Supplementation with Selenium yeast on the prooxidant–antioxidant activities and anti-tumor effects in breast tumor xenograft-bearing mice

https://doi.org/10.1016/j.jnutbio.2015.07.028Get rights and content

Abstract

Selenium (Se) is essential for antioxidant activity involved in immune function and anti-carcinogenic action, whereas at higher concentrations, Se may have pro-oxidant properties. The present study was aimed at determining the effects of Se supplementation, as Se yeast, on oxidative stress in non-tumor/tumor tissues, as well as regulation of the apoptotic process, and immune responses in mice-bearing breast tumor xenografts. Female BALB/cByJNarl mice were divided into control (CNL and CNL-con), Se-supplemented control (CNL-HS, given as a single oral dose of 912 ng Se daily), breast tumor-bearing (TB and TB-con), TB-LS (228 ng Se), TB-MS (456 ng Se) and TB-HS (912 ng Se) groups. All mice were treated with/without Se for 14 days. A number of variables were further measured. Compared with the TB groups, tumor bearing mice with Se supplement had increased plasma Se concentrations, reduced erythrocyte Se-dependent glutathione peroxidase (GPx) activity and malondialdehyde (MDA) products and inhibited tumor growth. They have also higher Se concentrations in non-tumor and tumor tissues. Significantly elevated concentrations of MDA and reduced GPx activities, as well as increased anti-apoptotic bcl-2 and tumor suppressor p53 concentrations in tumor tissues were observed as Se accumulated in tumor, whereas lower MDA products were found in various non-tumor tissues than did the corresponding values. Further, there were elevated concentrations of Th1-derived cytokines and decreased Th2-type interleukin (IL)-4 in tumor-bearing mice with the treatment of Se. In conclusion, accumulation of Se in tumors may induce oxidative stress and p53-dependent pro-oxidative apoptosis, thus inhibiting the growth of breast tumor.

Introduction

Breast cancer is the most common type of cancer for women worldwide and has become women’s leading cause of cancer death. In Taiwan, breast cancer has become the fourth most common cause of cancer-related death for women, especially for those who are over age of 50 [1]. With the mounting reports on breast cancer related issues for women, it is important to inhibit the development and progression of tumor in patients to increase their life expectancy, although the precise mechanisms of anti-breast cancer remain unknown [2].

Oxidative stress, defined as a disruption between pro-oxidant and antioxidant systems, could contribute to increased reactive oxygen species (ROS) production, which has been linked to greater breast cancer risk [3]. Moreover, chronic inflammation can cause oxidative stress, which is derived from immune cells and within epithelial cells [4]. Oxidative stress causes DNA damage and mutation, stimulates tumor development and angiogenesis, deregulates immune responses, and promotes tumor metastasis [5]. Thus, supplemental antioxidants might prevent ROS damage and decrease carcinogenic risks.

Selenium (Se) is well known as an essential micronutrient and an essential co-factor for the antioxidant enzyme glutathione peroxidase (GPx) and is helpful in eliminating ROS and maintaining redox balance [6]. Further evidence shows that Se modulates cell-mediated immunity and B-cell function [7]. Compared with the healthy controls, patients with breast cancer exhibit markedly higher oxidative stress and lower blood Se concentrations and GPx activity [8], [9]. When compared to normal tissues, expression of Se-binding protein 1 (SeBP1) is reduced in tumor tissues and SeBP1 levels are lower with advancing clinical stages of breast cancer; additionally, lower SeBP1 expression or inadequate Se intake is associated with poor survival rate [10]. There is growing evidence that Se protects mammary epithelial cells from oxidative DNA damage, inhibits the initiation phase of carcinogenesis, stimulates DNA repair, modulates inflammatory and immune responses, regulates apoptosis in tumor pre-stages and prevents cells from angiogenesis [11], [12]. These findings suggest that Se has a chemopreventive property that contributes to its role in the antioxidant activities to reduce oxidative stress [13].

A previous study has recently indicated that Se might affect not only cancer risk, but cancer treatment [11]. A hypothesis has been proposed that Se could act as pro-oxidant rather than an antioxidant in tumor cells, although the mechanism of Se on cancer therapy is not yet fully understood and identified [14]. Se may induce apoptosis through the generation of ROS, thereby eradicating tumor cells [15]. ROS plays a pivotal role in triggering apoptosis involved in the tumor cell death pathway; thus elevated ROS can be used as a therapeutic strategy to eliminate tumor cells [16]. Apparently, Se has a dual role that protects normal tissues from the damaging effects of ROS, and promotes ROS-induced apoptotic death of tumor tissues. Given that, Se supplementation must exhibit selective toxicity against tumor tissues, but not to normal tissues.

The role of Se on the redox-dependent mechanisms in breast cancer therapy in vivo is poorly understood. There is limited information regarding the effect of supplemental Se on the pattern of distribution of Se and oxidative stress in normal and tumor tissues. Therefore, the purpose of the present research was to examine Se homeostasis and the status of pro-oxidants, antioxidants in the blood, and normal and tumor tissues, as well as apoptosis-related oncogenes bcl-2 and p53 in tumors and the immunomodulatory effects under supplemental Se (in the form of Se yeast) in the xenograft mouse of breast tumor.

