Oxidant stress induction and signalling in xenografted (human breast cancer-tissues) plus estradiol treated or N-ethyl-N-nitrosourea treated female rats via altered estrogen sulfotransferase (rSULT1E1) expressions and SOD1/catalase regulations
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N-ethyl-N-nitrosourea (ENU) is highly used in rodent models of tumerogenesis/carcinogenesis. Xenografting human-cancer tissues/cells with estradiol (E2) treatment is also used to generate rodent-models of gynaecological cancers. The altered metabolic-redox environment leading to establishment of pre-tumorigenesis condition and their mechanism are less studied. Here, female Wister rats were treated with these drugs at their pre-tumerogenic dosage (one group ENU single intra-peritoneal dose of 90 mg/kg b.w. and another group were implanted with human breast tumor (stage-IIIB) and fed with 2.5 mg of 17β-estradiol once in a week for 4 months). After 4 months, animals were sacrificed; their serum and liver tissues were tested. A brief comparison was made with a rat model (regarded as positive control) of toxicity induced by mutagenic environmental pollutant arsenic (0.6 ppm daily/4 weeks). The increase in serum alkaline phosphatase and glutamate-pyruvate transaminase suggests the possible organ toxicity is favoured by the increase in hepatic/systemic free radicals and oxidative stress in all drug application models. But the increase in the serum E2 level as noted in the ELISA data with impairment in the hepatic estrogen sulfotransferase (SULT1E1) protein expression (immuno-blot data) were noticed with interfered hepatic free-thiols only in ENU and xenograft-E2 group compared to arsenic group. It is also evident in the in vitro result from E2/GSH/NAC added hepatic slices with altered antioxidant regulations. Moreover, impairment in hepatic SOD1, catalase and glutathiole peroxidase activities (PAGEzymographic data), especially in the ENU-treated group makes them more vulnerable to the oxidative threat in creating pre-tumerogenic microenvironment. This is evident in the result of their higher DNA-damage and histological abnormalities. The Bioinformatics study revealed an important role of rSULT1E1 in the regulations of E2 metabolism. This study is important for the exploration of the pre-tumerogenic condition by ENU and E2 by impairing SULT1E1 expression and E2 regulations via oxidant-stress signalling. The finding may help to find new therapeutic-targets to treat gynaecological-cancers more effectively.
KeywordsN-ethyl-N-nitrosourea (ENU) Xenograft-estradiol Hepatocellular toxicity Oxidative stress Estrogen sulfotransferase
University Grants Commission, New Delhi provided JRF and SRF to AN who is a Ph.D. students working in the Post Graduate Department of Biochemistry, OIST.
Compliance with ethical standards
The author(s) declared no potential conflicts of interests with respect to the authorship and/or publication of this article.
- 12.Sanchez-Perez Y, Carrasco-Legleu C, Garcia-Cuellar C, Pérez-Carreon J, Hernández-Garcia S, Salcido-Neyoy M, Aleman-Lazarini L, Villa-Trevino S (2005) Oxidative stress in carcinogenesis. Correlation between lipid peroxidation and induction of preneoplastic lesions in rat hepatocarcinogenesis. Cancer Lett 217(1):25–32CrossRefGoogle Scholar
- 18.Nelson HD, Zakher B, Cantor A, Fu R, Griffin JO, Meara ES, Buist DS, Kerlikowske K, van Ravesteyn NT, Trentham-Dietz A, Mandelblatt JS, Miglioretti DL (2012) Risk factors for breast cancer for women aged 40 to 49 years: a systematic review and meta-analysis. Ann Intern Med 156(9), 635–648CrossRefGoogle Scholar
- 39.Acharyya N, Chattopadhyay S, Maiti S (2014) Chemoprevention against arsenic-induced mutagenic DNA breakage and apoptotic liver damage in rat via antioxidant and SOD1 upregulation by green tea (Camellia sinensis) which recovers broken DNA resulted from arsenic-H2O2 related in vitro oxidant stress. J Environ Sci Health C 32(4):338–361CrossRefGoogle Scholar
- 66.Guerra RC, Zuniga-Munoz A, Guarner Lans V, Diaz-Diaz E, Tena Betancourt CA, Pérez-Torres I (2014) Modulation of the activities of catalase, Cu-Zn, Mn superoxide dismutase, and glutathione peroxidase in adipocyte from ovariectomised female rats with metabolic syndrome. Int J Endocrinol. https://doi.org/10.1155/2014/175080 CrossRefPubMedPubMedCentralGoogle Scholar
- 77.Xu Y, Li Y, Li H, Pang Y, Zhao Y, Jiang R, Shen L, Zhou J, Wang X, Liu Q (2013) The accumulations of HIF-1α and HIF-2 α by JNK and ERK are involved in biphasic effects induced by different levels of arsenite in human bronchial epithelial cells. Toxicol Appl Pharmacol 266(2):187–197CrossRefGoogle Scholar
- 79.Manjula RT (2015) Depletion of glutathione during oxidative stress and efficacy of N-acetyl cysteine: an old drug with new approaches. Med Chem 5(1):037–039Google Scholar
- 81.Pullela PK, Alby K, Varela H, Sem DS (2006) Effect of thiol reductants on estrogen and estrogen receptor: revisiting previous assays. FASEB J 20:A74Google Scholar