Abstract
The trace element selenium and selenocysteine-carrying selenoproteins play a pivotal role in the brain. Beside the essential function during development and maintenance of brain action, selenium has also been associated with several neurological and neuro-oncological conditions. Reliable supply of selenium is important since selenium compounds can affect tumor microenvironment and neoangiogenesis in malignant gliomas (WHO grade III and IV [glioblastoma, GBM]) via induction of apoptosis and alteration of matrix metalloproteinases expression. Here, we summarize recent findings focusing on the anti-toxicity and cancer-preventive properties of selenium and their implication in current multimodal therapies including temozolomide (Temodal), cyclophosphamide (Endoxan), and cisplatin (DDP, Platiblastin, and Platinol). We shed light on unintended side effects in chemotherapy and the developments of novel combinatorial chemotherapeutics with selenium compounds. We found that selenium and selenium compounds have dual action profiles with direct anti-cancer and chemotherapy-intensifier effects as well as neuroprotective and cytoprotective agents. Current selenium trials and selenium supplementation with focus on neuro-oncology will be discussed with regard to low-adequate-to-high/toxic selenium status.
Similar content being viewed by others
References
Brauer AU, Savaskan NE (2004) Molecular actions of selenium in the brain: Neuroprotective mechanisms of an essential trace element. Rev Neurosci 15(1):19–32
Schweizer U, Brauer AU, Kohrle J, Nitsch R, Savaskan NE (2004) Selenium and brain function: a poorly recognized liaison. Brain Res Brain Res Rev 45(3):164–178
Pillai R, Uyehara-Lock JH, Bellinger FP (2014) Selenium and selenoprotein function in brain disorders. IUBMB Life 66(4):229–239
Byrns CN, Pitts MW, Gilman CA, Hashimoto AC, Berry MJ (2014) Mice lacking selenoprotein P and selenocysteine lyase exhibit severe neurological dysfunction, neurodegeneration, and audiogenic seizures. J Biol Chem 289(14):9662–9674
Bleys J, Navas-Acien A, Guallar E (2008) Serum selenium levels and all-cause, cancer, and cardiovascular mortality among US adults. Arch Intern Med 168(4):404–410
Ray AL, Semba RD, Walston J et al (2006) Low serum selenium and total carotenoids predict mortality among older women living in the community: the women's health and aging studies. J Nutr 136(1):172–176
Carlson BA, Yoo MH, Shrimali RK et al (2010) Role of selenium-containing proteins in T-cell and macrophage function. Proc Nutr Soc 69(3):300–310
Hall JA, Vorachek WR, Stewart WC et al (2013) Selenium supplementation restores innate and humoral immune responses in footrot-affected sheep. PLoS One 8(12):e82572
Naziroglu M, Senol N, Ghazizadeh V, Yuruker V (2014) Neuroprotection induced by N-acetylcysteine and selenium against traumatic brain injury-induced apoptosis and calcium entry in hippocampus of rat. Cell Mol Neurobiol 34(6):895–903
Streicher KL, Sylte MJ, Johnson SE, Sordillo LM (2004) Thioredoxin reductase regulates angiogenesis by increasing endothelial cell-derived vascular endothelial growth factor. Nutr Cancer 50(2):221–231
Kristal AR, Darke AK, Morris JS et al (2014) Baseline selenium status and effects of selenium and vitamin E supplementation on prostate cancer risk. J Natl Cancer Inst 106(3):djt456
Clark LC, Combs GF Jr, Turnbull BW et al (1996) Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. JAMA 276(24):1957–1963
Clark LC, Dalkin B, Krongrad A et al (1998) Decreased incidence of prostate cancer with selenium supplementation: Results of a double-blind cancer prevention trial. Br J Urol 81(5):730–734
Duffield-Lillico AJ, Reid ME, Turnbull BW et al (2002) Baseline characteristics and the effect of selenium supplementation on cancer incidence in a randomized clinical trial: a summary report of the Nutritional Prevention of Cancer Trial. Cancer Epidemiol Biomarkers Prev 11(7):630–639
