The excretion of five different 2-hydroxyoestrogen monomethyl ethers in human pregnancy urine

Gelbke, H; Knüppen, R.

doi:10.1016/0022-4731(76)90112-6

Cited by 44 publications

(27 citation statements)

References 31 publications

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“…Figure 2 indicated that treatment of CEM cells with 2-ME2 for 24 h resulted in a significantly higher number of cells in the G 2 /M phase at all tested concentrations, 1 mM (45.09%), 2 mM (73.41%), and 4 mM (83.12%), compared with controls (6.20%). The dose-dependent effect of 2-ME2 on G 2 /M phase arrest in CEM cells was largely at the expense of the G 1 and S phase compared with untreated CEM cells.…”

Section: Cell-cycle Distribution Of Cem Cells Following 2-me2 Treatmentmentioning

confidence: 99%

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2-Methoxyestradiol blocks cell-cycle progression at the G<sub>2</sub>/M phase and induces apoptosis in human acute T lymphoblastic leukemia CEM cells

Zhang¹,

Huang²,

Xu³

et al. 2010

ABBS

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2-Methoxyestradiol (2-ME2) is an endogenous metabolite of 17b-estradiol (E2) with estrogen receptor-independent anti-cancer activity. The current study sought to determine the mechanism of anti-cancer activity of 2-ME2 in human acute T lymphoblastic leukemia CEM cells. Results showed that 2-ME2 markedly suppressed proliferation of CEM cells in a time-and dose-dependent manner. 2-ME2-treated CEM cells underwent typical apoptotic changes. Exposure to 2-ME2 led to G 2 /M phase cell-cycle arrest, which preceded apoptosis characterized by the appearance of a sub-G 1 cell population. In addition, cytosolic cytochrome c release, increased procaspase-9 and -3 expressions, poly(ADP-ribose) polymerase (PARP) cleavage, and induced expression of caspase-8 were detected, suggesting that both the intrinsic apoptotic pathway and extrinsic apoptotic pathway were involved in 2-ME2-induced apoptosis. Moreover, the expression level of p21 protein was upregulated, whereas Bcl-2 and dysfunctional p53 protein were downregulated, which also contributed to 2-ME2-induced apoptosis. Our findings revealed that 2-ME2 might be a potent natural candidate for chemotherapeutic treatment of human acute T lymphoblastic leukemia when the precise effects of 2-ME2 were investigated further in other T leukemia cell lines and in primary T-cell leukemias.

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Section: Cell-cycle Distribution Of Cem Cells Following 2-me2 Treatmentmentioning

confidence: 99%

“…It is produced by sequential 2-hydroxylation and O-methylation of the parent compound and is present in human blood and urine at picomolar to nanomolar levels [2][3][4][5]. The potential role of 2-ME2 as an anti-cancer agent has been intensively investigated.…”

Section: Introductionmentioning

confidence: 99%

2-Methoxyestradiol blocks cell-cycle progression at the G<sub>2</sub>/M phase and induces apoptosis in human acute T lymphoblastic leukemia CEM cells

Zhang¹,

Huang²,

Xu³

et al. 2010

ABBS

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“…2-ME is produced by sequential 2-hydroxylation and O-methylation. 1 This metabolic modification causes a loss of its ability to bind the estrogen receptor. 2-ME has been shown to have potent tumorinhibiting effects in a number of cancer cell lines in vitro and in tumor xenograft models in vivo.…”

Section: Introductionmentioning

confidence: 99%

Free radical stress in chronic lymphocytic leukemia cells and its role in cellular sensitivity to ROS-generating anticancer agents

Zhou

Hileman

Plunkett

et al. 2003

Blood

290

199

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2-Methoxyestradiol (2-ME), a new anticancer agent currently in clinical trials, has been demonstrated to inhibit superoxide dismutase (SOD) and to induce apoptosis in leukemia cells through a free radicalmediated mechanism. Because the accumulation of superoxide (O 2 ؊ ) by inhibition of SOD depends on the cellular generation of O 2 ؊ , we hypothesized that the endogenous production of superoxide may be a critical factor that affects the antileukemia activity of 2-ME. In the present study, we investigated the relationship between cellular O 2 ؊ contents and the cytotoxic activity of 2-ME in primary leukemia cells from 50 patients with chronic lymphocytic leukemia (CLL). Quantitation of O 2؊ revealed that the basal cellular O 2 ؊ contents are heterogeneous among patients with CLL. The O 2 ؊ levels were significantly higher in CLL cells from patients with prior chemotherapy. CLL cells with higher basal O 2 ؊ contents were more sensitive to 2-ME in vitro than those with lower O 2 ؊ contents. There was a significant correlation between the 2-ME-induced O 2 ؊ increase and the loss of cell viability. Importantly, addition of arsenic trioxide, a compound capable of causing reactive oxygen species (ROS) generation, significantly enhanced the activity of 2-ME, even in the CLL cells that were resistant to 2-ME alone. These results suggest that the cellular generation of O 2 ؊ plays an important role in the cytotoxic action of 2-ME and that it is possible to use exogenous ROS-producing agents such as arsenic trioxide in combination with 2-ME to enhance the antileukemia activity and to overcome drug resistance. Introduction 2-Methoxyestradiol (2-ME) is an endogenous metabolite of 17␤-estradiol that is present in human urine and blood. 2-ME is produced by sequential 2-hydroxylation and O-methylation. 1 This metabolic modification causes a loss of its ability to bind the estrogen receptor. 2-ME has been shown to have potent tumorinhibiting effects in a number of cancer cell lines in vitro and in tumor xenograft models in vivo. [2][3][4][5][6][7][8][9] This compound is currently in clinical trials, as a single agent or in combination with other anticancer agents, for treatment of several types of human cancer, including breast cancer, prostate cancer, and multiple myeloma. 2-ME also shows antileukemia activity in vitro with therapeutic selectivity. 10

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“…Seegers et al (5) found that 2-methoxyestradiol (2ME; compound 3), a metabolite of both estradiol (7) and the oral contraceptive agent 17-ethynylestradiol (compound 4), was more potent than estradiol in producing mitotic perturbations and proposed that it was 2ME rather than estradiol that caused the observed disturbances. Although 2-methoxyestrogens are extremely weak in binding to cytosol estrogen receptors (8), 2ME is found in blood and urine after sequential hepatic hydroxylation and methylation ofestradiol (7).…”

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confidence: 99%

2-Methoxyestradiol, an endogenous mammalian metabolite, inhibits tubulin polymerization by interacting at the colchicine site.

