The cytotoxic effects of estradiol-17β, catecholestradiols and methoxyestradiols on dividing MCF-7 and Hela cells

Seegers, J.C.; Aveling, M.L.; Aswegen, C. H. Van; Cross, Marissa; Koch, Francois; Joubert, W. S.

doi:10.1016/0022-4731(89)90455-x

Cited by 137 publications

(114 citation statements)

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“…7,8 In addition to inhibiting cell and tumor growth 2-MeOE2 also inhibits angiogenesis as determined in vitro and in vivo. 8,10 In a previous study it was found that the sulfamoylation of 2-MeOE1 greatly enhanced its ability to inhibit the growth of ERϩ and ERϪ breast cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…6 Its selection for development as an anti-cancer agent was based on its ability to inhibit the proliferation of a wide range of cancer cells including estrogen receptor positive (ERϩ) and negative (ERϪ) breast cancer cells. 7,8 In vivo oral administration of 2-MeOE2 inhibited the growth of Meth-A sarcoma, B16 melanoma and human MDA-MB-435 breast carcinomas. 8,9 Relatively high doses of 2-MeOE2 (75-100 mg/kg/day) were administered to produce the reductions in tumor growth.…”

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confidence: 99%

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Inhibition of in vitro angiogenesis by 2‐methoxy‐ and 2‐ethyl‐estrogen sulfamates

Newman

Leese

Purohit

et al. 2004

Intl Journal of Cancer

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Sulfamoylation of 2-methoxyestrone (2-MeOE1) was shown previously to enhance its potency as an anti-proliferative agent against breast cancer cells. We have examined the ability of a series of 2-methoxyestradiol (2-MeOE2) and 2-ethylestradiol (2-EtE2) sulfamates to inhibit angiogenesis in vitro. 2-MeOE2 bis-sulfamate and 2-EtE2 sulfamate were potent inhibitors of human umbilical vein endothelial cell (HUVEC) proliferation with IC 50 values of 0.05 M and 0.01 M, respectively. A novel co-culture system, in which endothelial cells were cultured in a matrix of human dermal fibroblasts, was also used to assess the anti-angiogenic potential of these drugs. In this system endothelial cells proliferate and migrate through the culture matrix to form tubule structures. Key words: angiogenesis; breast cancer; estrogens; estrogen sulfamates; microtubulesEstrogens can be metabolised via either a 2-hydroxylase or 16␣-hydroxylase pathway and there is a growing awareness that the route of estrogen metabolism may influence the development of breast tumors. 2-Hydroxyestrogens and their 2-methoxy derivatives are non-estrogenic whereas 16␣-hydroxy metabolites are estrogenic due, in part, to their ability to form adducts with proteins. 1,2 Research carried out by Bradlow and others 3,4 has indicated that although the 2-hydroxylase pathway is associated with a reduced risk of breast cancer, increased formation of 16␣-hydroxy metabolites may increase breast cancer risk. It was suggested recently that the major derivative of 2-hydroxyestrogens, 2-methoxyestradiol (2-MeOE2, Fig. 1) may in fact be the endogenous estrogen metabolite that inhibits breast carcinogenesis. 5 2-MeOE2 is currently undergoing Phase I/II trials as a novel agent for breast cancer therapy. 6 Its selection for development as an anti-cancer agent was based on its ability to inhibit the proliferation of a wide range of cancer cells including estrogen receptor positive (ERϩ) and negative (ERϪ) breast cancer cells. 7,8 In vivo oral administration of 2-MeOE2 inhibited the growth of Meth-A sarcoma, B16 melanoma and human MDA-MB-435 breast carcinomas. 8,9 Relatively high doses of 2-MeOE2 (75-100 mg/kg/day) were administered to produce the reductions in tumor growth. In addition to its anti-proliferation effects 2-MeOE2 was also identified as the active ingredient of urine extracts that was able to inhibit angiogenesis. 9 Using brain-derived capillary endothelial cells 2-MeOE2 was found to be a specific inhibitor of the proliferation of these cells being 90ϫ more potent than 2-methoxyestrone (2-MeOE1) and 250ϫ more potent than estradiol. Several subsequent investigations have confirmed the potency of 2-MeOE2 as an inhibitor of endothelial cell growth and angiogenesis in vitro and in vivo. 8,10 The mechanism(s) by which 2-MeOE2 inhibits endothelial cell growth and angiogenesis remains to be elucidated.The estrogen sulfamate, estrone-3-O-sulfamate (EMATE) was initially identified as a potent steroid sulfatase inhibitor. 11,12 Unexpectedly, EMATE proved to be a potent estroge...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Inhibition of in vitro angiogenesis by 2‐methoxy‐ and 2‐ethyl‐estrogen sulfamates

Newman

Leese

Purohit

et al. 2004

Intl Journal of Cancer

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“…Support for this concept has emerged from studies in which chemotherapeutic agents are administered in a metronomic low-dose schedule in an attempt to combine their anti-proliferative and anti-angiogenic activities (Vacca et al, 1999;Hanahan et al, 2000). Over the last decade there has been considerable interest in the natural oestrogen metabolite, 2-methoxyoestradiol (2-MeOE2, Figure 1, 1) as a potential drug for cancer therapy (Seegers et al, 1989;Fotsis et al, 1994;Klauber et al, 1997;Brem, 1998;Zhu and Conney, 1998a, b;Lakhani et al, 2003;Dahut et al, 2006). This compound not only inhibits the proliferation of cancer cells in vitro and tumours in vivo but also displays anti-angiogenic activity (Fotsis et al, 1994;Klauber et al, 1997).…”

