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Current Cancer Drug Targets


ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Research Article

Gender Differences in the Antioxidant Response to Oxidative Stress in Experimental Brain Tumors

Author(s): María Jesús Ramírez-Expósito, María Dolores Mayas, María Pilar Carrera-González and José Manuel Martínez-Martos*

Volume 19 , Issue 8 , 2019

Page: [641 - 654] Pages: 14

DOI: 10.2174/1568009618666181018162549

Price: $65


Background: Brain tumorigenesis is related to oxidative stress and a decreased response of antioxidant defense systems. As it is well known that gender differences exist in the incidence and survival rates of brain tumors, it is important to recognize and understand the ways in which their biology can differ.

Objective: To analyze gender differences in redox status in animals with chemically-induced brain tumors.

Methods: Oxidative stress parameters, non-enzyme and enzyme antioxidant defense systems are assayed in animals with brain tumors induced by transplacental N-ethyl-N-nitrosourea (ENU) administration. Both tissue and plasma were analyzed to know if key changes in redox imbalance involved in brain tumor development were reflected systemically and could be used as biomarkers of the disease.

Results: Several oxidative stress parameters were modified in tumor tissue of male and female animals, changes that were not reflected at plasma level. Regarding antioxidant defense system, only glutathione (GSH) levels were decreased in both brain tumor tissue and plasma. Superoxide dismutase (SOD) and catalase (CAT) activities were decreased in brain tumor tissue of male and female animals, but plasma levels were only altered in male animals. However, different protein and mRNA expression patterns were found for both enzymes. On the contrary, glutathione peroxidase (GPx) activity showed increased levels in brain tumor tissue without gender differences, being protein and gene expression also increased in both males and female animals. However, these changes in GPx were not reflected at plasma level.

Conclusion: We conclude that brain tumorigenesis was related to oxidative stress and changes in brain enzyme and non-enzyme antioxidant defense systems with gender differences, whereas plasma did not reflect the main redox changes that occur at the brain level.

Keywords: Lipid peroxidation, Total antioxidant capacity, Glutathione, Superoxide dismutase, Catalase, Glutathione peroxidase.

