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Table of Contents
ORIGINAL ARTICLE
Year : 2019  |  Volume : 6  |  Issue : 2  |  Page : 68-75

Antiproliferative effect of oxidative stress induced by tellurite in breast carcinoma cells


1 Department of Microbiology and Molecular Genetics, University of the Punjab, Quaid-e-Azam Campus, Lahore, Pakistan
2 School of Biological Sciences, University of the Punjab, Quaid-e-Azam Campus, Lahore, Pakistan

Date of Submission06-Aug-2018
Date of Decision05-Jan-2019
Date of Acceptance09-Jan-2019
Date of Web Publication31-May-2019

Correspondence Address:
Dr. Abdul Rehman
Department of Microbiology and Molecular Genetics, University of the Punjab, New Campus, Lahore 54590
Pakistan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JCRP.JCRP_5_19

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  Abstract 


Background: Recent studies have revealed that tellurium (Te) compounds have pharmacological and/or antioxidant properties against tumors as they have antitumor and chemoprotective properties. The toxic nature of tellurium compounds and their beneficial effects as antitumor agents have led to an increasing number of studies on their toxicological and pharmacological modes of action. Materials and Methods: The breast cancer cell line, MDA-MB-231, was cultured in the absence or presence of tellurite for biochemical and morphological analysis to measure the extent of cell death. The roles of antioxidant compounds 3-methyladenine, N-acetylcysteine, and 1,2-bis (2-aminophenoxy) ethane-N, N, N′, N′-tetra acetic acid (acetoxymethyl ester) in supporting proliferation in the presence of tellurite were investigated. Results: There was significant oxidative stress in the tellurite-exposed cells, which curtailed cell Adenosine triphosphate (ATP) levels. Tellurite-induced cytotoxicity substantially increased lactate dehydrogenase leakage, lipid peroxidation, and DNA damage, as analyzed by micronuclei and comet formation. Conclusions: Tellurite-induced damage led to cell cycle arrest, resulting in cell death by activating apoptotic machinery by increasing p21 gene expression in tellurite-treated cells.

Keywords: Cell cycle, cell death, oxidative stress, p21 gene, tellurite


How to cite this article:
Noreen A, Rehman A, Aftab S, Shakoori AR. Antiproliferative effect of oxidative stress induced by tellurite in breast carcinoma cells. J Cancer Res Pract 2019;6:68-75

How to cite this URL:
Noreen A, Rehman A, Aftab S, Shakoori AR. Antiproliferative effect of oxidative stress induced by tellurite in breast carcinoma cells. J Cancer Res Pract [serial online] 2019 [cited 2019 Aug 19];6:68-75. Available from: http://www.ejcrp.org/text.asp?2019/6/2/68/259492




  Introduction Top


Worldwide, deaths due to cancer, and especially breast cancer, are increasing in women, and it is one of the most prevalent diseases in Pakistan. Among Asian women, almost 90,000 breast cancer cases are reported every year, and approximately 40,000 patients die due to this disease. In addition, approximately one in nine women in Pakistan are at risk of having breast cancer.[1] The production of high levels of reactive oxygen species (ROS) in tumor cells is one of the major attributes in these cells, which stimulate the proliferating ability of the defective cells. ROS are generated in the cytosol and then cross the nuclear membrane causing genetic instability, which provokes cell proliferation. Interestingly, low tellurite concentrations have been shown to stimulate cell growth and cytokine production; however, increasing concentrations of this metal have been shown to inhibit cell proliferation and induce cell death and apoptosis by inhibiting transcription factors. The role of tellurite in inducing apoptosis of carcinoma cells by increasing generation of ROS could be used to treat cancer.

