Inhibition of MCF-7 breast cancer cell proliferation and in vivo steroid sulphatase activity by 2-methoxyoestradiol-bis-sulphamate.

Abstract

The endogenous oestrogen metabolite, 2-methoxyoestradiol (2-MeOE2) inhibits the growth of breast cancer cells and is also a potent anti-angiogenic agent. We have previously shown that the 3-sulphamoylated derivatives of 2-methoxyoestrogens are more potent than the non-sulphamoylated compounds. In this study, we have compared the abilities of 2-methoxyoestradiol-bis-sulphamate (2-MeOE2bisMATE) and 2-MeOE2 to inhibit the growth of MCF-7 breast cancer cells. Both compounds inhibited cell growth with the IC(50) for 2-MeOE2bisMATE (0.4 microM) being six-fold lower than that for 2-MeOE2 (2.5 microM). Oestrogen sulphamates are potent inhibitors of steroid sulphatase (STS) activity. 2-MeOE2bisMATE was found to retain its STS inhibitory activity and in a placental microsome assay system it was equipotent with oestrone-3-O-sulphamate (EMATE). An in vivo study was also carried out to compare the potency of 2-MeOE2bisMATE with that of EMATE and the non-steroidal STS inhibitor, 667 coumarin sulphamate (667 COUMATE). After a single oral dose (10mg/kg) some recovery of STS activity was detected by day 3 (10%) with activity partially restored (55%) by day 7 after administration of 667 COUMATE. For the other two steroidal compounds, STS activity remained almost completely inactivated for up to 5 days with complete restoration of activity occurring by day 15. The anti-proliferative and STS inhibitory properties of 2-MeOE2bisMATE suggest that it has considerable potential for development as a novel anti-cancer drug.

• Authors: Bindumalini Raobaikady, Atul Purohit, Surinder K Chander, L W Lawrence Woo, Mathew P Leese, Barry V L Potter, Michael J Reed
• Journal: The Journal of steroid biochemistry and molecular biology (J Steroid Biochem Mol Biol) Vol. 84 Issue 2-3 Pg. 351-8 (Feb 2003) ISSN: 0960-0760 [Print] England
• PMID: 12711022 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Coumarins
• Enzyme Inhibitors
• Sulfonamides
• Sulfonic Acids
• irosustat
• Estradiol
• 2-Methoxyestradiol
• coumarin
• Arylsulfatases
• Steryl-Sulfatase

Topics

• 2-Methoxyestradiol
• Animals
• Arylsulfatases (metabolism)
• Cell Division
• Coumarins (pharmacology)
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (pharmacology)
• Estradiol (analogs & derivatives, analysis, metabolism)
• Female
• Humans
• Inhibitory Concentration 50
• Microsomes (metabolism)
• Models, Chemical
• Placenta (metabolism)
• Rats
• Rats, Wistar
• Steryl-Sulfatase
• Sulfonamides (pharmacology)
• Sulfonic Acids
• Time Factors
• Tumor Cells, Cultured