title: 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.affiliation: Endocrinology and Metabolic Medicine, Faculty of Medicine and Sterix Ltd., Imperial College, St. Mary's Hospital, London W2 1NY, UK. b.malini@ic.ac.uk
authors.forename: Bindumalini
authors.initials: B
authors.lastname: Raobaikady
authors.forename: Atul
authors.initials: A
authors.lastname: Purohit
authors.forename: Surinder K
authors.initials: SK
authors.lastname: Chander
authors.forename: L W Lawrence
authors.initials: LW
authors.lastname: Woo
authors.forename: Mathew P
authors.initials: MP
authors.lastname: Leese
authors.forename: Barry V L
authors.initials: BV
authors.lastname: Potter
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Reed
mesh_terms: D000077584:2-Methoxyestradiol; D000818:Animals; D001192:Arylsulfatases / Q000378:metabolism*; D002455:Cell Division; D003374:Coumarins / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives / Q000032:analysis / Q000378:metabolism*; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008861:Microsomes / Q000378:metabolism; D008956:Models, Chemical; D010920:Placenta / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D043266:Steryl-Sulfatase; D013449:Sulfonamides / Q000494:pharmacology; D013451:Sulfonic Acids; D013997:Time Factors; D014407:Tumor Cells, Cultured
chemical_list: D003374:Coumarins; D004791:Enzyme Inhibitors; D013449:Sulfonamides; D013451:Sulfonic Acids; C520511:irosustat; D004958:Estradiol; D000077584:2-Methoxyestradiol; C030123:coumarin; D001192:Arylsulfatases; D043266:Steryl-Sulfatase