In healthy cells, ROS production is combated by the antioxidant defense machinery which maintains a reduced environment. However, elevated levels of ROS cells can imbalance the reduced environment, leading to oxidative stress which ultimately causes mutation lipid peroxidation, malignant transformation, and cancer.[2],[3],[4]

In the periodic table, tellurium (Te) is placed between metal and nonmetal category and is therefore called a metalloid, under Group 16. Te is mainly classified in three groups, i.e., elemental Te (Te°); organic Te, which is further categorized into two types (dimethyl ditelluride and dimethyl telluride); and inorganic Te, which also exists in three forms (tellurite, tellurate, and telluride).[5],[6],[7] Selenium (Se) and Te are both chalcogens.[8] Te is used widely in industries such as glass and ceramics, as coloring and anti-knock agents,[9] and in semiconductor with other metals, i.e., bismuth, germanium (Ge), and antimony to form alloys for recordable disks (DVD-RW) and random access memory disks (DVD RAM).[10],[11],[12] It is also used in rubber vulcanization and thermoelectric materials as quantum dots.[5],[10],[13],[14]

Te lacks physiological properties that are shown by Se in animal cells and has antiproliferative and antioxidant properties.[15] Te is known to be a highly toxic metal. To understand the molecular mechanism of its toxicity is interesting;[16] however, the relevant literature about its toxicity is scare. Te generates ROS that are used in anticancer and protective pharmacological effects; however, there is a need for further studies to investigate its effects.[17],[18],[19],[20] Te acts as an inhibitor of Thioredoxin reductase (TrxR) and lipid peroxidation, which cause an imbalance between the generation and removal of ROS.

The aim of this study was to investigate the measurement of the loss or damage caused by tellurite and the induced oxidative stress in breast cancer cells (MDA-MB-231) and whether this could be used as an anticancer or antitumor agent.


  Materials And Methods Top


Culture maintenance, effect of tellurite, and metabolite inhibitors on MDA-231 cell line

The human breast cancer cell line, MDA-MB-231 American Type Culture Collection (ATCC), was used. Cells were cultured and maintained at a density of 5 × 104 cells/cm2 at 37°C in Dulbecco's modified Eagle medium (DMEM) (Gibco) supplemented with 10% fetal calf bovine serum (Gibco), 100 U/ml of penicillin (Sigma), 100 μg/ml of streptomycin (Sigma), and 2 mM L-glutamine (Gibco) in a 95% air 5% CO2 humidified atmosphere. The medium was changed after 48–72 h, and 80% confluence culture was split into 1:3 ratio.

Drug

Potassium tellurite stock solution (100 mM) was made in phosphate-buffered saline (PBS) and used at concentrations ranging from 0.01 to 1 mM.

Effect of tellurite

Cells were plated in a 24-well flat bottom plate (Nunc Delta, Thermo Scientific) containing complete DMEM. The medium was replaced with fresh medium after 48–72 h with or without tellurite at different concentrations and incubated for 7 days. Results were assessed by morphologically observing cells under an inverted microscope, and the number of cells was counted using a hemocytometer every day for up to 7 days.[6]

The 24-well flat-bottom plates were seeded with MDA-MB-231 cells in complete DMEM. The medium was replaced after 24 h with fresh medium containing tellurite and metabolite inhibitors: 3 mM N-acetylcysteine (NAC) (Sigma), 10 mM 3-methyladenine (MA) (Sigma), and 10 μM 1,2-bis (2-aminophenoxy) ethane-N, N, N′, N′-tetra acetic acid (acetoxymethyl ester) (BAPTA-AM) (Sigma) every 48–72 h up to 7 days and allowed to culture for 0–7 days as with the controls. Each experiment was repeated three times. The results were morphologically observed under an inverted microscope, and the number cells was counted using a hemocytometer every day for up to 7 days.[6]

Measurement of lactate dehydrogenase leakage activity

Cytotoxicity induced by tellurite was measured in cell pellets and culture medium to determine cell viability according to the method reported by Wroblewski and Ladue.[21] Cells were cultured with or without tellurite and centrifuged for 5 min at 3000 rpm. Then, in each sample (100 μl), 10 μl of pyruvate (0.8 mg/ml of PBS) to each (pellet and culture medium) and 20 μl of freshly prepared Nicotinamide adenine dinucleotide (NADH) solution (3 mg/ml PBS) were added and incubated at room temperature for 7 min. Then, 20 μl of oxamate (Sigma) (16.6 mg/ml of PBS) was added to stop the enzymatic reaction, and the changes in absorbance were measured at 340 nm using an ELISA reader (HumaReader plus, HUMAN).[22]

