2-Methoxyestradiol Arrests Cells in Mitosis without Depolymerizing Tubulin

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

doi:10.1006/bbrc.1996.1683

Cited by 105 publications

(76 citation statements)

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“…An earlier report indicated that treating the estrogen-dependent MCF-7 cell line with 2-MeOE 2 caused G2/M arrest associated with depolymerization of tubulin (Tishler et al, 1995). However, we observed no e ect of 2-MeOE 2 on tubulin structure in immuno¯uorescence studies of our lung cancer cell lines (data not shown) or in A431 cells, even at concentrations of 20 mM (Attalla et al, 1996). It has also been suggested that 2-MeOE 2 causes mitotic arrest in a leukemia cell line by inhibiting the calmodulin pathway (Attalla et al, 1996).…”

Section: Resultsmentioning

confidence: 57%

“…However, we observed no e ect of 2-MeOE 2 on tubulin structure in immuno¯uorescence studies of our lung cancer cell lines (data not shown) or in A431 cells, even at concentrations of 20 mM (Attalla et al, 1996). It has also been suggested that 2-MeOE 2 causes mitotic arrest in a leukemia cell line by inhibiting the calmodulin pathway (Attalla et al, 1996). Yet, when lung cancer cell lines are treated with 5 mM of 2-MeOE 2 , there is no e ect on the distribution of tumor cells in the di erent phases of the cell cycle (Mukhopadhyay and Roth, 1997).…”

Section: Resultsmentioning

confidence: 59%

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Superinduction of wild-type p53 protein after 2-methoxyestradiol treatment of Ad5p53-transduced cells induces tumor cell apoptosis

Mukhopadhyay

Roth

1998

Oncogene

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Because 2-methoxyestradiol (2-MeOE 2 ) induces and stabilizes wild-type p53 protein (wt p53) in human lung cancer cell lines posttranscriptionally, we sought to study its e ects on Ad5p53-transduced lung cancer cell lines at a low multiplicity of infection (1 MOI). Treating these cells with 2-MeOE 2 resulted in superinduction of wt p53 protein expression followed by apoptosis, as shown by terminal deoxynucleotidyl transferase (TdT) staining, and upregulation of wt p53 expression, as shown by Western blot analysis. When transduced with Ad5p53 alone at 1 MOI, the cell lines grew rapidly. Moreover, adenoviral-vector-mediated p53 gene transfer followed by 2-MeOE 2 treatment caused 80% growth inhibition in the cell lines regardless of their p53 status. Thus, p53 superinduction and apoptosis after 2-MeOE 2 treatment in Ad5p53-transduced cells appears to be a unique strategy with signi®cant implications for cancer gene therapy.

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Section: Resultsmentioning

confidence: 57%

Section: Resultsmentioning

confidence: 59%

Superinduction of wild-type p53 protein after 2-methoxyestradiol treatment of Ad5p53-transduced cells induces tumor cell apoptosis

Mukhopadhyay

Roth

1998

Oncogene

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“…Several reports demonstrated that 2ME 2 inhibits tubulin polymerization, 22,25 but generally at much higher concentrations than necessary for growth arrest. 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: Discussionmentioning

confidence: 93%

“…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: Discussionmentioning

confidence: 93%

“…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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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 Arrests Cells in Mitosis without Depolymerizing Tubulin

Cited by 105 publications

References 0 publications

Superinduction of wild-type p53 protein after 2-methoxyestradiol treatment of Ad5p53-transduced cells induces tumor cell apoptosis

Superinduction of wild-type p53 protein after 2-methoxyestradiol treatment of Ad5p53-transduced cells induces tumor cell apoptosis

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

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

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