title: The effects of 2-substituted oestrogen sulphamates on the growth of prostate and ovarian cancer cells.
abstract: The human endogenous metabolite 2-methoxyoestradiol (2-MeOE2) has been shown to inhibit the proliferation of breast cancer cells. We have previously shown that sulphamoylation of a series of 2-substituted oestrogens greatly enhances their ability to inhibit breast cancer cell proliferation and induce apoptosis. In this study, we have investigated the ability of a number of 2-substituted oestrogens and their sulphamoylated derivatives to inhibit the proliferation of two prostate cancer cell lines, an ovarian cancer cell line and its drug-resistant derivatives. 2-Methoxyoestrone, 2-ethyloestrone and 2-ethyloestradiol had little effect on the growth of the cell lines tested (IC(50)>10 microM). 2-MeOE2 did inhibit the growth of the cells (IC(50)<10 microM), but to a lesser extent than any of the sulphamoylated derivatives tested (IC(50)<1.0 microM). Cells treated with the sulphamoylated derivatives became detached and rounded, displaying a characteristic apoptotic appearance. FACS analysis revealed induced G(2)/M cell cycle arrest. Treatment of cells and subsequent drug removal indicated that the effects of the drugs on the cells were irreversible. Immunoblot analysis indicated that apoptosis may be induced by phosphorylation of BCL-2. From these studies, 2-substituted oestrogen sulphamates are emerging as a potent new class of drug that may be effective against AR+/AR- prostate and ovarian tumours, and against tumours that are resistant to conventional chemotherapeutic regimens.
authors.affiliation: Endocrinology and Metabolic Medicine, Faculty of Medicine and Sterix Ltd., