dc.contributor.author | Chen, Y. | en |
dc.contributor.author | Liu, X. | en |
dc.contributor.author | Pisha, E. | en |
dc.contributor.author | Constantinou, Andreas I. | en |
dc.contributor.author | Hua, Y. | en |
dc.contributor.author | Shen, L. | en |
dc.contributor.author | Van Breemen, R. B. | en |
dc.contributor.author | Elguindi, E. C. | en |
dc.contributor.author | Blond, S. Y. | en |
dc.contributor.author | Zhang, Fengwangdong | en |
dc.contributor.author | Bolton, J. L. | en |
dc.creator | Chen, Y. | en |
dc.creator | Liu, X. | en |
dc.creator | Pisha, E. | en |
dc.creator | Constantinou, Andreas I. | en |
dc.creator | Hua, Y. | en |
dc.creator | Shen, L. | en |
dc.creator | Van Breemen, R. B. | en |
dc.creator | Elguindi, E. C. | en |
dc.creator | Blond, S. Y. | en |
dc.creator | Zhang, Fengwangdong | en |
dc.creator | Bolton, J. L. | en |
dc.date.accessioned | 2019-11-04T12:50:19Z | |
dc.date.available | 2019-11-04T12:50:19Z | |
dc.date.issued | 2000 | |
dc.identifier.issn | 0893-228X | |
dc.identifier.uri | http://gnosis.library.ucy.ac.cy/handle/7/52976 | |
dc.description.abstract | Estrogen replacement therapy has been correlated with an increased risk of developing breast or endometrial cancer. 4-Hydroxyequilenin (4-OHEN) is a catechol metabolite of equilenin which is a minor component of the estrogen replacement formulation marketed under the name of Premarin (Wyeth-Ayerst). Previously, we showed that 4-OHEN autoxidizes to quinoids which can consume reducing equivalents and molecular oxygen, are potent cytotoxins, and cause a variety of damage to DNA, including formation of bulky stable adducts, apurinic sites, and oxidation of the phosphate-sugar backbone and purine/pyrimidine bases [Bolton, J. L., Pisha, E., Zhang, F., and Qiu, S. (1998) Chem. Res. Toxicol. 11, 1113-1127]. All of these deleterious effects could contribute to the cytotoxic and genotoxic effects of equilenin in vivo. In the study presented here, we examined the relative toxicity of 4-OHEN in estrogen receptor (ER) positive cells (MCF-7 and S30) compared to that in breast cancer cells without the estrogen receptor (MDA-MB-231). The data showed that 4-OHEN was 4-fold more toxic to MCF-7 cells (LC50 = 6.0 ± 0.2 μM) and 6-fold more toxic to S30 cells (LC50 = 4.0 ± 0.1 μM) than to MDA-MB-231 cells (LC50 = 24 ± 0.3 μM). Using the single-cell gel electrophoresis assay (comet assay) to assess DNA damage, we found that 4- OHEN causes concentration-dependent DNA single-strand cleavage in all three cell lines, and this effect could be enhanced by agents which catalyze redox cycling (NADH) or deplete cellular GSH (diethyl maleate). In addition, the ER+ cell lines (MCF-7 and S30) were considerably more sensitive to induction of DNA damage by 4-OHEN than the ER- cells (MDA-MB-231). 4-OHEN also caused a concentration-dependent increase in the amount of mutagenic lesion 8-oxo-dG in the S30 cells as determined by LC/MS-MS. Cell morphology assays showed that 4-OHEN induces apoptosis in these cell lines. As observed with the toxicity assay and the comet assay, the ER+ cells were more sensitive to induction of apoptosis by 4-OHEN than MDA-MB-231 cells. Finally, the endogenous catechol estrogen metabolite 4-hydroxyestrone (4-OHE) was considerably less effective at inducing DNA damage and apoptosis in breast cancer cell lines than 4-OHEN. Our data suggest that the cytotoxic effects of 4-OHEN may be related to its ability to induce DNA damage and apoptosis in hormone sensitive cells in vivo, and these effects may be potentiated by the estrogen receptor. | en |
dc.source | Chemical research in toxicology | en |
dc.source.uri | https://www.scopus.com/inward/record.uri?eid=2-s2.0-0034035343&doi=10.1021%2ftx990186j&partnerID=40&md5=968211ff8b2c8da0aec2ff8a38a153ff | |
dc.subject | article | en |
dc.subject | Female | en |
dc.subject | Humans | en |
dc.subject | breast cancer | en |
dc.subject | Breast Neoplasms | en |
dc.subject | cancer risk | en |
dc.subject | carcinogenesis | en |
dc.subject | cancer cell | en |
dc.subject | apoptosis | en |
dc.subject | DNA | en |
dc.subject | conjugated estrogen | en |
dc.subject | endometrium cancer | en |
dc.subject | estrogen | en |
dc.subject | Epithelial Cells | en |
dc.subject | cell strain MCF 7 | en |
dc.subject | concentration response | en |
dc.subject | Cell Survival | en |
dc.subject | DNA damage | en |
dc.subject | comet assay | en |
dc.subject | Tumor Cells, Cultured | en |
dc.subject | Dose-Response Relationship, Drug | en |
dc.subject | autooxidation | en |
dc.subject | cytotoxicity | en |
dc.subject | DNA Fragmentation | en |
dc.subject | DNA, Neoplasm | en |
dc.subject | Equilenin | en |
dc.subject | Estradiol Congeners | en |
dc.subject | Estrogens, Catechol | en |
dc.subject | genotoxicity | en |
dc.subject | Hydroxyestrones | en |
dc.subject | metabolite | en |
dc.title | A metabolite of equine estrogens, 4-hydroxyequilenin, induces DNA damage and apoptosis in breast cancer cell lines | en |
dc.type | info:eu-repo/semantics/article | |
dc.identifier.doi | 10.1021/tx990186j | |
dc.description.volume | 13 | |
dc.description.startingpage | 342 | |
dc.description.endingpage | 350 | |
dc.author.faculty | Σχολή Θετικών και Εφαρμοσμένων Επιστημών / Faculty of Pure and Applied Sciences | |
dc.author.department | Τμήμα Βιολογικών Επιστημών / Department of Biological Sciences | |
dc.type.uhtype | Article | en |
dc.description.notes | <p>Tradenames: premarin, Wyeth Ayerst | en |
dc.description.notes | Manufacturers: Sigma, United States | en |
dc.description.notes | Wyeth Ayerst | en |
dc.description.notes | Cited By :77</p> | en |
dc.source.abbreviation | Chem.Res.Toxicol. | en |
dc.contributor.orcid | Constantinou, Andreas I. [0000-0003-0365-1821] | |
dc.gnosis.orcid | 0000-0003-0365-1821 | |