Wen PY, Kesari S (2008) Malignant gliomas in adults. N Engl J Med 359(5):492–507
Ip C, Thompson HJ, Zhu Z, Ganther HE (2000) In vitro and in vivo studies of methylseleninic acid: evidence that a monomethylated selenium metabolite is critical for cancer chemoprevention. Cancer Res 60(11):2882–2886
Qi Y, Fu X, Xiong Z et al (2012) Methylseleninic acid enhances paclitaxel efficacy for the treatment of triple-negative breast cancer. PLoS One 7(2):e31539
Ganther HE (1999) Selenium metabolism, selenoproteins and mechanisms of cancer prevention: complexities with thioredoxin reductase. Carcinogenesis 20(9):1657–1666
Ganther HE (1971) Reduction of the selenotrisulfide derivative of glutathione to a persulfide analog by glutathione reductase. Biochemistry 10(22):4089–4098
Husain K, Morris C, Whitworth C, Trammell GL, Rybak LP, Somani SM (1998) Protection by ebselen against cisplatin-induced nephrotoxicity: Antioxidant system. Mol Cell Biochem 178(1–2):127–133
Itoh M, Suzuki KT (1997) Effects of dose on the methylation of selenium to monomethylselenol and trimethylselenonium ion in rats. Arch Toxicol 71(7):461–466
Papp LV, Lu J, Holmgren A, Khanna KK (2007) From selenium to selenoproteins: Synthesis, identity, and their role in human health. Antioxid Redox Signal 9(7):775–806
Patterson BH, Zech LA (1992) Development of a model for selenite metabolism in humans. J Nutr 122(3 Suppl):709–714
Kryukov GV, Castellano S, Novoselov SV et al (2003) Characterization of mammalian selenoproteomes. Science 300(5624):1439–1443
Loscalzo J (2014) Keshan disease, selenium deficiency, and the selenoproteome. N Engl J Med 370(18):1756–1760
Castellano S, Lobanov AV, Chapple C et al (2005) Diversity and functional plasticity of eukaryotic selenoproteins: Identification and characterization of the SelJ family. Proc Natl Acad Sci U S A 102(45):16188–16193
Savaskan NE, Borchert A, Brauer AU, Kuhn H (2007) Role for glutathione peroxidase-4 in brain development and neuronal apoptosis: Specific induction of enzyme expression in reactive astrocytes following brain injury. Free Radic Biol Med 43(2):191–201
Savaskan NE, Ufer C, Kuhn H, Borchert A (2007) Molecular biology of glutathione peroxidase 4: from genomic structure to developmental expression and neural function. Biol Chem 388(10):1007–1017
Ufer C, Wang CC, Fahling M et al (2008) Translational regulation of glutathione peroxidase 4 expression through guanine-rich sequence-binding factor 1 is essential for embryonic brain development. Genes Dev 22(13):1838–1850
Beckett GJ, Arthur JR (2005) Selenium and endocrine systems. J Endocrinol 184(3):455–465
Battin EE, Brumaghim JL (2009) Antioxidant activity of sulfur and selenium: a review of reactive oxygen species scavenging, glutathione peroxidase, and metal-binding antioxidant mechanisms. Cell Biochem Biophys 55(1):1–23
Uden PC, Bird SM, Kotrebai M et al (1998) Analytical selenoamino acid studies by chromatography with interfaced atomic mass spectrometry and atomic emission spectral detection. Fresenius J Anal Chem 362(5):447–456
Trepanier G, Furling D, Puymirat J, Mirault ME (1996) Immunocytochemical localization of seleno-glutathione peroxidase in the adult mouse brain. Neuroscience 75(1):231–243
Zhang Y, Zhou Y, Schweizer U et al (2008) Comparative analysis of selenocysteine machinery and selenoproteome gene expression in mouse brain identifies neurons as key functional sites of selenium in mammals. J Biol Chem 283(4):2427–2438
Hill KE, Zhou J, McMahan WJ et al (2003) Deletion of selenoprotein P alters distribution of selenium in the mouse. J Biol Chem 278(16):13640–13646
