title: Neuronal nitric oxide synthase induction in the antitumorigenic and neurotoxic effects of 2-methoxyestradiol.
abstract: OBJECTIVE
  2-Methoxyestradiol, one of the natural 17β-estradiol derivatives, is a novel, potent anticancer agent currently being evaluated in advanced phases of clinical trials. The main goal of the study was to investigate the anticancer activity of 2-methoxy-estradiol towards osteosarcoma cells and its possible neurodegenerative effects. We used an experimental model of neurotoxicity and anticancer activity of the physiological agent, 2-methoxyestradiol. Thus, we used highly metastatic osteosarcoma 143B and mouse immortalized hippocampal HT22 cell lines. The cells were treated with pharmacological (1 μM, 10 μM) concentrations of 2-methoxyestradiol.
  
  
  METHODS
  Neuronal nitric oxide synthase and 3-nitrotyrosine protein levels were determined by western blotting. Cell viability and induction of cell death were measured by MTT and PI/Annexin V staining and a DNA fragmentation ELISA kit, respectively. Intracellular levels of nitric oxide were determined by flow cytometry.
  
  
  RESULTS
  Here we demonstrated that the signaling pathways of neurodegenerative diseases and cancer may overlap. We presented evidence that 2-methoxyestradiol, in contrast to 17β-estradiol, specifically affects neuronal nitric oxide synthase and augments 3-nitrotyrosine level leading to osteosarcoma and immortalized hippocampal cell death.
  
  
  CONCLUSIONS
  We report the dual facets of 2-methoxyestradiol, that causes cancer cell death, but on the other hand may play a key role as a neurotoxin.
authors.affiliation: Department of Medical Chemistry, Medical University of Gdansk, Gdansk 80-211, Poland. m.gorska@gumed.edu.pl.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Gorska
authors.affiliation: Department of Medical Chemistry, Medical University of Gdansk, Gdansk 80-211, Poland.
authors.forename: Alicja
authors.initials: A
authors.lastname: Kuban-Jankowska
authors.affiliation: Department of Histology, Medical University of Gdansk, Gdansk 80-211, Poland. mzmijewski@gumed.edu.pl.
authors.forename: Michal Aleksander
authors.initials: MA
authors.lastname: Zmijewski
authors.affiliation: Department of Medical Chemistry, Medical University of Gdansk, Gdansk 80-211, Poland. monika.gorzynik@urz.pl.
authors.forename: Monika
authors.initials: M
authors.lastname: Gorzynik
authors.affiliation: Department of Medical Chemistry, Medical University of Gdansk, Gdansk 80-211, Poland. mszkatula@gumed.edu.pl.
authors.forename: Michal
authors.initials: M
authors.lastname: Szkatula
authors.affiliation: Department of Medical Chemistry, Medical University of Gdansk, Gdansk 80-211, Poland. mwozniak@gumed.edu.pl.
authors.forename: Michal
authors.initials: M
authors.lastname: Wozniak
mesh_terms: D000077584:2-Methoxyestradiol; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004790:Enzyme Induction / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D052248:Nitric Oxide Synthase Type I / Q000096:biosynthesis / Q000235:genetics*; D012516:Osteosarcoma / Q000188:drug therapy; D018384:Oxidative Stress
chemical_list: D000970:Antineoplastic Agents; D004958:Estradiol; D000077584:2-Methoxyestradiol; D052248:Nitric Oxide Synthase Type I