2-Methoxyestradiol-Induced Phosphorylation of Bcl-2: Uncoupling from JNK/SAPK Activation

Attalla, Hesham; Westberg, Johan A.; Andersson, Leif C.; Adlercreutz, Herman; Mäkelä, Tomi P.

doi:10.1006/bbrc.1998.8870

Cited by 82 publications

(72 citation statements)

References 17 publications

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“…23 Others have found stabilization of microtubules, a mechanism resembling that of other compounds affecting microtubule dynamics, like Taxol. 23,24 Similarly, we found bundling of microtubules after 2ME 2 treatment of human melanoma cells, at the same concentration effective in growth inhibition.…”

Section: Discussionsupporting

confidence: 65%

“…This observation might be important in the light of the inherent resistance of melanomas to drug-induced apoptosis. 38,39 Reports on the effects of 2ME 2 on the expression of apoptosis regulating proteins (e.g., p53 and Bcl-2) 16,24,26,29,36,40 suggest that 2ME 2 may have a potential to overcome apoptosis resistance of melanoma cells.…”

Section: Discussionmentioning

confidence: 99%

“…Its antiproliferative activity has been attributed to the disruption of microtubule function through its effects on tubulin polymerization or depolymerization, or altering microtubule stability. [22][23][24][25] It has also been suggested that 2ME 2 regulates apoptosis by influencing caspase activation, upregulation of the death receptor 5 protein or p53, phosphorylation and inactivation of Bcl-2, or increasing superoxide production. 10,11,16,24,26 -29 In the case of human melanoma, the in vitro apoptosis-inducing effect of 2ME 2 has been reported on 1 cell line, 29 while its in vivo antitumor or antimetastatic effect remained to be determined.…”

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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: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 99%

mentioning

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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“…It was previously shown that 2-MeOE2 induces apoptosis by increasing the phosphorylation of oncoproteins such as BCL-2. 16,38,39 It is known that phosphorylation occurs during the arrest of cells at the G2-M phase of the cell cycle. 39 It has previously been reported that a sulphamoylated analogue, 2-MeOEMATE, also induces BCL-2 phosphorylation in MCF-7 cells, leading to the induction of apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…[12][13][14] Although the exact mechanism by which 2-MeOE2 induces its antiangiogenic and antitumour effects is not known, several cellular responses, such as G2-M cell cycle arrest, caspase-3 activation, BCL-2 phosphorylation, increased expression of FAS and p53, downregulation of HIF-1, mitochondrial release of cytochrome c, and inhibition of tubulin polymerisation, have been reported. 4,5,9,10,[15][16][17][18][19][20][21] However, it has been shown that its antimitotic effects are mediated via inhibition of tubulin polymerisation by binding to the colchicine binding site on tubulin. 19,20 Because of the antiproliferative properties associated with 2-MeOE2, several analogues of 2-MeOE2 have been synthesised and tested for various biological activities.…”

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Inhibition of MDA-MB-231 cell cycle progression and cell proliferation by C-2-substituted oestradiolmono- andbis-3-O-sulphamates

et al. 2005

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A natural metabolite of oestradiol (E2), 2-methoxyoestradiol (2-MeOE2), exerts both antitumour and antiangiogenic effects. 2-MeOE2 is currently in clinical trials for the treatment of a variety of cancers. We have previously shown that a number of sulphamoylated analogues of 2-MeOE2 possess enhanced potency and bioavailability with respect to 2-MeOE2. In our study, the effects of C-2-substituted E2 derivatives, with sulphamoylation at the C-3 and/or C-17 position, on ERa 2ve MDA-MB-231 breast cancer cells were evaluated. Sulphamoylated derivatives were potent inhibitors of cell proliferation, and these effects were irreversible when compared to growth inhibitory effects induced by 2-MeOE2. Cell cycle analysis suggested that these derivatives caused cells to arrest at the G2-M phase of the cell cycle. Sulphamoylated analogues suppressed the clonogenic potential of MDA-MB-231 cells and also their growth on Matrigel 1 culture substratum. Immunofluorescence studies showed fragmented nuclear bodies and an abnormal microtubule cytoskeleton in cells exposed to one of the potent compounds, 2-MeOE2-bis-sulphamate. In addition, these analogues induced phosphorylation of BCL-2, a protein considered to be the guardian of microtubule integrity. In each of the assays, the sulphamoylated derivatives were at least 10-fold more potent than the parent compound 2-MeOE2. In view of the enhanced potencies associated with sulphamoylated E2 derivatives in ERa 2ve cells, these analogues should hold considerable therapeutic potential for the treatment of hormone-independent breast cancers. ' 2005 Wiley-Liss, Inc.

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The effect of 2-methoxyoestrone-3-O-sulphamate on the growth of breast cancer cells and induced mammary tumours

et al. 2000

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2‐Methoxyoestrogens are emerging as a new class of drug that can inhibit tumour growth and angiogenesis. As sulphamoylation of oestrogens enhances their potency and bioavailability we have synthesized 2‐methoxyoestrone‐3‐O‐sulphamate (2‐MeOEMATE) and compared its ability to inhibit the proliferation of breast cancer cells with that of 2‐methoxyoestrone (2‐MeOE1). 2‐MeOEMATE (1 μM) inhibited the growth of oestrogen receptor positive MCF‐7 breast cancer cells by 52% whereas 2‐MeOE1 had little effect at this concentration. 2‐MeOEMATE also inhibited the growth of oestrogen receptor negative MDA‐MB‐231 breast cancer cells. Exposure of cells to 2‐MeOEMATE caused them to round up and become detached suggesting that this compound may induce cells to undergo apoptosis. Cell cycle analysis revealed that 2‐MeOEMATE caused cells to arrest in the G2/M phase with the increase in G2/M arrested cells being detectable by 12 hr. Exposure of MCF‐7 cells to 2 L‐MeOEMATE for 24 hr followed by culture in drug‐free medium for 24 hr did not reverse the arrest of cells in the G2/M phase. TUNEL analysis confirmed that 2‐MeOEMATE induced apoptosis in a significant proportion of treated MCF‐7 cells. In an in vivo study, employing nitrosomethylurea‐induced mammary tumours in intact rats, 2‐MeOE1 (20mg/kg/d, p.o. for 11 days) had little effect on tumour growth. In contrast, the same dose of 2‐MeOEMATE resulted in the almost complete regression of 2/3 tumours over an 11‐day period. We conclude that 2‐MeOEMATE should have considerable therapeutic potential for the treatment of breast tumours. Int. J. Cancer 85:584–589, 2000. © 2000 Wiley‐Liss, Inc.

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2-Methoxyestradiol-Induced Phosphorylation of Bcl-2: Uncoupling from JNK/SAPK Activation

Cited by 82 publications

References 17 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

Inhibition of MDA-MB-231 cell cycle progression and cell proliferation by C-2-substituted oestradiolmono- andbis-3-O-sulphamates

The effect of 2-methoxyoestrone-3-O-sulphamate on the growth of breast cancer cells and induced mammary tumours

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