Schomburg L, Schweizer U, Holtmann B, Flohe L, Sendtner M, Kohrle J (2003) Gene disruption discloses role of selenoprotein P in selenium delivery to target tissues. Biochem J 370(Pt 2):397–402
Saijoh K, Saito N, Lee MJ, Fujii M, Kobayashi T, Sumino K (1995) Molecular cloning of cDNA encoding a bovine selenoprotein P-like protein containing 12 selenocysteines and a (His-Pro) rich domain insertion, and its regional expression. Brain Res Mol Brain Res 30(2):301–311
Yan J, Barrett JN (1998) Purification from bovine serum of a survival-promoting factor for cultured central neurons and its identification as selenoprotein-P. J Neurosci 18(21):8682–8691
Scharpf M, Schweizer U, Arzberger T, Roggendorf W, Schomburg L, Kohrle J (2007) Neuronal and ependymal expression of selenoprotein P in the human brain. J Neural Transm 114(7):877–884
Raman AV, Pitts MW, Seyedali A et al (2012) Absence of selenoprotein P but not selenocysteine lyase results in severe neurological dysfunction. Genes Brain Behav 11(5):601–613
Hill KE, Wu S, Motley AK et al (2012) Production of selenoprotein P (Sepp1) by hepatocytes is central to selenium homeostasis. J Biol Chem 287(48):40414–40424
Kurokawa S, Hill KE, McDonald WH, Burk RF (2012) Long isoform mouse selenoprotein P (Sepp1) supplies rat myoblast L8 cells with selenium via endocytosis mediated by heparin binding properties and apolipoprotein E receptor-2 (ApoER2). J Biol Chem 287(34):28717–28726
Ellis DR, Salt DE (2003) Plants, selenium and human health. Curr Opin Plant Biol 6(3):273–279
Reid ME, Duffield-Lillico AJ, Slate E et al (2008) The nutritional prevention of cancer: 400 mcg per day selenium treatment. Nutr Cancer 60(2):155–163
Wallace K, Kelsey KT, Schned A, Morris JS, Andrew AS, Karagas MR (2009) Selenium and risk of bladder cancer: a population-based case–control study. Cancer Prev Res 2(1):70–73
Tan JA, An WY, Li RB (1987) The geo-medical characteristics of Keshan disease. Keshan disease prevention and treatment in China, pp 254–264
Philipov P, Tzatchev K (1988) Selenium concentrations in serum of patients with cerebral and extracerebral tumors. Zentralbl Neurochir 49(4):344–347
DeAngelis LM (2001) Brain tumors. N Engl J Med 344(2):114–123
Brat DJ, Castellano-Sanchez AA, Hunter SB et al (2004) Pseudopalisades in glioblastoma are hypoxic, express extracellular matrix proteases, and are formed by an actively migrating cell population. Cancer Res 64(3):920–927
Giannelli G, Falk-Marzillier J, Schiraldi O, Stetler-Stevenson WG, Quaranta V (1997) Induction of cell migration by matrix metalloprotease-2 cleavage of laminin-5. Science 277(5323):225–228
Rooprai HK, Kyriazis I, Nuttall RK et al (2007) Inhibition of invasion and induction of apoptosis by selenium in human malignant brain tumour cells in vitro. Int J Oncol 30(5):1263–1271
Roomi MW, Ivanov V, Kalinovsky T, Niedzwiecki A, Rath M (2007) Inhibition of glioma cell line A-172 MMP activity and cell invasion in vitro by a nutrient mixture. Med Oncol 24(2):231–238
Yoon SO, Kim MM, Chung AS (2001) Inhibitory effect of selenite on invasion of HT1080 tumor cells. J Biol Chem 276(23):20085–20092
Sarkar FH, Li Y (2006) Using chemopreventive agents to enhance the efficacy of cancer therapy. Cancer Res 66(7):3347–3350
Uğuz AC, Naziroğlu M, Espino J et al (2009) Selenium modulates oxidative stress-induced cell apoptosis in human myeloid HL-60 cells through regulation of calcium release and caspase-3 and −9 activities. J Membr Biol 232:15–23
Kahya MC, Nazıroğlu M, Ciğ B (2014) Selenium reduces mobile phone (900 MHz)-induced oxidative stress, mitochondrial function, and apoptosis in breast cancer cells. Biol Trace Elem Res 160(2):285–293
Sugie S, Tanaka T, El-Bayoumy K (2000) Chemoprevention of carcinogenesis by organoselenium compounds. J Health Sci 46(6):422–425
Whanger PD (2004) Selenium and its relationship to cancer: an update. Br J Nutr 91(1):11–28
