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Molecules 2014, 19(9), 13267-13281; https://doi.org/10.3390/molecules190913267

Neuronal Nitric Oxide Synthase Induction in the Antitumorigenic and Neurotoxic Effects of 2-Methoxyestradiol

1
Department of Medical Chemistry, Medical University of Gdansk, Gdansk 80-211, Poland
2
Department of Histology, Medical University of Gdansk, Gdansk 80-211, Poland
*
Author to whom correspondence should be addressed.
Received: 3 June 2014 / Revised: 8 August 2014 / Accepted: 18 August 2014 / Published: 28 August 2014
(This article belongs to the Section Medicinal Chemistry)
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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. Experimental: 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. View Full-Text
Keywords: osteosarcoma; hippocampus; cancer; neurodegenerative disease; 2-methoxyestradiol; neuronal nitric oxide synthase; 3-nitrotyrosine osteosarcoma; hippocampus; cancer; neurodegenerative disease; 2-methoxyestradiol; neuronal nitric oxide synthase; 3-nitrotyrosine
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This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).
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Gorska, M.; Kuban-Jankowska, A.; Zmijewski, M.A.; Gorzynik, M.; Szkatula, M.; Wozniak, M. Neuronal Nitric Oxide Synthase Induction in the Antitumorigenic and Neurotoxic Effects of 2-Methoxyestradiol. Molecules 2014, 19, 13267-13281.

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