Section snippets

Animals

Sexually mature female BALB/cByJNarl mice were obtained from the National Laboratory Animal Breeding Research Centre (LABRC, Taipei, Taiwan) and maintained under specific pathogen-free condition. All mice were fed rodent chow (Ralston Purina, Lab Diet #5001, St. Louis, MO, USA) and distilled deionized water (18.3 MΩ cm resistance, Milli-Q; Millipore, Bedford, MA, USA) ad libitum. The animal rooms were maintained at a 12-h light/dark cycle with a room temperature of 24±1°C. The experiment

Food intake, body weight and tissue weights

The Se (as sodium selenate) concentration in laboratory chow was 0.26 μg/g. There were no deaths during experiment in all the groups. No significant differences were observed in final body weights and average daily consumption of pelleted food among the different groups throughout the experimental period (p>0.05; Table 1). However, the highest levels of tumor weight in the TB group were compared with those of tumor-bearing groups, and the levels of tumor weight were as follow: TB > TB-con,

Discussion

This in vivo study presents the preliminary results involving breast tumor xenograft -bearing mice supplemented with the micronutrient, Se. The TB-LS, TB-MS, and TB-HS groups had higher Se concentrations and lower oxidative stress status, as reflected by reduced amounts of MDA, in the circulation and tissues including the liver, kidney, brain, lung, and immunological tissues (spleen and thymus), compared with TB mice not supplemented with Se. Se supplementation showed that tumor Se accumulation

Conclusion

The present findings contribute to the field’s understandings of Se supplementation (as Se yeast) acting on a mouse xenograft model bearing breast tumor. The experiment results demonstrated that Se supplementation increased Se concentrations in normal and tumor tissues, as well as inhibited tumor growth in a dose-dependent manner in breast tumor -bearing mice. In maintaining the balance of pro-oxidants and anti-oxidants in normal tissues, Se accumulation in tumors can cause an increase in

Author contributions

Conceived and designed the experiments: CHG, SH, PCC. Performed the experiments: CHG, PCC. Analyzed the data: CHG, DYH. Contributed reagents/materials/analysis tools: CHG, PCC. Wrote the paper: CHG.

Competing interests

The authors do not have any conflicts of interest to declare.

Acknowledgements

The research is funded by Do Well Laboratories Inc., Irvine CA, U.S.A. (Irvine, CA 92614, USA). Great appreciation is extended to everyone who has contributed to the project.

References (48)

  • D.M. Hardbower et al.

    Chronic inflammation and oxidative stress: The smoking gun for Helicobacter pylori-induced gastric cancer?

    Gut Microbes

    (2013)
  • S. Pervin et al.

    Oxidative stress specifically down regulates survivin to promote breast tumour formation

    Br J Cancer

    (2013)
  • G. Ravn-Haren et al.

    Associations between GPX1 Pro198Leu polymorphism, erythrocyte GPX activity, alcohol consumption and breast cancer risk in a prospective cohort study

    Carcinogenesis

    (2006)
  • S. Zhang et al.

    Reduced selenium-binding protein 1 in breast cancer correlates with poor survival and resistance to the anti-proliferative effects of selenium

    PLoS One

    (2013)
  • M.H. Yazdi et al.

    The preventive oral supplementation of a selenium nanoparticle-enriched probiotic increases the immune response and lifespan of 4 T1 breast cancer bearing mice

    Arzneimittelforschung

    (2012)
  • Y.C. Chen et al.

    Dietary selenium supplementation modifies breast tumor growth and metastasis

    Int J Cancer

    (2013)
  • J. Lu et al.

    Selenium and cancer chemoprevention: hypotheses integrating the actions of selenoproteins and selenium metabolites in epithelial and non-epithelial target cells

    Antioxid Redox Signal

    (2005)
  • J. Brozmanová et al.

    Selenium: a double-edged sword for defense and offence in cancer

    Arch Toxicol

    (2010)
  • H. Wang et al.

    Reduction of splenic immunosuppressive cells and enhancement of anti-tumor immunity by synergy of fish oil and selenium yeast

    PLoS One

    (2013)
  • C.H. Guo et al.

    Effects of zinc supplementation on plasma copper/zinc ratios, oxidative stress, and immunological status in hemodialysis patients

    Int J Med Sci

    (2013)
  • M.P. Rayman

    The use of high-selenium yeast to raise selenium status: how does it measure up?

    Br J Nutr

    (2004)
  • G.K. Jacobson

    Dietary selenium and selenized yeast

    Agro Food Industry Hi Tech

    (2010)
  • M.P. Longnecker et al.

    Use of selenium concentration in whole blood, serum, toenails, or urine as a surrogate measure of selenium intake

    Epidemiology

    (1996)
  • N.K. Yadav et al.

    Assessment of biochemical profiles in premenopausal and postmenopausal women with breast cancer

    Asian Pac J Cancer Prev

    (2012)
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