Graphical Abstract
Davis, F.G.; Malmer, B.S.; Aldape, K.; Barnholtz-Sloan, J.S.; Bondy, M.L.; Brannstrom, T.; Bruner, J.M.; Burger, P.C.; Collins, V.P.; Inskip, P.D. Issues of diagnostic review in brain tumor studies: From the brain tumor epidemiology consortium. Cancer Epidemiol. Biomarkers Prev., 2008, 17, 484-489.
Rinaldi, M.; Caffo, M.; Minutoli, L.; Marini, H.; Abbritti, R.V.; Squadrito, F.; Trichilo, V.; Valenti, A.; Barresi, V.; Altavilla, D. Ros and brain gliomas: An overview of potential and innovative therapeutic strategies. Int. J. Mol. Sci., 2016, 17.
Illan-Cabeza, N.A.; Garcia-Garcia, A.R.; Martinez-Martos, J.M.; Ramirez-Exposito, M.J.; Pena-Ruiz, T.; Moreno-Carretero, M.N. A potential antitumor agent, (6-amino-1-methyl-5-nitrosouracilato-n3)-triphenylphosphine-gold(i): Structural studies and in vivo biological effects against experimental glioma. Eur. J. Med. Chem., 2013, 64, 260-272.
Martinez-Martos, J.M.; Mayas, M.D.; Carrera, P.; de Saavedra, J.M.A.; Sanchez-Agesta, R.; Arrazola, M.; Ramirez-Exposito, M.J. Phenolic compounds oleuropein and hydroxytyrosol exert differential effects on glioma development via antioxidant defense systems. J. Funct. Foods, 2014, 11, 221-234.
Ramirez-Exposito, M.J.; Martinez-Martos, J.M. Anti-inflammatory and antitumor effects of hydroxytyrosol but not oleuropein on experimental glioma in vivo. A putative role for the renin-angiotensin system. Biomedicines, 2018, 6.
Acharya, A.; Das, I.; Chandhok, D.; Saha, T. Redox regulation in cancer: A double-edged sword with therapeutic potential. Oxid. Med. Cell. Longev., 2010, 3, 23-34.
Herrera, A.C.; Panis, C.; Victorino, V.J.; Campos, F.C.; Colado-Simao, A.N.; Cecchini, A.L.; Cecchini, R. Molecular subtype is determinant on inflammatory status and immunological profile from invasive breast cancer patients. Cancer Immunol. Immunother., 2012, 61, 2193-2201.
Papacocea, T.; Papacocea, R.; Badarau, A.; Ion, A.D.; Buraga, I.; Gaman, L.; Papacocea, A. Oxidative stress and antioxidants in brain tumors. Therapeutics, Pharmacol. Clin. Toxicol. , 2011, XV, 234-239.
Rajaraman, P.; Hutchinson, A.; Rothman, N.; Black, P.M.; Fine, H.A.; Loeffler, J.S.; Selker, R.G.; Shapiro, W.R.; Linet, M.S.; Inskip, P.D. Oxidative response gene polymorphisms and risk of adult brain tumors. Neuro-oncol., 2008, 10, 709-715.
Kryston, T.B.; Georgiev, A.B.; Pissis, P.; Georgakilas, A.G. Role of oxidative stress and DNA damage in human carcinogenesis. Mutat. Res., 2011, 711, 193-201.
Pelicano, H.; Feng, L.; Zhou, Y.; Carew, J.S.; Hileman, E.O.; Plunkett, W.; Keating, M.J.; Huang, P. Inhibition of mitochondrial respiration: A novel strategy to enhance drug-induced apoptosis in human leukemia cells by a reactive oxygen species-mediated mechanism. J. Biol. Chem., 2003, 278, 37832-37839.
de Miguel, M.; Cordero, M.D. Oxidative therapy against cancer.Oxidative estress and diseases; Lushchak, V., Ed. In Tech: Croatia,. , 2012, pp. 497-520.
Liang, L.P.; Patel, M. Seizure-induced changes in mitochondrial redox status. Free Radic. Biol. Med., 2006, 40, 316-322.
Ramirez-Exposito, M.J.; Martinez-Martos, J.M. The delicate equilibrium between oxidants and antioxidants in brain glioma. Curr. Neuropharmacol., 2018.
Watson, J. Oxidants, antioxidants and the current incurability of metastatic cancers. Open Biol., 2013, 3, 120144.
Druckrey, H.; Ivankovic, S.; Preussmann, R. Teratogenic and carcinogenic effects in the offspring after single injection of ethylnitrosourea to pregnant rats. Nature, 1966, 210, 1378-1379.
