The University of Southampton
University of Southampton Institutional Repository

2-MeOE2bisMATE induces caspase-dependent apoptosis in CAL51 breast cancer cells and overcomes resistance to TRAIL via cooperative activation of caspases

2-MeOE2bisMATE induces caspase-dependent apoptosis in CAL51 breast cancer cells and overcomes resistance to TRAIL via cooperative activation of caspases
2-MeOE2bisMATE induces caspase-dependent apoptosis in CAL51 breast cancer cells and overcomes resistance to TRAIL via cooperative activation of caspases
2-Methoxyoestradiol (2-MeOE2) is an endogenous oestrogen metabolite which inhibits tubulin polymerisation and has anti-tumour and anti-angiogenic activity. 2-MeOE2 induces apoptosis in a wide range of cancer cell types and has recently been demonstrated to cooperate with TRAIL to induce apoptosis in breast cancer cells. 2-Methoxyoestradiol-3,17-bis-O,O-sulphamate (2-MeOE2bisMATE) is a sulfamoylated derivative of 2-MeOE2 with enhanced activity and improved pharmacokinetic properties, and 2-MeOE2bisMATE is a promising candidate for early clinical trials. It is important, therefore, to understand the mechanisms by which 2-MeOE2bisMATE acts, and whether it retains the ability to cooperate with TRAIL. We demonstrate that 2-MeOE2bisMATE-induced apoptosis of CAL51 breast cancer cells was associated with rapid activation of caspase 3 and 9, but not caspase 8 (as measured by BID cleavage) and was completely prevented by the caspase inhibitor zVADfmk. Interfering with Fas- or TRAIL-receptor function did not prevent 2-MeOE2bisMATE-induced apoptosis. Whereas CAL51 cells were resistant to TRAIL-induced apoptosis, 2-MeOE2bisMATE and TRAIL cooperated to induce cell death. This apoptosis was associated with enhanced activation of caspases, but not increased expression of the DR5 TRAIL receptor, previously demonstrated to be induced by 2-MeOE2. Therefore, 2-MeOE2bisMATE-induced apoptosis is dependent on caspases and like 2-MeOE2, 2-MeOE2bisMATE can overcome resistance to TRAIL by stimulating activation of downstream caspases. Our results suggest that 2-MeOE2bisMATE and TRAIL might be a particularly effective combination of anti-cancer agents.
caspase, death receptor, 2-Methoxyoestradiol, oestrogen
1360-8185
323-332
Wood, L.
ad6746ad-7b7d-4386-862a-c6ffa94adacb
Leese, M.P.
dae74513-e0de-4a80-8600-7b4bdedc1c91
Mouzakiti, A.
ba10b7ea-1eb1-47e9-8dbc-4048a43024e2
Purohit, A.
244d02b1-a22c-435e-bbae-8cc97d44c733
Potter, B.V.
0244e337-e9e7-4c24-9750-75b683326c7d
Reed, M.J.
dc770ba6-b5fa-4232-b5d9-c7b51569c5d4
Packham, G.
fdabe56f-2c58-469c-aadf-38878f233394
Wood, L.
ad6746ad-7b7d-4386-862a-c6ffa94adacb
Leese, M.P.
dae74513-e0de-4a80-8600-7b4bdedc1c91
Mouzakiti, A.
ba10b7ea-1eb1-47e9-8dbc-4048a43024e2
Purohit, A.
244d02b1-a22c-435e-bbae-8cc97d44c733
Potter, B.V.
0244e337-e9e7-4c24-9750-75b683326c7d
Reed, M.J.
dc770ba6-b5fa-4232-b5d9-c7b51569c5d4
Packham, G.
fdabe56f-2c58-469c-aadf-38878f233394

Wood, L., Leese, M.P., Mouzakiti, A., Purohit, A., Potter, B.V., Reed, M.J. and Packham, G. (2004) 2-MeOE2bisMATE induces caspase-dependent apoptosis in CAL51 breast cancer cells and overcomes resistance to TRAIL via cooperative activation of caspases. Apoptosis, 9 (3), 323-332. (doi:10.1023/B:APPT.0000025809.80684.bd).

Record type: Article

Abstract

2-Methoxyoestradiol (2-MeOE2) is an endogenous oestrogen metabolite which inhibits tubulin polymerisation and has anti-tumour and anti-angiogenic activity. 2-MeOE2 induces apoptosis in a wide range of cancer cell types and has recently been demonstrated to cooperate with TRAIL to induce apoptosis in breast cancer cells. 2-Methoxyoestradiol-3,17-bis-O,O-sulphamate (2-MeOE2bisMATE) is a sulfamoylated derivative of 2-MeOE2 with enhanced activity and improved pharmacokinetic properties, and 2-MeOE2bisMATE is a promising candidate for early clinical trials. It is important, therefore, to understand the mechanisms by which 2-MeOE2bisMATE acts, and whether it retains the ability to cooperate with TRAIL. We demonstrate that 2-MeOE2bisMATE-induced apoptosis of CAL51 breast cancer cells was associated with rapid activation of caspase 3 and 9, but not caspase 8 (as measured by BID cleavage) and was completely prevented by the caspase inhibitor zVADfmk. Interfering with Fas- or TRAIL-receptor function did not prevent 2-MeOE2bisMATE-induced apoptosis. Whereas CAL51 cells were resistant to TRAIL-induced apoptosis, 2-MeOE2bisMATE and TRAIL cooperated to induce cell death. This apoptosis was associated with enhanced activation of caspases, but not increased expression of the DR5 TRAIL receptor, previously demonstrated to be induced by 2-MeOE2. Therefore, 2-MeOE2bisMATE-induced apoptosis is dependent on caspases and like 2-MeOE2, 2-MeOE2bisMATE can overcome resistance to TRAIL by stimulating activation of downstream caspases. Our results suggest that 2-MeOE2bisMATE and TRAIL might be a particularly effective combination of anti-cancer agents.

This record has no associated files available for download.

More information

Published date: 2004
Keywords: caspase, death receptor, 2-Methoxyoestradiol, oestrogen

Identifiers

Local EPrints ID: 26667
URI: http://eprints.soton.ac.uk/id/eprint/26667
ISSN: 1360-8185
PURE UUID: 028c42c7-8c29-4c86-8d4b-270cb7af0705
ORCID for G. Packham: ORCID iD orcid.org/0000-0002-9232-5691

Catalogue record

Date deposited: 21 Apr 2006
Last modified: 16 Mar 2024 03:14

Export record

Altmetrics

Contributors

Author: L. Wood
Author: M.P. Leese
Author: A. Mouzakiti
Author: A. Purohit
Author: B.V. Potter
Author: M.J. Reed
Author: G. Packham ORCID iD

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×