Neutral red assay

The cytotoxicity assay was performed according to the modified method described by Borenfreund and Puerner.[23] For the measurement of neutral red dye absorbed in viable cells, MDA-MB-231 cells were cultured in complete DMEM in a 24-well plate (Nun Clun) for 24 h, treated with tellurite for the next 24 h, washed with PBS, and then incubated at 37°C for 6 h with 150 μl neutral red dye (Sigma) with 5% CO2. The cells were again washed thrice with PBS followed by the addition of 100 μl of neutral red dye and incubation on a shaker at 100 rpm for 30 min, and the absorbance was measured at 540 nm using an ELISA reader (HumaReader plus, HUMAN).

Comet assay

The comet assay was performed according to Santos et al.[24] with modifications under an alkaline environment. The cells were cultured for 24 h and treated with tellurite, trypsinized, and collected in PBS. One hundred microliters of cells in PBS was mixed in 1% low melting agarose (400 μl), and 100 μl of this mixture was layered on 1.5% agarose in TAE, covered with a cover slip, and allowed to solidify for 20 min at 4°C. The cover slip was then removed and immersed in lysis solution (2.5 M NaCl, 100 mM EDTA, 1% Triton X 100, 10 Mm Tris pH-10) for 1 h, washed with PBS for 5 min, dipped in an electrophoretic tank in alkaline buffer (300 mM NaOH, 1 mM EDTA pH-13) for 20 min (freshly prepared), and then subjected to electrophoresis at 25 V for 20 min. This was followed by neutralization (0.4 mM Tris pH-7) for 15 min and fixation with absolute ethanol for 10 min and then stored at 4°C before analysis. For analysis, the cells were stained with 30 μl ethidium bromide (20 μg/ml) and observed at ×10 with a fluorescence microscope.[25]

Micronucleus test

Cells were cultured for 24 h under standard conditions, and the medium was exchanged with the stress medium and allowed to culture for at least one cycle. The cells were then fixed with 70% ethanol and 2% formaldehyde for 5–10 min, dried completely, and the slides were stained with 5% May–Grunwald–Giemsa for 5 min. The images were taken under a bright field microscope.

Lipid peroxidation assay

Thiobarbituric acid (TBA)-reactive species were measured with a slight modification of the lipid peroxidation determination method reported by Hicks and Gebicki[26] and Ohkawa et al.[27] The cells were cultured under standard condition, then the medium was exchanged with the stress medium, and 100 μl of sample was then mixed with 20% acetic acid buffer, 6% TBA (Sigma), and 8.1% SDS and incubated for 1 h in boiling water. The color production was observed and measured at 532 nm.

IC50 calculation

IC50(concentration inhibiting 50% of lipid peroxidation) for lipid peroxidation was determined using the method reported by Dixon and Webb.[28]

Measurement of ATP level

ATP was measured using a StayBrite™ Highly Stable ATP Bioluminescence Assay Kit according to the manufacturer's instructions (BioVision).

p21 gene expression

To extract total RNA, MDA-MB-231 cells were grown up to 80% confluency with or without (control) tellurite treatment for 1 day. The cells were placed in (100-mm diameter) culture plates after the media had been aspirated and washed twice with PBS, and 1 ml of TRIzol® was added. All cells were dissolved according to standard RNA extraction procedures and purified using DNase 1 provided in an RNase-free (Fermentas) kit, and the purified RNA was reverse transcribed to synthesize the cDNA using a Thermo Scientific RevertAid first strand cDNA synthesis kit. Then, 500 ng of cDNA was used for quantitative real-time polymerase chain reaction (RT-PCR). The reaction was carried out using Thermo Scientific Maxima SYBR Green/ROX qPCR Master Mix (2X) #K0221, and 5 μM of each forward and reverse primer of p21 was used (forward: 5′-CTGGGGATGTCCGTCAGAAC-3′, reverse: 5′-CATTAGCGCATCACAGTCGC-3′) according to Chin et al.[29] A two-step cycling protocol (initial denaturation at 95°C for 3 min, followed by 40 cycles each of denaturation at 95°C for 15 s and annealing and extension at 55°C for 30 s) was performed on a Bio-Rad MYiQ™2. A two-color RT-PCR detection system (Bio-Rad) was used. Glucuronidase-β was used as a housekeeping gene, and the same experimental conditions were used to normalize Ct values of target p21 gene transcripts and changes in gene expression in n-fold relative to the target were calculated.

