2-MeOE2bisMATE and 2-EtE2bisMATE induce cell cycle arrest and apoptosis in breast cancer xenografts as shown by a novel ex vivo technique

Paul A. Foster, Yaik T. Ho, Simon P. Newman, Philip G. Kasprzyk, Mathew P. Leese, Barry V. L. Potter, Michael J. Reed, Atul Purohit

Research output: Contribution to journalArticle

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Abstract

Breast cancer is the leading cause of cancer deaths among women worldwide. The theory of targeting both cancer cells directly and their blood supply has significant therapeutic potential. However, to date, there are few clinically successful single agents that meet these criteria. 2-Methoxyestradiol-3,17-O,O-bis-sulfamate (2-MeOE2bisMATE) and 2-ethylestradiol-3,17-O,O-bis-sulfamate (2-EtE2bisMATE) are potent inhibitors of proliferation in a range of cancer cells. The work presented here demonstrates the potent in vitro and in vivo effects of these compounds. They cause apoptosis via the intrinsic mitochondrial pathway in both MDA-MB-231 breast cancer cells and endothelial cells. Furthermore, they are potent anti-angiogenic inhibitors in vivo, as shown by their ability to reduce endothelial staining in MDA-MB-231 xenograft tumors. We have developed a novel, flow cytometry based, ex vivo method which shows in cells recovered from MDA-MB-231 tumors treated with 2-MeOE2bisMATE and 2-EtE2bisMATE an increase in intra-tumoral G(2)-M arrest and apoptosis. The degree of apoptosis inversely correlates to tumor volume. Further in vivo studies reveal that both 2-MeOE2bisMATE and 2-EtE2bisMATE are orally bioavailable and extremely efficacious when compared to clinically tested drugs. As these compounds are anti-proliferative against breast cancer and endothelial cells they have the potential to be potent, dual acting clinical drugs of the future.
Original languageEnglish
Pages (from-to)251-260
JournalBreast Cancer Research and Treatment
Volume111
Issue number2
DOIs
Publication statusPublished - 2008

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Cell Cycle Checkpoints
Heterografts
Apoptosis
Breast Neoplasms
Neoplasms
Endothelial Cells
Angiogenesis Inhibitors
Tumor Burden
Pharmaceutical Preparations
Cause of Death
Flow Cytometry
2-methoxyestradiol-3,17-bis-O,O-sulfamate
2-ethylestradiol sulfamate
Staining and Labeling
Therapeutics

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2-MeOE2bisMATE and 2-EtE2bisMATE induce cell cycle arrest and apoptosis in breast cancer xenografts as shown by a novel ex vivo technique. / Foster, Paul A.; Ho, Yaik T.; Newman, Simon P.; Kasprzyk, Philip G.; Leese, Mathew P.; Potter, Barry V. L.; Reed, Michael J.; Purohit, Atul.

In: Breast Cancer Research and Treatment, Vol. 111, No. 2, 2008, p. 251-260.

Research output: Contribution to journalArticle

Foster, Paul A. ; Ho, Yaik T. ; Newman, Simon P. ; Kasprzyk, Philip G. ; Leese, Mathew P. ; Potter, Barry V. L. ; Reed, Michael J. ; Purohit, Atul. / 2-MeOE2bisMATE and 2-EtE2bisMATE induce cell cycle arrest and apoptosis in breast cancer xenografts as shown by a novel ex vivo technique. In: Breast Cancer Research and Treatment. 2008 ; Vol. 111, No. 2. pp. 251-260.
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