Inhibition of MDA-MB-231 cell cycle progression and cell proliferation by C-2-substituted oestradiol mono- and bis-3-O-sulphamates
Article first published online: 4 MAY 2005
Copyright © 2005 Wiley-Liss, Inc.
International Journal of Cancer
Volume 117, Issue 1, pages 150–159, 20 October 2005
How to Cite
Raobaikady, B., Reed, M. J., Leese, M. P., Potter, B. V.L. and Purohit, A. (2005), Inhibition of MDA-MB-231 cell cycle progression and cell proliferation by C-2-substituted oestradiol mono- and bis-3-O-sulphamates. Int. J. Cancer, 117: 150–159. doi: 10.1002/ijc.21066
- Issue published online: 2 AUG 2005
- Article first published online: 4 MAY 2005
- Manuscript Accepted: 26 JAN 2005
- Manuscript Received: 17 SEP 2004
- Sterix Ltd., a member of the Ipsen Group
- oestrogen sulphamates;
- antiproliferative effects;
- breast cancer
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 ERα −ve 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® 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 ERα −ve cells, these analogues should hold considerable therapeutic potential for the treatment of hormone-independent breast cancers. © 2005 Wiley-Liss, Inc.