Role of 2-methoxyestradiol, an Endogenous Estrogen Metabolite, in Health and Disease

Abstract

Estradiol (E2) is a steroid hormone whose physiological actions are mainly mediated by its interaction with intracellular estrogen receptors (ER) leading to modification on the mRNA and protein synthesis in its target cells. However, estrogens can also activate several intracellular signal transduction cascades by non-genomic mechanisms. Estrogens must be inactivated and removed from blood through its conversion to soluble compounds with an apparent low estrogenic activity and decreased affinity for ER. In this context, 2-methoxyestradiol (2ME2) is generated by a sequential hydroxylation of E2 via the enzyme cytochrome P450 isoform 1A1 to produce 2-hydroxyestradiol (2OHE2) followed by a conjugation reaction catalyzed by the enzyme Catechol-O-Methyltransferase generating 2ME2 from 2OHE2. Recent evidence indicates that physiological concentration of 2ME2 may regulate several biological processes while high concentrations of this metabolite may induce pathophysiological alterations in several tissues. In the last years, 2ME2 has also been described as a promising anticancer drug although its cellular and molecular mechanisms are still being disclosed. Herein, we will review the available literature concerning the role of 2ME2 in health and disease. We will focus on to describing the intracellular mechanisms by which 2ME2 exerts its effects on reproductive and non-reproductive tissues. The promising anticancer effects of 2ME2 and its synthetic derivatives will also be discussed. Finally, a group of 2ME2-target genes that could be used as biomarkers of 2ME2 under physiological or pathophysiological conditions will be reviewed.

FTIR and Raman Characterization of TiO2 Nanoparticles Coated with Polyethylene Glycol as Carrier for 2-Methoxyestradiol

“…2-Methoxyestradiol (2ME) is an endogenous estrogen metabolite with antiangiogenic and anticancer properties, although it has a poor solubility and low bioavailability for in vivo models [18]. With the purpose of maintaining its high anticancer efficacy, different reports are found in the literature about the incorporation of 2ME in different types of NPs, such as metallic NPs [19,20], polymerics NPs, and other nanostructured materials [21,22].…”

“…These studies confirm that NPs conjugated with 2ME are more effective from the point of view of cancer cell killing in comparison to 2ME alone. In this work, based on the suitable properties of TiO 2 and PEG, as well as the potential use of 2ME in the treatment of many cancer types [18], we formulated 2ME-loaded TiO 2 -PEG nanoparticles that protect the anticancer agent from early degradation. TiO 2 nanoparticles were modified with PEG to improve their suspension stability, and then 2ME was loaded on TiO 2 -PEG conjugate (TiO 2 -PEG-2ME).…”

Estradiol increases IP3 by a nongenomic mechanism in the smooth muscle cells from the rat oviduct

“…Alternatively, E 2 may be first metabolized into 2-methoxyestradiol to increase IP 3 production in the oviductal smooth muscle cells. In this context, various biological effects of E 2 including regulation of egg transport in the rat oviduct or modulation of the antihypertensive and neuroprotective effects of E 2 , requires previous conversion from E 2 to 2ME in its target organs (reviewed in Dubey & Jackson (2001) and Parada-Bustamante et al (2015)). …”

Red Maca (Lepidium meyenii) did not affect cell viability despite increased androgen receptor and prostate-specific antigen gene expression in the human prostate cancer cell line LNCaP

“…Therefore, it is probable that red Maca could be used as a source for active principles against a wide range of male pathologies. In LNCaP cells, we also explored whether red Maca extract is able to potentiate apoptotic activity induced by two anticancer drugs Taxol and 2-methoxyestradiol (2ME) (Kato et al, 2007;Parada-Bustamante et al, 2015). In LNCaP cells, we also explored whether red Maca extract is able to potentiate apoptotic activity induced by two anticancer drugs Taxol and 2-methoxyestradiol (2ME) (Kato et al, 2007;Parada-Bustamante et al, 2015).…”

“…Herein, the effect of red Maca aqueous extract on the growth of an androgen-sensitive human prostate cancer cell line LNCaP (Ferruelo et al, 2014;Xu, Yu, Qu, & Sui, 2013) was investigated. In LNCaP cells, we also explored whether red Maca extract is able to potentiate apoptotic activity induced by two anticancer drugs Taxol and 2-methoxyestradiol (2ME) (Kato et al, 2007;Parada-Bustamante et al, 2015). Finally, the effect of red Maca extract on the mRNA level for two androgen target genes, androgen receptor (Ar) and prostate-specific antigen (Psa) was investigated in LNCaP cells.…”