Statistical analysis

All independent experiments were performed three times, and all data were presented as mean ± standard deviation. The Student's t-test was used to assess differences between means of two groups. One-way ANOVA was used to assess differences among different groups, and P <0.05 was considered statistically significant.


  Results Top


Cytotoxicity assay

[Figure 1] shows that cytotoxicity was significantly increased in the treated cells, and at 0.1 mM tellurite, a significant difference (P < 0.05) was ascertained compared to the controls, which indicated more cell death with increasing concentration. The percentage of live cells in the neutral red assay with different tellurite concentrations ranging from 0.01 to 1 mM is shown in [Figure 1].
Figure 1: Antiproliferative effect of tellurite concentration measured by neutral red assay

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Effect of tellurite on MDA-231 cell line

MDA-MB-231 cells were morphologically characterized under an inverted microscope. The cells showed different morphologies with disordered nuclei in epithelial type layering as they presented as single (round), clusters (elongated mass), and connecting cells (spindle) over time to form an invasive mass.

The morphology of the MDA-MB-231 cells sharply changed with increasing concentrations of tellurite, and increasing apoptosis and necrosis of the cells occurred with time [Figure 2]a, even at a low concentration. The number of cells decreased with increasing time and concentrations so that the cells died earlier with a high concentration (1 mM).
Figure 2: (a) Morphological changes in MDA-MB-231 cells after tellurite treatment using Nikon eclipsed phase contrast microscope, and all three independent experiments were performed under identical condition. Morphology of cells sharply (remarkably) changed with increasing conc. of Te and time. Treated cells changed their morphology at the start all cells were rounded and detached later mostly cells are attached and changed their shape from spherical to spindle, invasive, the size of cell increases, flattened, vacuolization of cytoplasm, cells become more elongated and healthy cell becomes more flattened and highly spreader shape with more prominent and visible with increasing volume of cell attached to surface in low concentration as compared to control and their no reduced with increasing concentration of Te; as concentration increases cells goes to rounded small shaped and detached as dying cells, fewer number of cells changed their shape and mostly remain in round later formed debris at high concentrations of Te; and death of cells by apoptosis and necrotic process inducing cell shrinkage, membrane integrity loosed, condensed chromatin, condensed cytoplasm, fragmented nucleus material and in large number of the cells detached from surface and formed apoptotic bodies. (b) Effect of tellurite concentration on MDA-MB-231 cells survival

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Tellurite induced morphological changes in the treated cells compared to the control cells as observed with a phase contrast inverted microscope [Figure 2]a. The untreated cells retained normal shape, while the treated cells withdrew from the surface with rounding, membrane blebbing and apoptotic body, nuclear fragmentation, and arrow and nuclear shrinking of the MDA-MB-231 cells.

The MDA-MB-231 cells clearly showed a decline in growth when exposed to 1 mM tellurite, and all of the cells had died after 48 h of incubation. Similar results were found at 0.5 mM after 72 h stress. At 0.1 mM, cell growth was slowed after 24 h, and a more significant decrease was observed with IC50 after 72 h. At 0.05 mM and 0.01 mM tellurite stress, the cells continued to proliferate up to 72 and 84 h, respectively. A decline in growth phase was determined after this time period [Figure 2]b.

