HH and Witting PK: Selenite-mediated production of superoxide radical anions in A549 cancer cells is accompanied by a selective increase in SOD1 concentration, enhanced apoptosis and Se-Cu bonding. J Biol Inorg Chem. 19:813–828. 2014. View Article : Google Scholar : PubMed/NCBI


Yang GQ and Gu LZ: The requirements and acceptable daily intake of trace element selenium in human body. Prog Physiol Sci. 23:184–186. 1992.


Guan L, Han B, Li J, Li Z, Huang F, Yang Y and Xu C: Exposure of human leukemia NB4 cells to increasing concentrations of selenite switches the signaling from pro-survival to pro-apoptosis. Ann Hematol. 88:733–742. 2009. View Article : Google Scholar : PubMed/NCBI


Li Z, Shi K, Guan L, Cao T, Jiang Q, Yang Y and Xu C: ROS leads to MnSOD upregulation through ERK2 translocation and p53 activation in selenite-induced apoptosis of NB4 cells. FEBS Lett. 584:2291–2297. 2010. View Article : Google Scholar : PubMed/NCBI


Guan L, Han B, Li Z, Hua F, Huang F, Wei W, Yang Y and Xu C: Sodium selenite induces apoptosis by ROS-mediated endoplasmic reticulum stress and mitochondrial dysfunction in human acute promyelocytic leukemia NB4 cells. Apoptosis. 14:218–225. 2009. View Article : Google Scholar : PubMed/NCBI


Mi L, Xiao Z, Hood BL, Dakshanamurthy S, Wang X, Govind S, Conrads TP, Veenstra TD and Chung FL: Covalent binding to tubulin by isothiocyanates. A mechanism of cell growth arrest and apoptosis. J Biol Chem. 283:22136–22146. 2008. View Article : Google Scholar : PubMed/NCBI


Jiang Q, Wang Y, Li T, Shi K, Li Z, Ma Y, Li F, Luo H, Yang Y and Xu C: Heat shock protein 90-mediated inactivation of nuclear factor-κB switches autophagy to apoptosis through BECN1 transcriptional inhibition in selenite-induced NB4 cells. Mol Biol Cell. 22:1167–1180. 2011. View Article : Google Scholar : PubMed/NCBI


Wang HY and Ou BX: Experimental study on selenium preventing nasopharyngeal carcinoma. Zhonghua Yu Fang Yi Xue Za Zhi. 26:281–283. 1992.(In Chinese). PubMed/NCBI


Park JS, Ryu JY, Jeon HK, Cho YJ, Park YA, Choi JJ, Lee JW, Kim BG and Bae DS: The effects of selenium on tumor growth in epithelial ovarian carcinoma. J Gynecol Oncol. 23:190–196. 2012. View Article : Google Scholar : PubMed/NCBI


Park SH, Kim JH, Chi GY, Kim GY, Chang YC, Moon SK, Nam SW, Kim WJ, Yoo YH and Choi YH: Induction of apoptosis and autophagy by sodium selenite in A549 human lung carcinoma cells through generation of reactive oxygen species. Toxicol Lett. 212:252–261. 2012. View Article : Google Scholar : PubMed/NCBI


Králová V, Benešová S, Cervinka M and Rudolf E: Selenite-induced apoptosis and autophagy in colon cancer cells. Toxicol In Vitro. 26:258–268. 2012. View Article : Google Scholar


Sharma G, Park J, Sharma AR, Jung JS, Kim H, Chakraborty C, Song DK, Lee SS and Nam JS: Methoxy poly(ethyleneglycol)-poly(lactide) nanoparticles encapsulating quercetin act as an effective anticancer agent by inducing apoptosis in breast cancer. Pharm Res. 32:723–735. 2015. View Article : Google Scholar

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Cui Z, Li C, Li X, Zhang Q, Zhang Y, Shao J and Zhou K: Sodium selenite (Na2SeO3) induces apoptosis through the mitochondrial pathway in CNE-2 nasopharyngeal carcinoma cells. Int J Oncol 46: 2506-2514, 2015
Cui, Z., Li, C., Li, X., Zhang, Q., Zhang, Y., Shao, J., & Zhou, K. (2015). Sodium selenite (Na2SeO3) induces apoptosis through the mitochondrial pathway in CNE-2 nasopharyngeal carcinoma cells. International Journal of Oncology, 46, 2506-2514.
Cui, Z., Li, C., Li, X., Zhang, Q., Zhang, Y., Shao, J., Zhou, K."Sodium selenite (Na2SeO3) induces apoptosis through the mitochondrial pathway in CNE-2 nasopharyngeal carcinoma cells". International Journal of Oncology 46.6 (2015): 2506-2514.
Cui, Z., Li, C., Li, X., Zhang, Q., Zhang, Y., Shao, J., Zhou, K."Sodium selenite (Na2SeO3) induces apoptosis through the mitochondrial pathway in CNE-2 nasopharyngeal carcinoma cells". International Journal of Oncology 46, no. 6 (2015): 2506-2514.