title: Neuronal Nitric Oxide Synthase-Mediated Genotoxicity of 2-Methoxyestradiol in Hippocampal HT22 Cell Line.
abstract: 2-methoxyestradiol, metabolite of 17β-estradiol, is considered a potential anticancer agent, currently investigated in several clinical trials. This natural compound was found to be effective towards great number of cancers, including colon, breast, lung, and osteosarcoma and has been reported to be relatively non-toxic towards non-malignant cells. The aim of the study was to determine the potential neurotoxicity and genotoxicity of 2-methoxyestradiol at physiological and pharmacological relevant concentrations in hippocampal HT22 cell line. Herein, we determined influence of 2-methoxyestradiol on proliferation, inhibition of cell cycle, induction of apoptosis, and DNA damage in the HT22 cells. The study was performed using imaging cytometry and comet assay techniques. Herein, we demonstrated that 2-methoxyestradiol, at pharmacologically and also physiologically relevant concentrations, increases nuclear localization of neuronal nitric oxide synthase. It potentially results in DNA strand breaks and increases in genomic instability in hippocampal HT22 cell line. Thus, we are postulating that naturally occurring 2-methoxyestradiol may be considered a physiological modulator of neuron survival.
authors.affiliation: Department of Medical Chemistry, Medical University of Gdansk, Gdansk 80-211, Debinki 1 St, Poland. m.gorska@gumed.edu.pl.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Gorska
authors.affiliation: Department of Histology, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Michal A
authors.initials: MA
authors.lastname: Zmijewski
authors.affiliation: Department of Medical Chemistry, Medical University of Gdansk, Gdansk 80-211, Debinki 1 St, Poland.
authors.forename: Alicja
authors.initials: A
authors.lastname: Kuban-Jankowska
authors.affiliation: Department of Genetics, University of Rzeszow, Rzeszow, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Wnuk
authors.affiliation: Department of Genetics, University of Rzeszow, Rzeszow, Poland.
authors.forename: Iwona
authors.initials: I
authors.lastname: Rzeszutek
authors.affiliation: Department of Medical Chemistry, Medical University of Gdansk, Gdansk 80-211, Debinki 1 St, Poland.
authors.forename: Michal
authors.initials: M
authors.lastname: Wozniak
mesh_terms: D000077584:2-Methoxyestradiol; D000818:Animals; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000031:analogs & derivatives* / Q000633:toxicity; D006624:Hippocampus / Q000187:drug effects* / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D052248:Nitric Oxide Synthase Type I / Q000096:biosynthesis*; D050257:Tubulin Modulators / Q000633:toxicity
chemical_list: D050257:Tubulin Modulators; D004958:Estradiol; D000077584:2-Methoxyestradiol; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse
keywords: 2-methoxyestradiol; DNA damage; Hippocampus; Neuronal nitric oxide synthase; Reactive nitrogen species