Zhou N, Xiao H, Li TK, Nur EKA, Liu LF (2003) DNA damage-mediated apoptosis induced by selenium compounds. J Biol Chem 278(32):29532–29537
Jung HJ, Seo YR (2010) Current issues of selenium in cancer chemoprevention. Biofactors 36(2):153–158
Chintala S, Toth K, Cao S et al (2010) Se-methylselenocysteine sensitizes hypoxic tumor cells to irinotecan by targeting hypoxia-inducible factor 1 alpha. Cancer Chemother Pharmacol 66(5):899–911
Hu H, Li GX, Wang L, Watts J, Combs GF Jr, Lu J (2008) Methylseleninic acid enhances taxane drug efficacy against human prostate cancer and down-regulates antiapoptotic proteins Bcl-XL and survivin. Clin Cancer Res 14(4):1150–1158
Tan Q, Li J, Yin HW et al (2010) Augmented antitumor effects of combination therapy of cisplatin with ethaselen as a novel thioredoxin reductase inhibitor on human A549 cell in vivo. Invest New Drugs 28(3):205–215
Wei MX, Tamiya T, Chase M et al (1994) Experimental tumor therapy in mice using the cyclophosphamide-activating cytochrome P450 2B1 gene. Hum Gene Ther 5(8):969–978
Roy P, Yu LJ, Crespi CL, Waxman DJ (1999) Development of a substrate-activity based approach to identify the major human liver P-450 catalysts of cyclophosphamide and ifosfamide activation based on cDNA-expressed activities and liver microsomal P-450 profiles. Drug Metab Dispos 27(6):655–666
Fraiser LH, Kanekal S, Kehrer JP (1991) Cyclophosphamide toxicity. Characterising and avoiding the problem. Drugs 42(5):781–795
Chabra A, Shokrzadeh M, Naghshvar F, Salehi F, Ahmadi A (2014) Melatonin ameliorates oxidative stress and reproductive toxicity induced by cyclophosphamide in male mice. Hum Exp Toxicol 33(2):185–195
Das UB, Mallick M, Debnath JM, Ghosh D (2002) Protective effect of ascorbic acid on cyclophosphamide-induced testicular gametogenic and androgenic disorders in male rats. Asian J Androl 4(3):201–207
Ghosh D, Das UB, Ghosh S, Mallick M, Debnath J (2002) Testicular gametogenic and steroidogenic activities in cyclophosphamide treated rat: a correlative study with testicular oxidative stress. Drug Chem Toxicol 25(3):281–292
Manda K, Bhatia AL (2003) Prophylactic action of melatonin against cyclophosphamide-induced oxidative stress in mice. Cell Biol Toxicol 19(6):367–372
Korkmaz A, Topal T, Oter S (2007) Pathophysiological aspects of cyclophosphamide and ifosfamide induced hemorrhagic cystitis; implication of reactive oxygen and nitrogen species as well as PARP activation. Cell Biol Toxicol 23(5):303–312
Behrman HR, Preston SL (1989) Luteolytic actions of peroxide in rat ovarian cells. Endocrinology 124(6):2895–2900
Selvakumar E, Prahalathan C, Sudharsan PT, Varalakshmi P (2006) Chemoprotective effect of lipoic acid against cyclophosphamide-induced changes in the rat sperm. Toxicology 217(1):71–78
Tripathi DN, Jena GB (2008) Ebselen attenuates cyclophosphamide-induced oxidative stress and DNA damage in mice. Free Radic Res 42(11–12):966–977
Bhattacharjee A, Basu A, Ghosh P, Biswas J, Bhattacharya S (2014) Protective effect of Selenium nanoparticle against cyclophosphamide induced hepatotoxicity and genotoxicity in Swiss albino mice. J Biomater Appl 29(2):303–317
Kornblith PL, Walker M (1988) Chemotherapy for malignant gliomas. J Neurosurg 68(1):1–17
Kyritsis AP (1993) Chemotherapy for malignant gliomas. Oncology 7(9):93–100
Pech IV, Peterson K, Cairncross JG (1998) Chemotherapy for brain tumors. Oncology 12(4):537–543, 547
Ghorbani A, Omidvar B, Parsi A (2013) Protective effect of selenium on cisplatin induced nephrotoxicity: a double-blind controlled randomized clinical trial. J Nephropathol 2(2):129–134
Nematbakhsh M, Ashrafi F, Pezeshki Z et al (2012) A histopathological study of nephrotoxicity, hepatoxicity or testicular toxicity: which one is the first observation as side effect of Cisplatin-induced toxicity in animal model? J Nephropathol 1(3):190–193