D’Amato

Lin

Flynn

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

377

313

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A metabolite of estradiol, 2-methoxyestradiol (2ME), inhibits angiogenesis In the chicken embryo chorioallantoic membrane assay. Since 2ME causes mitotic perturbalions, we ea ined Its interactions with tubulin. In our standard 1.0 M glutamate system (plus 1.0 mM MgCl2 at 3rC), superstoichiometric concentrations (relative to tubulin) of 2ME inhibited the nucleation and propagation phases of tubulin assembly but did not affect the reaction extent. Although polymer formed In the presence of 2ME was more cold-stable than control polymer, morphology was little changed. Under suboptimal reaction conditions (0.8 M glutamate/no MgCl2 at 26WC), substoichiometric 2ME totally inhibited polymerization. No other estrogenic compound was as effective as 2ME as an inhibitor of polymerization or of the binding of colchicine to tubulin. Inhibition ofcolchicine binding was competitive (KM,22 aM). Thus, a m an metabolite of estradiol binds to the colchicine site of tubulin and, depending on reaction conditions, either inhibits assembly or seems to be incorporated into a polymer with altered stability properties.There is growing evidence that estrogenic compounds affect cell division and act directly on microtubules by interacting with tubulin. The most extensively studied of these compounds is the synthetic analog diethylstilbestrol (DES; Fig. 1, compound 1) and related agents (1-3). These drugs cause disturbances in mitosis, inhibit microtubule assembly at relatively high concentrations, and inhibit the binding of colchicine to tubulin. Estradiol (compound 2), the major estrogenic hormone of human beings, also causes disturbances ofmitosis in cultured cells (1,4,5). These perturbations include aneuploidy, multinucleation, and mitotic arrest, and estradiol has been reported to inhibit the polymerization of rat brain tubulin (6). Seegers et al. (5) found that 2-methoxyestradiol (2ME; compound 3), a metabolite of both estradiol (7) and the oral contraceptive agent 17-ethynylestradiol (compound 4), was more potent than estradiol in producing mitotic perturbations and proposed that it was 2ME rather than estradiol that caused the observed disturbances. Although 2-methoxyestrogens are extremely weak in binding to cytosol estrogen receptors (8), 2ME is found in blood and urine after sequential hepatic hydroxylation and methylation ofestradiol (7).We recently found that 2ME inhibited angiogenesis in the chicken embryo chorioallantoic membrane assay of Crum et al. (9). Disks of2ME (100 Mg) produced large avascular zones 48 hr after implantation on a 6-day embryo, similar to in vitro results of others (10). In attempting to define the mechanistic basis, we observed that 2ME inhibited microtubule assembly. This finding led us to study the interactions of 2ME with purified tubulin.MATERIALS AND METHODS Materials. Purified bovine brain tubulin and H2-CSA4 were prepared as described (11,12). Monosodium glutamate (2.0 M) was adjusted to pH 6.6 with HCl. 2ME, 2-fluoroestradiol, 2-methoxy-17-ethynylestradiol, 2-methoxyestradiol 3-0-meth...

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The excretion of five different 2-hydroxyoestrogen monomethyl ethers in human pregnancy urine

Cited by 44 publications

References 31 publications

2-Methoxyestradiol blocks cell-cycle progression at the G<sub>2</sub>/M phase and induces apoptosis in human acute T lymphoblastic leukemia CEM cells

2-Methoxyestradiol blocks cell-cycle progression at the G<sub>2</sub>/M phase and induces apoptosis in human acute T lymphoblastic leukemia CEM cells

Free radical stress in chronic lymphocytic leukemia cells and its role in cellular sensitivity to ROS-generating anticancer agents

2-Methoxyestradiol, an endogenous mammalian metabolite, inhibits tubulin polymerization by interacting at the colchicine site.

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The excretion of five different 2-hydroxyoestrogen monomethyl ethers in human pregnancy urine

Cited by 44 publications

References 31 publications

2-Methoxyestradiol blocks cell-cycle progression at the G&lt;sub&gt;2&lt;/sub&gt;/M phase and induces apoptosis in human acute T lymphoblastic leukemia CEM cells

2-Methoxyestradiol blocks cell-cycle progression at the G&lt;sub&gt;2&lt;/sub&gt;/M phase and induces apoptosis in human acute T lymphoblastic leukemia CEM cells

Free radical stress in chronic lymphocytic leukemia cells and its role in cellular sensitivity to ROS-generating anticancer agents

2-Methoxyestradiol, an endogenous mammalian metabolite, inhibits tubulin polymerization by interacting at the colchicine site.

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Product

Resources

About

2-Methoxyestradiol blocks cell-cycle progression at the G<sub>2</sub>/M phase and induces apoptosis in human acute T lymphoblastic leukemia CEM cells

2-Methoxyestradiol blocks cell-cycle progression at the G<sub>2</sub>/M phase and induces apoptosis in human acute T lymphoblastic leukemia CEM cells