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Differential effects of estrone and estrone-3-O-sulfamate derivatives on mitotic. Arrest apoptosis, and microtubule assembly in human breast cancer cells

Differential effects of estrone and estrone-3-O-sulfamate derivatives on mitotic. Arrest apoptosis, and microtubule assembly in human breast cancer cells
Differential effects of estrone and estrone-3-O-sulfamate derivatives on mitotic. Arrest apoptosis, and microtubule assembly in human breast cancer cells
There is considerable interest in the potential use of estrogen derivatives for the treatment and prevention of breast cancer. We demonstrated previously that the sulfamoylated estrone derivative 2-methoxyestrone-3-O-sulfamate (2-MeOEMATE) induced G2-M cell cycle arrest and modest levels of apoptosis in breast cancer cells in vitro, whereas the parent estrone derivative, 2-methoxyestrone, did not. 2-MeOEMATE also induced breast tumor regression in vivo in intact rats. To further explore the significance of sulfamoylation on the anticancer activity of estrone derivatives and to elucidate their mechanism of action, we synthesized two additional agents, 2-ethylestrone and 2-ethylestrone-3-O-sulfamate (2-EtEMATE). 2-MeOEMATE and 2-EtEMATE inhibited the growth of a panel of estrogen receptor-negative and -positive breast cancer cell lines in vitro, induced mitotic arrest and apoptosis, and suppressed the long-term clonogenic potential of MCF7 and CAL51 breast cancer cells. In each assay, the sulfamoylated estrone derivatives were >10-fold more potent than their parent compounds. The sulfamoylated estrone derivatives were also significantly more potent inhibitors of cell growth than the previously studied endogenous estradiol metabolite 2-methoxyestradiol. 2-MeOEMATE and 2-EtEMATE functioned as antimicrotubule agents and inhibited the ability of paclitaxel to promote tubulin assembly in vitro. Like other antimicrotubule agents, the sulfamoylated estrone derivatives induced BCL-2 and BCL-XL phosphorylation and increased p53 expression. 2-MeOEMATE and 2-EtEMATE are novel antimicrotubule agents that have potent anticancer activity in breast cancer cells in vitro and may be beneficial as anticancer agents in vivo.
0008-5472
5441-5450
MacCarthy-Morrogh, Lucy.
eccaec54-0db4-4cfb-90b9-564b9e3bbca1
Townsend, Paul A.
a2680443-664e-46d0-b4dd-97456ba810db
Purohit, Atul.
464be3c5-4cba-41d8-80b3-dfa8a6e40a34
Hejaz, Hatem A.M.
6b685e13-e26b-4114-af9b-829f52398484
Potter, Barry V.L.
a2fd9ce8-0e83-4aee-a362-25a750c5c0c8
Reed, Michael J.
b55b77a3-d7fb-47d1-92f6-0f738e360a70
Packham, Graham.
fdabe56f-2c58-469c-aadf-38878f233394
MacCarthy-Morrogh, Lucy.
eccaec54-0db4-4cfb-90b9-564b9e3bbca1
Townsend, Paul A.
a2680443-664e-46d0-b4dd-97456ba810db
Purohit, Atul.
464be3c5-4cba-41d8-80b3-dfa8a6e40a34
Hejaz, Hatem A.M.
6b685e13-e26b-4114-af9b-829f52398484
Potter, Barry V.L.
a2fd9ce8-0e83-4aee-a362-25a750c5c0c8
Reed, Michael J.
b55b77a3-d7fb-47d1-92f6-0f738e360a70
Packham, Graham.
fdabe56f-2c58-469c-aadf-38878f233394

MacCarthy-Morrogh, Lucy., Townsend, Paul A., Purohit, Atul., Hejaz, Hatem A.M., Potter, Barry V.L., Reed, Michael J. and Packham, Graham. (2000) Differential effects of estrone and estrone-3-O-sulfamate derivatives on mitotic. Arrest apoptosis, and microtubule assembly in human breast cancer cells. Cancer Research, 60, 5441-5450.

Record type: Article

Abstract

There is considerable interest in the potential use of estrogen derivatives for the treatment and prevention of breast cancer. We demonstrated previously that the sulfamoylated estrone derivative 2-methoxyestrone-3-O-sulfamate (2-MeOEMATE) induced G2-M cell cycle arrest and modest levels of apoptosis in breast cancer cells in vitro, whereas the parent estrone derivative, 2-methoxyestrone, did not. 2-MeOEMATE also induced breast tumor regression in vivo in intact rats. To further explore the significance of sulfamoylation on the anticancer activity of estrone derivatives and to elucidate their mechanism of action, we synthesized two additional agents, 2-ethylestrone and 2-ethylestrone-3-O-sulfamate (2-EtEMATE). 2-MeOEMATE and 2-EtEMATE inhibited the growth of a panel of estrogen receptor-negative and -positive breast cancer cell lines in vitro, induced mitotic arrest and apoptosis, and suppressed the long-term clonogenic potential of MCF7 and CAL51 breast cancer cells. In each assay, the sulfamoylated estrone derivatives were >10-fold more potent than their parent compounds. The sulfamoylated estrone derivatives were also significantly more potent inhibitors of cell growth than the previously studied endogenous estradiol metabolite 2-methoxyestradiol. 2-MeOEMATE and 2-EtEMATE functioned as antimicrotubule agents and inhibited the ability of paclitaxel to promote tubulin assembly in vitro. Like other antimicrotubule agents, the sulfamoylated estrone derivatives induced BCL-2 and BCL-XL phosphorylation and increased p53 expression. 2-MeOEMATE and 2-EtEMATE are novel antimicrotubule agents that have potent anticancer activity in breast cancer cells in vitro and may be beneficial as anticancer agents in vivo.

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More information

Published date: 2000
Additional Information: PMID: 11034086

Identifiers

Local EPrints ID: 157211
URI: http://eprints.soton.ac.uk/id/eprint/157211
ISSN: 0008-5472
PURE UUID: 60921381-5797-4819-a626-74a17731c446
ORCID for Graham. Packham: ORCID iD orcid.org/0000-0002-9232-5691

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Date deposited: 08 Jun 2010 12:40
Last modified: 23 Jul 2022 01:46

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Contributors

Author: Lucy. MacCarthy-Morrogh
Author: Paul A. Townsend
Author: Atul. Purohit
Author: Hatem A.M. Hejaz
Author: Barry V.L. Potter
Author: Michael J. Reed
Author: Graham. Packham ORCID iD

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