The physiological estrogen metabolite 2-methoxyestradiol reduces tumor growth and induces apoptosis in human solid tumors

Schumacher, Guido; Neuhaus, Peter

doi:10.1007/s004320000233

Cited by 78 publications

(63 citation statements)

References 30 publications

(42 reference statements)

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“…This is the first demonstration of the in vivo effect of 2ME 2 on melanoma. Moreover, most previous studies investigating the antimetastatic effect of 2ME 2 used lung colony assays, 10,11,17,21 and only 1 explored its effects on hepatic metastasis formation, 42 although in humans liver is a common site of metastasis in several cancer types including melanoma.…”

Section: Discussionmentioning

confidence: 99%

“…10,11,14 -16 2ME 2 has been demonstrated to induce G 2 /M cell cycle arrest and apoptosis in a variety of tumor cell lines in vitro, 10,[17][18][19][20] and to inhibit the growth and vascularization of primary tumors, or lung colony formation in mice injected with murine or human tumor cells. 10,11,14,15,17,18,20,21 Several mechanisms of action have been suggested for the effects of 2ME 2 . Its antiproliferative activity has been attributed to the disruption of microtubule function through its effects on tubulin polymerization or depolymerization, or altering microtubule stability.…”

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confidence: 99%

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In vitro and in vivo antitumor effect of 2‐methoxyestradiol on human melanoma

Dobos

Tı́már

Bocsi

et al. 2004

Intl Journal of Cancer

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2-methoxyestradiol (2ME 2 ) is an endogenous metabolite of estradiol with estrogen-receptor-independent antitumor and antiangiogenic activity. We examined the effects of 2ME 2 on the cellular proliferation of 8 human melanoma cell lines. We show that 2ME 2 inhibited cell proliferation by inducing apoptosis and an arrest in the G 2 /M phase, and the mechanism of action involved microtubules, mitochondrial damage and caspase activation. In male SCID mice, 2ME 2 was effective in reducing primary tumor weight and the number of liver metastases after intrasplenic injection of human melanoma cells. In the metastases, we found a significantly higher rate of apoptotic cells after 2ME 2 treatment. These findings on the antitumor effect of 2ME 2 in cell culture as well as in an animal model may have implications for designing alternative treatment options for patients with advanced malignant melanoma. © 2004 Wiley-Liss, Inc. Key words: 2-methoxyestradiol; melanoma; apoptosis; metastasisThe possibility that endocrine factors may influence the clinical course of human malignant melanoma is suggested by the higher survival rate in premenopausal vs. postmenopausal women or men of any ages. 1,2 The epidemiological data were supported by studies using melanoma cell lines grown in experimental animals. 3,4 Our previous experiments showed that intrasplenic injection of human melanoma cells resulted in a significantly higher number of liver metastases in male than in female SCID mice. 5 On the other hand, investigations on the sex hormone receptor status of human cutaneous melanomas yielded conflicting results; while earlier studies applying biochemical methods for the detection of estrogen receptors (ER) gave positive results in some cases, other approaches using monoclonal anti-ER antibodies generally failed to demonstrate the presence of type I receptors in melanoma tissues. 1,6 It has been suggested that low-affinity type II ERs may be responsible for the observed hormone binding. Nevertheless, most investigators have shown the lack of an effect of estrogens on the proliferative activity of human melanoma cells. 7,8 There are less data available on the presence of other sex hormone receptors (progesterone and androgens) and their effect on the biological behavior of melanoma cells. 1,9 One possible mechanism behind the observed female superiority in survival of melanoma patients is the tumor growth inhibitory effect of 2-methoxyestradiol (2ME 2 ), an endogenous metabolite of estradiol exerting its activities independently of the ERs. 2ME 2 is formed by the sequential hydroxylation and methylation at the 2-position; it is produced during the normal route of detoxification, especially in the liver, and excreted through the urinary system. 10 -12 This is the only estradiol metabolite devoid of estrogenic activity in vivo and has no known physiological function. Its affinity to ER␣ and to ER␤ is 500-fold and 3,200-fold lower than that of estradiol, respectively, and its activity is independent of the presence of estrogen receptor...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

In vitro and in vivo antitumor effect of 2‐methoxyestradiol on human melanoma

Dobos

Tı́már

Bocsi

et al. 2004

Intl Journal of Cancer

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“…It is orally active at inhibiting tumor growth and metastatic spreading in several tumor models, at doses showing no clinical signs of toxicity (Fotsis et al, 1994;Schumacher and Neuhaus, 2001). These effects have been linked to its ability to inhibit angiogenesis and to induce apoptosis of tumor cells (Mukhopadhyay and Roth, 1997;Yue et al, 1997;Qadan et al, 2001) Many cellular responses to 2-Me treatment have been described, including accumulation of cells in G2/M phase, formation of reactive oxygen species (ROS), inhibition of tubulin polymerization, activation of c-jun N-terminal-activated kinase (JNK), increased expression of FAS, p53 and p21 WAF1 , Bcl-2 phosphorylation and mitochondrial release of cytochrome c (Hamel et al, 1996;Mukhopadhyay and Roth, 1997;Yue et al, 1997;Attalla et al, 1998;Huang et al, 2000;Lin et al, 2000;Kumar et al, 2001;Qadan et al, 2001;Qanungo et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

2-Methoxyestradiol induces apoptosis in Ewing sarcoma cells through mitochondrial hydrogen peroxide production