Koestner, A.; Swenberg, J.A.; Wechsler, W. Transplacental production with ethylnitrosourea of neoplasms of the nervous system in sprague-dawley rats. Am. J. Pathol., 1971, 63, 37-56.
Schiffer, D.; Giordana, M.T.; Pezzotta, S.; Lechner, C.; Paoletti, P. Cerebral tumors induced by transplacental enu: Study of the different tumoral stages, particularly of early proliferations. Acta Neuropathol., 1978, 41, 27-31.
Zook, B.C.; Simmens, S.J.; Jones, R.V. Evaluation of enu-induced gliomas in rats: Nomenclature, immunochemistry, and malignancy. Toxicol. Pathol., 2000, 28, 193-201.
Mahlke, M.A.; Cortez, L.A.; Ortiz, M.A.; Rodriguez, M.; Uchida, K.; Shigenaga, M.K.; Lee, S.; Zhang, Y.; Tominaga, K.; Hubbard, G.B. The anti-tumor effects of calorie restriction are correlated with reduced oxidative stress in enu-induced gliomas. Pathobiol. Aging Age Relat. Dis., 2011, 1.
Kokkinakis, D.M.; Rushing, E.J.; Shareef, M.M.; Ahmed, M.M.; Yang, S.; Singha, U.K.; Luo, J. Physiology and gene expression characteristics of carcinogen-initiated and tumor-transformed glial progenitor cells derived from the cns of methylnitrosourea (mnu)-treated sprague-dawley rats. J. Neuropathol. Exp. Neurol., 2004, 63, 1182-1199.
Bulnes, S.; Lafuente, J.V. Vegf immunopositivity related to malignancy degree, proliferative activity and angiogenesis in enu-induced gliomas. J. Mol. Neurosci., 2007, 33, 163-172.
Bartsch, H.; Hietanen, E.; Malaveille, C. Carcinogenic nitrosamines: Free radical aspects of their action. Free Radic. Biol. Med., 1989, 7, 637-644.
Hietanen, E.; Bartsch, H. Gastrointestinal cancers: Role of nitrosamines and free radicals. Eur. J. Cancer Prev., 1992, 1(Suppl. 3), 51-54.
Paxinos, G.; Watson, C. The rat brain in stereotaxic coordinates, 7th edition. ed.; Elsevier Academic Press: Amsterdam ; Boston, 2013, p. 472 pages.
Martinez-Martos, J.M.; Ramirez-Exposito, M.J.; Mayas-Torres, M.D.; Garcia-Lopez, M.J.; Ramirez-Sanchez, M. Utility of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (mtt) assay to measure mitochondrial activity in k+- and atp-stimulated rodent cortex synaptosomes. Neurosci. Res. Commun., 2000, 27, 103-107.
Ramirez-Exposito, M.J.; Urbano-Polo, N.; Duenas, B.; Navarro-Cecilia, J.; Ramirez-Tortosa, C.; Martin-Salvago, M.D.; Martinez-Martos, J.M. Redox status in the sentinel lymph node of women with breast cancer. Ups. J. Med. Sci., 2017, 122, 207-216.
Ramirez-Exposito, M.J.; Sanchez-Lopez, E.; Cueto-Urena, C.; Duenas, B.; Carrera-Gonzalez, P.; Navarro-Cecilia, J.; Mayas, M.D.; Arias de Saavedra, J.M.; Sanchez-Agesta, R.; Martinez-Martos, J.M. Circulating oxidative stress parameters in pre- and post-menopausal healthy women and in women suffering from breast cancer treated or not with neoadjuvant chemotherapy. Exp. Gerontol., 2014, 58, 34-42.
Puertas, M.C.; Martinez-Martos, J.M.; Cobo, M.P.; Carrera, M.P.; Mayas, M.D.; Ramirez-Exposito, M.J. Plasma oxidative stress parameters in men and women with early stage alzheimer type dementia. Exp. Gerontol., 2012, 47, 625-630.
Visioli, F.; Bellomo, G.; Galli, C. Free radical-scavenging properties of olive oil polyphenols. Biochem. Biophys. Res. Commun., 1998, 247, 60-64.
Ikeno, Y.; Shimokawa, I.; Higami, Y.; Ikeda, T. Gfap expression in the subcutaneous tumors of immature glial cell line (hits glioma) derived from enu-induced rat glioma. J. Neurooncol., 1993, 17, 191-204.
Kish, P.E.; Blaivas, M.; Strawderman, M.; Muraszko, K.M.; Ross, D.A.; Ross, B.D.; McMahon, G. Magnetic resonance imaging of ethyl-nitrosourea-induced rat gliomas: A model for experimental therapeutics of low-grade gliomas. J. Neurooncol., 2001, 53, 243-257.
