Two faces of the estrogen metabolite 2-methoxyestradiol in vitro and in vivo

Abstract

2-Methoxyestradiol (2-ME), an endogenous metabolite of 17β-estradiol (E2), interacts with estrogen receptors (ERs) and microtubules, however, 2-ME has a low affinity for ERs. Furthermore, 2‑ME has been identified as a potential novel antitumor agent, combining its anti‑proliferative effects on a variety of tumor cell types with its anti‑angiogenic action. Therefore, 2‑ME is of interest due to its potential anticancer therapeutic effects. In the current study, the estrogenic effect of 2‑ME on CaBP‑9k, ERα, and progesterone receptor (PR) mRNA levels in the absence and presence of E2 and progesterone (P4) in in vivo and in vitro models was examined. In GH3 cells, the mRNA level of CaBP‑9k was induced in the E2 treatment group (concentration, 10‑9 M), and the expression of CaBP‑9k was also upregulated in the 2‑ME‑treated group (concentration, 10‑7 M). Uterine lactoferrin (Ltf) mRNA expression was also increased in the 2‑ME group [dose, 40 mg/kg body weight (BW)], which was comparable to the response with E2 (dose, 40 µg/kg BW) observed in mice. As inhibitors of ER and PR activity, ICI 182,780 and mifepristone (RU486) were observed to reverse the E2 or 2‑ME mediated increase of CaBP‑9k and Ltf mRNA expression. In addition, it was found that 2‑ME significantly decreased the levels of ERα and increased PR transcripts. Consistent with the in vitro results, the mRNA levels revealed decreased ERα and increased PR in in vivo treatment of E2 and 2‑ME. These findings demonstrate that the expression of estrogenic markers, CaBP‑9k and Ltf, is regulated by 2‑ME in in vitro and in vivo models, therefore, estrogenic activi-ties of 2-ME may be increased in females during the estrous cycle via the ER and/or PR-mediated signaling pathway.

Clinical Significance of Low 2‐Methoxyestradiol Levels in Serum and Tissue of Recurrent Juvenile‐Onset Laryngeal Papillomatosis

“…Our results show that tissue 2-ME-2 concentration is significantly lower in patients of the recurrent group than in ones of the nonrecurrence group even though the difference in serum 2-ME-2 concentration between the groups is insignificant. 13,15,16 This inhibitory effect can be biphasic, as reported by Lee et al and Mabjeesh et al At a low dosage, 2-ME-2 acts as a stimulant of tumor growth, whereas at a high dosage it exhibits the reverse effect on MCF-7 human breast tumor cells. [15][16][17] Therefore, in our future studies, we should explore further to determine the exact effect of 2-ME-2 at various concentrations.…”

“…13,15,16 This inhibitory effect can be biphasic, as reported by Lee et al and Mabjeesh et al At a low dosage, 2-ME-2 acts as a stimulant of tumor growth, whereas at a high dosage it exhibits the reverse effect on MCF-7 human breast tumor cells. [15][16][17] Therefore, in our future studies, we should explore further to determine the exact effect of 2-ME-2 at various concentrations. Also, how 2-ME-2 works needs to be considered carefully case by case for patients of other racial backgrounds.…”

Effect of 2-methoxyestradiol on SK-LMS-1 uterine leiomyosarcoma cells

“…However, in a previous study, treatment with 2-ME at concentrations lower than anticancer therapeutic concentrations, revealed an estrogenic effect based on uterine weight gain and increasing expression levels of estrogen biomarkers in in vitro and in vivo models (45). Therefore, it may affect the estrogen and/or progesterone receptor, and retaining 2-ME in the body may be affect endocrine homeostasis and its function.…”

Neuroprotective effects of estrogen in CNS injuries: insights from animal models

“…2ME2 significantly increases progesterone receptor transcripts both in vitro and in vivo, suggesting that the estrogenic activities of 2ME2 may be mediated via the ER and/or progesterone receptor signaling pathway. 84 Premarin is also known to possess profound neuroprotective effects. Its neuroprotective effects have been useful for saving neurons from irreversible injury in the CNS.…”