[Figure 3]a shows the percentage (%) leakage in the MDA-MB-231 cells of lactate dehydrogenase (LDH) with increasing concentrations of tellurite from 0 to 1 mM. Cell death increased significantly (P < 0.05) with increasing concentrations of tellurite as there was less enzyme leakage with low stress and high enzyme leakage with stronger stress in a dose-dependent manner [Figure 3]a.
Figure 3: (a) The lactate dehydrogenase leakage (%) to measure cell viability. (b) Effect of metabolite inhibitors on cell inhibition with and without tellurite. Experiment thrice repeated and mean ± standard error (n = 3) was measured

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Effect of metabolite inhibitors

Cell death (%) was measured in the MDA-MBA-231 cells in the presence of metabolite inhibitors with antioxidant properties, i.e., NAC and BAPTA-AM. Varying concentrations of tellurite could not reduce tellurite toxicity. BAPTA-AM showed more LDH leakage compared to NAC [Supplementary Figure 1].



Metabolite inhibitors are normally involved in cell maintenance and act as antioxidants during tellurite induced-oxidative stress. These factors were not reduced or eliminated by BAPTA-AM or MA, but NAC showed a greater capacity to fight against tellurite oxidative stress and helped to induce cell proliferation [Figure 3]b.

Comet assay

Tellurite induced more DNA damage in MDA-MB-231 cells [Figure 4]a, where the percentage (%) DNA in the tail of a comet increased with increasing concentrations of tellurite (0.01, 0.1, and 1 mM), i.e., 40.62, 68.445, and 77.376, respectively, compared to the nontellurite-treated DNA in tails (22%). Fluorescence microscopy revealed the same results [Figure 4]b.
Figure 4: (a) DNA damage measurement in MDA-MB-231 with tellurite stress. (b) Fluorescence microscopy of Comet formed by MDA-MB-231 cells. (c) Induction of micronuclei formation

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Micronucleus test

Tellurite induced micronuclei formation in the treated cells [Figure 4]c. The graphical representation of micronuclei is shown in [Supplementary Figure 2]. No micronuclei were seen in the control cells compared to the treated cells [Figure 4]c with a significant difference (P < 0.05).



Lipid peroxidation assay

[Figure 5]a shows the MDA measurements with different concentrations of tellurite with metabolite inhibitors. Treatment with 0.1 mM tellurite and two metabolite inhibitors (BAPTA-AM and NAC) resulted in MDA production peaks at 4.3 and 3.9 nmol, respectively. [Supplementary Figure 3] shows that the production of MDA increased with increasing concentrations of tellurite.
Figure 5: (a) Metabolite inhibitors effect on lipids peroxidation with tellurite on MDA-MB-231 cells. (b) Tellurite's effect on ATP level in MDA-MB 231 cells. (c) Effect of tellurite on p21 gene expression of MDA-MB-231's RNA

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Measurement of ATP level

In the MDA-MB-231 cells, the level of ATP decreased as the tellurite concentration increased, which clearly indicated the cytotoxicity of tellurite and the induction of toxicity within the cells, and the death of cells by depleting ATP levels due to damaged ATP-producing machinery [Figure 5]b.

p21 gene expression

RNA of the MDA-MB-231 cells in quantitative RT-PCR showed upregulation of p21 gene expression with increasing tellurite concentration, and a 10-fold greater expression at 1 mM tellurite was noted compared to the controls (without tellurite) [Figure 5]c.


  Discussion Top


In this study, cytotoxic, genotoxic and antiproliferative effects were found in human breast cancer MDA-MB-231 cells with 0–1 mM tellurite presented in a dose-dependent manner. Tellurite had a cytotoxic effect and the IC50 was 0.1 mM on MDA-MB-231 cells that significantly retarded growth after 72 h as assessed by cell viability assays. Our results showed that as the concentration of tellurite increased from 0 to 1 mM, antiproliferation of cells also increased.