Slikker, W., III; Mei, N.; Chen, T. N-ethyl-n-nitrosourea (enu) increased brain mutations in prenatal and neonatal mice but not in the adults. Toxicol. Sci., 2004, 81, 112-120.
Federico, A.; Morgillo, F.; Tuccillo, C.; Ciardiello, F.; Loguercio, C. Chronic inflammation and oxidative stress in human carcinogenesis. Int. J. Cancer, 2007, 121, 2381-2386.
Zhang, Y.; Chen, S.Y.; Hsu, T.; Santella, R.M. Immunohistochemical detection of malondialdehyde-DNA adducts in human oral mucosa cells. Carcinogenesis, 2002, 23, 207-211.
Zengin, E.; Atukeren, P.; Kokoglu, E.; Gumustas, M.K.; Zengin, U. Alterations in lipid peroxidation and antioxidant status in different types of intracranial tumors within their relative peritumoral tissues. Clin. Neurol. Neurosurg., 2009, 111, 345-351.
Cirak, B.; Inci, S.; Palaoglu, S.; Bertan, V. Lipid peroxidation in cerebral tumors. Clin. Chim. Acta, 2003, 327, 103-107.
Guo, J.; Prokai, L. To tag or not to tag: A comparative evaluation of immunoaffinity-labeling and tandem mass spectrometry for the identification and localization of posttranslational protein carbonylation by 4-hydroxy-2-nonenal, an end-product of lipid peroxidation. J. Proteomics, 2011, 74, 2360-2369.
Amstad, P.; Moret, R.; Cerutti, P. Glutathione peroxidase compensates for the hypersensitivity of cu,zn-superoxide dismutase overproducers to oxidant stress. J. Biol. Chem., 1994, 269, 1606-1609.
Sun, Y.; St Clair, D.K.; Xu, Y.; Crooks, P.A.; St Clair, W.H. A nadph oxidase-dependent redox signaling pathway mediates the selective radiosensitization effect of parthenolide in prostate cancer cells. Cancer Res., 2010, 70, 2880-2890.
Shi, J.; Sun, B.; Shi, W.; Zuo, H.; Cui, D.; Ni, L.; Chen, J. Decreasing gsh and increasing ros in chemosensitivity gliomas with idh1 mutation. Tumour Biol., 2015, 36, 655-662.
Navarro, J.; Obrador, E.; Carretero, J.; Petschen, I.; Avino, J.; Perez, P.; Estrela, J.M. Changes in glutathione status and the antioxidant system in blood and in cancer cells associate with tumour growth in vivo. Free Radic. Biol. Med., 1999, 26, 410-418.
Gilca, M.; Stoian, I.; Lixandru, D.; Gaman, L.; Virgolici, B.; Atanasiu, V. Protection of erythrocyte membrane against oxidative damage by geriforte in healthy human subjects. Rom. J. Intern. Med., 2009, 47, 289-295.
Che, M.; Wang, R.; Li, X.; Wang, H.Y.; Zheng, X.F.S. Expanding roles of superoxide dismutases in cell regulation and cancer. Drug Discov. Today, 2016, 21, 143-149.
Popov, B.; Gadjeva, V.; Valkanov, P.; Popova, S.; Tolekova, A. Lipid peroxidation, superoxide dismutase and catalase activities in brain tumor tissues. Arch. Physiol. Biochem., 2003, 111, 455-459.
Aggarwal, S.; Subberwal, M.; Kumar, S.; Sharma, M. Brain tumor and role of beta-carotene, a-tocopherol, superoxide dismutase and glutathione peroxidase. J. Cancer Res. Ther., 2006, 2, 24-27.
Del Maestro, R.F.; McDonald, W.; Anderson, R. In Oxy radicals and their scavenger systems; Greenwald, R.; Cohen, G., Eds.; Elsevier: New York, 1983, pp. 28-35.
Crapo, J.D.; Oury, T.; Rabouille, C.; Slot, J.W.; Chang, L.Y. Copperzinc superoxide dismutase is primarily a cytosolic protein in human cells. Proc. Natl. Acad. Sci. USA, 1992, 89, 10405-10409.
MacMillan-Crow, L.A.; Thompson, J.A. Tyrosine modifications and inactivation of active site manganese superoxide dismutase mutant (y34f) by peroxynitrite. Arch. Biochem. Biophys., 1999, 366, 82-88.
Kienhofer, J.; Haussler, D.J.; Ruckelshausen, F.; Muessig, E.; Weber, K.; Pimentel, D.; Ullrich, V.; Burkle, A.; Bachschmid, M.M. Association of mitochondrial antioxidant enzymes with mitochondrial DNA as integral nucleoid constituents. FASEB J., 2009, 23, 2034-2044.
