title: The role of 17beta-hydroxysteroid dehydrogenases in modulating the activity of 2-methoxyestradiol in breast cancer cells.
abstract: The bis-sulfamoylated derivative of 2-methoxyestradiol (2-MeOE2), 2-methoxyestradiol-3,17-O,O-bis-sulfamate (2-MeOE2bisMATE), has shown potent antiproliferative and antiangiogenic activity in vitro and inhibits tumor growth in vivo. 2-MeOE2bisMATE is bioavailable, in contrast to 2-MeOE2 that has poor bioavailability. In this study, we have examined the role of 17beta-hydroxysteroid dehydrogenase (17beta-HSD) type 2 in the metabolism of 2-MeOE2. In MDA-MB-231 cells, which express high levels of 17beta-HSD type 2, and in MCF-7 cells transfected with 17beta-HSD type 2, high-performance liquid chromatography analysis showed that a significant proportion of 2-MeOE2 was metabolized to inactive 2-methoxyestrone. Furthermore, MCF-7 cells transfected with 17beta-HSD type 2 were protected from the cytotoxic effects of 2-MeOE2. In contrast, no significant metabolism of 2-MeOE2bisMATE was detected in transfected cells and 17beta-HSD type 2 transfection did not offer protection against 2-MeOE2bisMATE cytotoxicity. This study may go some way to explaining the poor bioavailability of 2-MeOE2, as the gastrointestinal mucosa expresses high levels of 17beta-HSD type 2. In addition, this study shows the value of synthesizing sulfamoylated derivatives of 2-MeOE2 with C17-position modifications as these compounds have improved bioavailability and potency both in vitro and in vivo.
authors.affiliation: Endocrinology and Metabolic Medicine, Faculty of Medicine, Imperial College, St Mary's Hospital, London, United Kingdom. simon.newman@imperial.ac.uk
authors.forename: Simon P
authors.initials: SP
authors.lastname: Newman
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Ireson
authors.forename: Helena J
authors.initials: HJ
authors.lastname: Tutill
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Day
authors.forename: Michael F C
authors.initials: MF
authors.lastname: Parsons
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
authors.forename: Atul
authors.initials: A
authors.lastname: Purohit
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000378:metabolism*; D000077584:2-Methoxyestradiol; D001711:Biotransformation; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D004958:Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D006801:Humans; D013237:Stereoisomerism; D014162:Transfection
chemical_list: C500344:2-methoxyestradiol-3,17-bis-O,O-sulfamate; D004958:Estradiol; D000077584:2-Methoxyestradiol; D015067:17-Hydroxysteroid Dehydrogenases