title: Inhibition of MDA-MB-231 cell cycle progression and cell proliferation by C-2-substituted oestradiol mono- and bis-3-O-sulphamates.
abstract: 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 ERalpha -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 ERalpha -ve cells, these analogues should hold considerable therapeutic potential for the treatment of hormone-independent breast cancers.
authors.affiliation: Endocrinology and Metabolic Medicine and Sterix Ltd., Faculty of Medicine, Imperial College, St. Mary's Hospital, London, United Kingdom. bmalini@imperial.ac.uk
authors.forename: Bindumalini
authors.initials: B
authors.lastname: Raobaikady
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Reed
authors.forename: Mathew P
authors.initials: MP
authors.lastname: Leese
authors.forename: Barry V L
authors.initials: BV
authors.lastname: Potter
authors.forename: Atul
authors.initials: A
authors.lastname: Purohit
mesh_terms: D000077584:2-Methoxyestradiol; D001943:Breast Neoplasms / Q000188:drug therapy*; D002455:Cell Division / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D003094:Collagen / Q000378:metabolism; D004338:Drug Combinations; D004958:Estradiol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D016195:G2 Phase / Q000187:drug effects*; D006801:Humans; D007797:Laminin / Q000378:metabolism; D010766:Phosphorylation; D011509:Proteoglycans / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013451:Sulfonic Acids / Q000138:chemical synthesis / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
chemical_list: C475284:2-ethyloestradiol-bis-sulfamate; D004338:Drug Combinations; D047628:Estrogen Receptor alpha; D007797:Laminin; D011509:Proteoglycans; D019253:Proto-Oncogene Proteins c-bcl-2; D013451:Sulfonic Acids; C059485:matrigel; D004958:Estradiol; D000077584:2-Methoxyestradiol; D003094:Collagen; C005741:sulfamic acid