Regulation of Mitochondrial Dynamics in Parkinson’s Disease—Is 2-Methoxyestradiol a Missing Piece?

Abstract

Mitochondria, as “power house of the cell”, are crucial players in cell pathophysiology. Beyond adenosine triphosphate (ATP) production, they take part in a generation of reactive oxygen species (ROS), regulation of cell signaling and cell death. Dysregulation of mitochondrial dynamics may lead to cancers and neurodegeneration; however, the fusion/fission cycle allows mitochondria to adapt to metabolic needs of the cell. There are multiple data suggesting that disturbed mitochondrial homeostasis can lead to Parkinson’s disease (PD) development. 2-methoxyestradiol (2-ME), metabolite of 17β-estradiol (E2) and potential anticancer agent, was demonstrated to inhibit cell growth of hippocampal HT22 cells by means of nitric oxide synthase (NOS) production and oxidative stress at both pharmacologically and also physiologically relevant concentrations. Moreover, 2-ME was suggested to inhibit mitochondrial biogenesis and to be a dynamic regulator. This review is a comprehensive discussion, from both scientific and clinical point of view, about the influence of 2-ME on mitochondria and its plausible role as a modulator of neuron survival.

2-Methoxyestradiol Damages DNA in Glioblastoma Cells by Regulating nNOS and Heat Shock Proteins

“…As molecular pathways of cancer development and cancerogenesis may overlap [ 51 , 52 ], the role of mitochondria in both processes is very interesting. We believe that 2-ME may be a missing link connecting these two pathways [ 25 ].…”

“…The induction of oxidative stress is a common factor leading to the development of both neurodegeneration and cancers [ 25 , 55 , 56 ], and one of the mechanisms of 2-ME is the generation of ROS and RNS in many cell lines [ 21 , 22 , 23 , 45 , 54 , 57 , 58 , 59 , 60 ]. The mode of action of many anticancer agents is the induction of oxidative stress.…”

“…This elevated NO level results in DNA strand breakage and, ultimately, cell death [ 21 , 22 ]. Moreover, pharmacological doses of 2-ME trigger apoptosis in mouse hippocampus HT22 cells, which poses the question of whether 2-ME may lead to neurodegenerative disorders and act as a hormone per se [ 23 , 24 , 25 ]. Furthermore, 2-ME was demonstrated to regulate mitochondrial biogenesis in 143b cells, particularly at physiologically relevant doses.…”

Induction of 2-hydroxycatecholestrogens O-methylation: A missing puzzle piece in diagnostics and treatment of lung cancer

“…In addition, in vitro studies have confirmed the antitumor potential of 2-ME in the treatment of breast, colon and lung cancer [ [18] , [19] , [20] , [21] , [22] , [23] , [24] , [25] , [26] , [27] , [28] , [29] ]. However, 2-ME did not enter Phase III clinical trials due to the low bioavailability upon oral administration.…”

“…Despite numerous studies, the detailed mode of anticancer action of 2-ME has not yet been fully elucidated. Previously, we have evidenced that from the mechanistic point of view 2-ME induces the expression and nuclear translocation of the neuronal nitric oxide synthase (nNOS) leading to local nitro-oxidative stress and DNA damage, which ultimately results in death of actively dividing cells or carcinogenesis [ 2 , 20 ]. We have further proved that 2-ME at both physiological and pharmacological concentrations induces mitochondrial fission and mitophagy resulting in BAX activation and osteosarcoma cell death [ 21 ].…”