Doz F, Pinkerton R (1994) What is the place of carboplatin in paediatric oncology? Eur J Cancer 30A(2):194–201
Calvert AH, Harland SJ, Newell DR et al (1982) Early clinical studies with cis-diammine-1,1-cyclobutane dicarboxylate platinum II. Cancer Chemother Pharmacol 9(3):140–147
Foster BJ, Clagett-Carr K, Leyland-Jones B, Hoth D (1985) Results of NCI-sponsored phase I trials with carboplatin. Cancer Treat Rev 12(Suppl A):43–49
Cornelison TL, Reed E (1993) Nephrotoxicity and hydration management for cisplatin, carboplatin, and ormaplatin. Gynecol Oncol 50(2):147–158
Pinzani V, Bressolle F, Haug IJ, Galtier M, Blayac JP, Balmes P (1994) Cisplatin-induced renal toxicity and toxicity-modulating strategies: a review. Cancer Chemother Pharmacol 35(1):1–9
Sahni V, Choudhury D, Ahmed Z (2009) Chemotherapy-associated renal dysfunction. Nat Rev Nephrol 5(8):450–462
Naziroglu M, Karaoğlu A, Aksoy AO (2004) Selenium and high dose vitamin E administration protects cisplatin-induced oxidative damage to renal, liver and lens tissues in rats. Toxicology 195:221–230
Chamberlain MC (2010) Temozolomide: Therapeutic limitations in the treatment of adult high-grade gliomas. Expert Rev Neurother 10(10):1537–1544
Omar AI, Mason WP (2010) Temozolomide: the evidence for its therapeutic efficacy in malignant astrocytomas. Core Evid 4:93–111
Chakravarti A, Erkkinen MG, Nestler U et al (2006) Temozolomide-mediated radiation enhancement in glioblastoma: a report on underlying mechanisms. Clin Cancer Res 12(15):4738–4746
Carmo A, Carvalheiro H, Crespo I, Nunes I, Lopes MC (2011) Effect of temozolomide on the U-118 glioma cell line. Oncol Lett 2(6):1165–1170
Gao S, Yang XJ, Zhang WG, Ji YW, Pan Q (2009) Mechanism of thalidomide to enhance cytotoxicity of temozolomide in U251-MG glioma cells in vitro. Chin Med J 122(11):1260–1266
Cheng Y, Sk UH, Zhang Y et al (2012) Rational incorporation of selenium into temozolomide elicits superior antitumor activity associated with both apoptotic and autophagic cell death. PLoS One 7(4):e35104
Letavayova L, Vlckova V, Brozmanova J (2006) Selenium: from cancer prevention to DNA damage. Toxicology 227(1–2):1–14
Biswas S, Talukder G, Sharma A (2000) Chromosome damage induced by selenium salts in human peripheral lymphocytes. Toxicol In Vitro 14(5):405–408
Letavayova L, Vlasakova D, Spallholz JE, Brozmanova J, Chovanec M (2008) Toxicity and mutagenicity of selenium compounds in Saccharomyces cerevisiae. Mutat Res 638(1–2):1–10
Wycherly BJ, Moak MA, Christensen MJ (2004) High dietary intake of sodium selenite induces oxidative DNA damage in rat liver. Nutr Cancer 48(1):78–83
Blot WJ, Li JY, Taylor PR et al (1993) Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J Natl Cancer Inst 85(18):1483–1492
Hercberg S, Galan P, Preziosi P et al (2004) The SU.VI.MAX Study: a randomized, placebo-controlled trial of the health effects of antioxidant vitamins and minerals. Arch Intern Med 164(21):2335–2342
Hercberg S, Ezzedine K, Guinot C et al (2007) Antioxidant supplementation increases the risk of skin cancers in women but not in men. J Nutr 137(9):2098–2105
Lippman SM, Klein EA, Goodman PJ et al (2009) Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 301(1):39–51
Goossens ME, Buntinx F, Joniau S et al (2012) Designing the selenium and bladder cancer trial (SELEBLAT), a phase lll randomized chemoprevention study with selenium on recurrence of bladder cancer in Belgium. BMC Urol 12:8
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Yakubov, E., Buchfelder, M., Eyüpoglu, I.Y. et al. Selenium Action in Neuro-Oncology. Biol Trace Elem Res 161, 246–254 (2014). https://doi.org/10.1007/s12011-014-0111-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12011-014-0111-8