Lund, D.D.; Chu, Y.; Miller, J.D.; Heistad, D.D. Protective effect of extracellular superoxide dismutase on endothelial function during aging. Am. J. Physiol. Heart Circ. Physiol., 2009, 296, H1920-H1925.
Oberley, T.D.; Oberley, L.W. Antioxidant enzyme levels in cancer. Histol. Histopathol., 1997, 12, 525-535.
Dhar, S.K.; St Clair, D.K. Manganese superoxide dismutase regulation and cancer. Free Radic. Biol. Med., 2012, 52, 2209-2222.
Hempel, N.; Carrico, P.M.; Melendez, J.A. Manganese superoxide dismutase (sod2) and redox-control of signaling events that drive metastasis. Anticancer. Agents Med. Chem., 2011, 11, 191-201.
Papa, L.; Hahn, M.; Marsh, E.L.; Evans, B.S.; Germain, D. Sod2 to sod1 switch in breast cancer. J. Biol. Chem., 2014, 289, 5412-5416.
Papa, L.; Manfredi, G.; Germain, D. Sod1, an unexpected novel target for cancer therapy. Genes Cancer, 2014, 5, 15-21.
Huang, P.; Feng, L.; Oldham, E.A.; Keating, M.J.; Plunkett, W. Superoxide dismutase as a target for the selective killing of cancer cells. Nature, 2000, 407, 390-395.
Yilmaz, N.; Dulger, H.; Kiymaz, N.; Yilmaz, C.; Bayram, I.; Ragip, B.; Oger, M. Lipid peroxidation in patients with brain tumor. Int. J. Neurosci., 2006, 116, 937-943.
Gauchez, A.S.; Riondel, J.; Jacrot, M.; Calop, J.; Favier, A. Antioxidant status and lipid peroxidation in athymic mice xenografted with two types of human tumors. Biol. Trace Elem. Res., 1995, 47, 103-109.
Rao, G.M.; Rao, A.V.; Raja, A.; Rao, S.; Rao, A. Role of antioxidant enzymes in brain tumours. Clin. Chim. Acta, 2000, 296, 203-212.
Chu, F.F. The human glutathione peroxidase genes gpx2, gpx3, and gpx4 map to chromosomes 14, 5, and 19, respectively. Cytogenet. Cell Genet., 1994, 66, 96-98.
Esworthy, R.S.; Doan, K.; Doroshow, J.H.; Chu, F.F. Cloning and sequencing of the cdna encoding a human testis phospholipid hydroperoxide glutathione peroxidase. Gene, 1994, 144, 317-318.
Hall, L.; Williams, K.; Perry, A.C.; Frayne, J.; Jury, J.A. The majority of human glutathione peroxidase type 5 (gpx5) transcripts are incorrectly spliced: Implications for the role of gpx5 in the male reproductive tract. Biochem. J., 1998, 333(Pt 1), 5-9.
Freeman, B.A.; Crapo, J.D. Biology of disease: Free radicals and tissue injury. Lab. Invest., 1982, 47, 412-426.
Meister, A. Glutathione, ascorbate, and cellular protection. Cancer Res., 1994, 54, 1969s-1975s.
Baliga, M.S.; Diwadkar-Navsariwala, V.; Koh, T.; Fayad, R.; Fantuzzi, G.; Diamond, A.M. Selenoprotein deficiency enhances radiation-induced micronuclei formation. Mol. Nutr. Food Res., 2008, 52, 1300-1304.
Lei, X.G.; Cheng, W.H.; McClung, J.P. Metabolic regulation and function of glutathione peroxidase-1. Annu. Rev. Nutr., 2007, 27, 41-61.
Zhuo, P.; Diamond, A.M. Molecular mechanisms by which selenoproteins affect cancer risk and progression. Biochim. Biophys. Acta, 2009, 1790, 1546-1554.
Yagublu, V.; Arthur, J.R.; Babayeva, S.N.; Nicol, F.; Post, S.; Keese, M. Expression of selenium-containing proteins in human colon carcinoma tissue. Anticancer Res., 2011, 31, 2693-2698.
Chandra, J.; Samali, A.; Orrenius, S. Triggering and modulation of apoptosis by oxidative stress. Free Radic. Biol. Med., 2000, 29, 323-333.
Amstad, P.; Peskin, A.; Shah, G.; Mirault, M.E.; Moret, R.; Zbinden, I.; Cerutti, P. The balance between cu, zn-superoxide dismutase and catalase affects the sensitivity of mouse epidermal cells to oxidative stress. Biochemistry, 1991, 30, 9305-9313.

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