2-Methoxyestradiol induces mitochondria dependent apoptotic signaling in pancreatic cancer cells

Qanungo, Suparna; Basu, Aruna; Das, Madhusudan; Haldar, Subrata

doi:10.1038/sj.onc.1205508

Cited by 53 publications

(63 citation statements)

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“…A mitochondria-dependent mechanism was demonstrated in leukemia, pancreatic carcinoma, Ewing sarcoma and multiple myeloma cells. 19,27,37,41 On the other hand, the use of the FIGURE 3 -Effect of 2ME 2 on the microtubular organization in HT168-M1 human melanoma cells. Cells were cultured on coverslips and treated with Taxol (100 nM, 10 min) or 2ME 2 (5 M, 1 hr).…”

Section: Discussionmentioning

confidence: 99%

“…It was reported to inhibit the bFGF-induced proliferation and tube formation of endothelial cells in vitro, as well as bFGF-and VEGFinduced neovascularization in vivo in chick chorioallantoic membrane and mouse corneal micropocket assays. 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 .…”

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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%

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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). However, little is known about the molecular events implicated in the ability of 2-Me to initiate the apoptotic cascade.…”

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 addition, 2ME exerts antiproliferative and antiangiogenic effects (Hughes et al, 2002;Tinley et al, 2003). It has also been reported that 2ME induces apoptosis in various cell types (Zoubine et al, 1999;Lin et al, 2001;Bu et al, 2002;Qanungo et al, 2002). In a recent communication, Huang et al (2000) demonstrated that 2ME potently induces apoptosis in human leukemia cells through a mechanism that involves the selective inhibition of superoxide dismutase (SOD) and accumulation of reactive oxygen species (ROS).…”

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confidence: 99%