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confidence: 99%

In vivo inhibition of angiogenesis by sulphamoylated derivatives of 2-methoxyoestradiol

et al. 2007

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Drugs that inhibit growth of tumours and their blood supply could have considerable therapeutic potential. 2-Methoxyoestradiol-3,17-O,O-bis-sulphamate (2-MeOE2bisMATE) has been shown to inhibit the proliferation of MCF-7 (ER+) breast cancer cells and angiogenesis in vitro. 2-MeOE2bisMATE and its analogue, 17-Cym-2-MeOE2MATE, were investigated for their ability to inhibit in vivo angiogenesis and tumour growth. The mouse Matrigel plug assay for angiogenesis was used to investigate the effect of compounds on neovascularisation and was quantified using a FITC-dextran injection technique. Nude mice bearing tumours derived from MCF-7 cells were used to assess efficacy on tumour growth. Tumour sections were stained for VEGFR-2 and Ki67 to assess tumour angiogenesis and cell proliferation respectively. Matrigel plugs supplemented with basic fibroblast growth factor resulted in increased neovascularisation over 7 days. Oral administration of 2-MeOE2bisMATE for 7 days at 10 or 50 mg kg À1 significantly reduced neovascularisation to or below control levels respectively. 17-Cym-2-MeOE2MATE at 20 mg kg À1 was equally effective. 2-MeOE2bisMATE, dosed daily for 21 days, caused a 52% reduction in tumour growth at 5 mg kg À1 and 38% regression at 20 mg kg À1 . 17-Cym-2-MeOE2MATE (20 mg kg À1 ) reduced tumour growth by 92%. Immunohistochemistry revealed a reduction in angiogenesis and proliferation. Matrigel plug and tumour imaging after FITC-dextran injection indicated that 2-MeOE2bisMATE caused a marked disruption of vasculature. These sulphamoylated oestrogen derivatives have been shown to be potent inhibitors of angiogenesis in vivo. This, together with their ability to inhibit tumour growth, indicates the potential of this new class of drugs for further development for cancer therapy.

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“…1,5,6,9,15,16 We have previously confirmed antiproliferative effects and morphological hallmarks of apoptosis in 2 ME-exposed HeLa, as well as WHCO3 squamous oesophageal carcinoma cells and revealed that 2 ME was responsible for an altered ratio of Bax/ Bcl-2 in favour of Bax suggesting that this could lead to the induction of apoptosis in both these cells. 17,18 However, the exact action mechanism of 2 ME is complicated, still not clearly defined and appears to vary according to cell type.…”

Section: Discussionmentioning

confidence: 80%

“…1-3 2 ME exerts both anti-angiogenic and anti-tumour effects regardless of the cell's hormone receptor status and is responsible for mitotic accumulation and abnormal mitotic spindle formation in both estrogen receptor (ER) positive and ER negative cells. [4][5][6] As a consequence, this endogenous estradiol metabolite has emerged as a promising anti-cancer agent. 5 Recent evidence has implicated 2 ME in the activation of c-Jun NH2-terminal kinase signalling, generation of reactive oxygen species and induction of apoptosis via both the extrinsic and intrinsic pathways.…”

Section: Introductionmentioning

confidence: 99%

In vitro effects of 2‐methoxyestradiol on cell morphology and Cdc2 Kinase activity in SNO oesophageal carcinoma cells

Joubert

Marais

2007

Cell Biochemistry & Function

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The effects of 1 x 10 -6 M exogenous 2-methoxyestradiol (2 ME) were determined on cell morphology and cell division cycle (Cdc) 2 kinase activity in SNO oesophageal carcinoma cells. Mitotic indices revealed an increase in metaphase cells (11.2%) when compared to the 0.5% vehicle-treated cells after 18 h of exposure to 2 ME. Vehicletreated control cells did not show any hallmarks of apoptosis after 18 h of exposure to dimethyl sulphoxide. Only 0.5% of 2 ME-treated cells showed characteristics of apoptosis. Conversely, increased morphological hallmarks of apoptosis were observed in SNO-treated cells after 21.5 h of 2 ME exposure. When compared to the 0.5% in vehicle-treated cells, 4.7% of cells were in apoptosis. Furthermore, 34.1% of cells were blocked in metaphase after 21.5 h of 2 ME exposure compared to 0.6% of vehicle-control cells. In addition, Cdc2 kinase activity was statistically significantly increased (1.3-fold) (p < 0.005) in 2 ME-treated cells when compared to vehicle-treated controls. The present preliminary study suggests that the accumulation observed in metaphase cells and the increase in Cdc2 kinase activity caused by 2 ME are consistent with morphological hallmarks of mitotic arrest and disrupted mitotic spindle formation, thus leading to induction of apoptosis in SNO cells.

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The cytotoxic effects of estradiol-17β, catecholestradiols and methoxyestradiols on dividing MCF-7 and Hela cells

Cited by 137 publications

References 10 publications

Inhibition of in vitro angiogenesis by 2‐methoxy‐ and 2‐ethyl‐estrogen sulfamates

Inhibition of in vitro angiogenesis by 2‐methoxy‐ and 2‐ethyl‐estrogen sulfamates

In vivo inhibition of angiogenesis by sulphamoylated derivatives of 2-methoxyoestradiol

In vitro effects of 2‐methoxyestradiol on cell morphology and Cdc2 Kinase activity in SNO oesophageal carcinoma cells

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