Various exo- and endo-genous factors cause stress, and in this study, tellurite induced oxidative stress which led to genetic damage and instability and micronuclei formation [Supplementary Figure 2], as reported in a previous study.[30] Ethiraj et al.[31] and Meinerz et al.[32] reported that tellurite compounds induced micronuclei formation compared to controls. Shao et al.[33] reported that irradiated MDA-MB-231 cells with helium particles of varying number induced MN formation, and that MDA-MB-231 cells irradiated with 1 and 53 He2+ particles induced more formation of MN in a dose-dependent manner. Radiation-exposed MCF7 cells have also been shown to induce damage with genetic materials resulting in MN formation.[34]

In the present study, MDA-MB-231 cells treated with tellurite showed positive results [Figure 3]b by comet formation [Figure 3]b. In tellurite-treated cells with increasing tellurite concentration, DNA length, height, area, and mean intensity significantly increased (P < 0.05) [Figure 3]a compared to the control cells where no comet formation took place, and no tail formation was noted. The toxicity of tellurite damaging DNA by fragmentation is known as genotoxicity. Le Hegarat et al.[35] also reported similar results of DNA damage in HepRG cells. In addition, arsenic-induced genotoxicity in macrophages and mesenchymal stem cells was reported by Sengupta and Bishayi[36] and Ahmad et al.[25] respectively. Mesenchymal stem cells have also ben reported to show positive results for DNA damage via flow cytometry.[37]

Sandoval et al.[6] reported that tellurite undergoes redox cycling leading to ROS formation and cancer cell death. Murine hepatocarcinoma transplantable liver tumor cells were challenged with tellurite either in the presence or absence of different compounds including NAC, MA, BAPTA-AM, and catalase. NAC inhibition of tellurite-mediated toxicity suggested the major role of oxidative stress. Tellurite also decreased both glutathione and ATP content by 57% and 80%, respectively. Although the calcium chelator BAPTA-AM did not show an effect, the rapid phosphorylation of eIF2-alpha suggests that, in addition to oxidative stress, endoplasmic reticulum stress may be involved in the mechanisms, leading to cell death by tellurite.

Tellurite induced toxicity by stimulating more lipid peroxidation with increasing concentrations compared to the presence of metabolite inhibitors (i.e., BAPTA-AM and NAC). Metabolite inhibitors were helpful in decreasing the toxic effect of tellurite to maintain cell homeostasis for growth and were efficient even in the presence of tellurite stress, which is different to the findings of Puntel et al.[38] Organochalcogen compounds can act as free radical trapping agents or glutathione peroxidase mimetics, reducing oxidative stress in inflammatory diseases. Lu et al.[39] synthesized and screened a library of organoselenium and organotellurium compounds for H2O2 scavenging activity, using the macrophagic cell lines RAW264.7 and THP-1, as well as human mono- and poly-nuclear cells. These compounds have also been used as immunomodulatory, anti-inflammatory, and anti-apoptotic agents in Parkinson's and diabetes models.[40],[41] Tellurite causes acute and chronic toxicity; however, the mechanism of its toxicity is very unusual and various studies have reported that tellurite induces a single strand break, which leads to the activation of cell death as a nonessential micronutrient in the body.[42]

In the present study, tellurite enhanced p21 gene expression with increasing concentration. Gene p21 is involved in cell cycle regulation by controlling cyclin-dependent kinases (CDKS) of the cell cycle (CDK2 [E, A]; CDC2 [A, B]). In this study, tellurite increased the level of p21 gene expression by lowering cyclin-CDK complex, as damage to DNA leads to induction of cell cycle arrest and cell death by activating the apoptotic machinery as reported in various studies,[29],[43],[44] in which resveratrol induced apoptosis by triggering p21 gene expression. All of these findings are very similar to the present study.


  Conclusions Top


The results of this study suggest that tellurite can be used as an anti-proliferator of MDA-MB-231 cells by arresting the cell cycle by upregulating p21 gene expression. Few investigations have studied tellurite compounds compared to Se, and very few studies have been conducted to investigate the biological mechanism of tellurite and its pharmacological benefits.[45],[46] In the current study, only one breast cancer cell line was used, and future studies are needed with more cell lines to verify our findings.

Acknowledgment

This work was supported by the research grant no. PU/Envr (59) from University of the Punjab, Lahore, Pakistan, which is gratefully acknowledged.

Financial support and sponsorship

This work was supported by the research grant no. PU/Envr (59) from University of the Punjab, Lahore, Pakistan.

Conflicts of interest

There are no conflicts of interest.



 
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