2003

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The Ewing sarcoma is the second most common bone tumor in children and young adults. Despite the advances in therapy, the 5-year survival rate for patients with metastatic disease is poor, indicating the need for alternative treatments. Here, we report that 2-methoxyestradiol (2-Me), a natural estrogen metabolite, induced a caspase-dependent apoptosis of Ewing sarcoma-derived cells independently of their p53 status. 2-Me-induced apoptosis occurred through the mitochondrial death pathway as evidenced by reduction of the mitochondrial transmembrane potential, cytochrome c release and caspase-9 activation. Treatment of cells with 2-Me resulted in generation of intracellular H 2 O 2 , which occurred earlier than caspase-9 activation. The H 2 O 2 -reducing agent Ebselen and the lipid peroxidation inhibitor vitamin E decreased both 2-Me-induced caspase-9 activation and cell death, thus providing evidence for a role of H 2 O 2 and lipid peroxides in the initiation of this process. Rotenone, an inhibitor of the mitochondrial respiratory chain, abolished both apoptosis and H 2 O 2 production, thereby identifying mitochondria as the source of H 2 O 2 . Moreover, we observed that treatment of cells with 2-Me or H 2 O 2 induced activation of the c-Jun N-terminal kinase (JNK). Overexpression of a dominantnegative mutant of JNK1 reduced 2-Me-induced apoptosis indicating that JNK participates in this process. Altogether, our results provide evidence that 2-Me triggers apoptosis of Ewing sarcoma cells through induction of a mitochondria redox-dependent mechanism and suggest that this compound or other agents that selectively increase the level of reactive oxygen species may prove useful to the development of novel strategies for treatment of Ewing tumors.

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“…In particular, the growth-inhibiting effects of 2-hydroxylated 17␤-estradiol (2OH-17␤-estradiol) and 2-methoxy-17␤-estradiol (2MeO-17␤-estradiol), the methylation product of 2OH-17␤-estradiol, have been the focus of recent research (7)(8)(9). Interestingly, several of these effects are independent of estrogen receptors, and relatively high concentrations of hormones, between 10 Ϫ7 and 10 Ϫ6 M, have been used in previous studies (7)(8)(9). In healthy women, the plasma concentration of 2OH-estrone plus 2OH-17␤-estradiol is ϳ10 Ϫ9 M, and circulating levels of 2-methoxyestrogens are also 10 Ϫ9 M (8).…”

mentioning

confidence: 99%

Estrone/17β‐estradiol conversion to, and tumor necrosis factor inhibition by, estrogen metabolites in synovial cells of patients with rheumatoid arthritis and patients with osteoarthritis

Schmidt

Hartung

Capellino

et al. 2009

Arthritis & Rheumatism

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Objective. The role of estrogens in rheumatoid arthritis (RA) is debated since both proinflammatory and antiinflammatory effects have been reported. Important evidence of the dual role of estrogens is conversion to various proinflammatory or antiinflammatory metabolites. This study was undertaken to examine the downstream conversion of estrogens in synovial cells from patients with RA or osteoarthritis (OA).Methods. We studied serum levels of estrone, estrone sulfate, and estrone sulfate membrane transporters, intracellular interconversion of estrone and 17␤-estradiol, and conversion of estrone/17␤-estradiol to various estrogen metabolites in RA and OA synovial cells. The effect of estrogen metabolites on tumor necrosis factor (TNF) secretion was also studied in RA and OA synovial cells.Results. Serum levels of estrone sulfate were similar in healthy controls and RA patients. Estrone sulfate transporters were present in synovial tissue. Interconversion of estrone and 17␤-estradiol and the expression of converting enzymes of the cytochrome P450 family were similar in RA and OA cells. Using estrone and 17␤-estradiol as substrates, RA and OA synovial cells produced 16␣-, 4-, and 2-hydroxylated estrogens and their 4-and 2-methylation products. The levels of 16␣-hydroxylated estrone/17␤-estradiol (16␣OH-estrone/16␣OH-17␤-estradiol) were higher than the levels of all other estrogen metabolites. RA synovial cells produced more 16␣OH-estrone than did OA synovial cells. Importantly, the 16␣OH estrogens did not inhibit TNF secretion, whereas all other estrogen metabolites had marked inhibitory effects.Conclusion. Our findings indicate that precursor estrogens are converted to proinflammatory metabolites, particularly in RA synovial cells. RA synovial cells mainly produce the proproliferative 16␣OH-estrone, which, in addition to 16␣OH-17␤-estradiol, is one of the only 2 estrogens studied that does not inhibit TNF secretion. A preponderance of 16␣-hydroxylated estrogens is an unfavorable sign in synovial inflammation.

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The physiological estrogen metabolite 2-methoxyestradiol reduces tumor growth and induces apoptosis in human solid tumors

Cited by 78 publications

References 30 publications

In vitro and in vivo antitumor effect of 2‐methoxyestradiol on human melanoma

In vitro and in vivo antitumor effect of 2‐methoxyestradiol on human melanoma

2-Methoxyestradiol induces apoptosis in Ewing sarcoma cells through mitochondrial hydrogen peroxide production

Estrone/17β‐estradiol conversion to, and tumor necrosis factor inhibition by, estrogen metabolites in synovial cells of patients with rheumatoid arthritis and patients with osteoarthritis

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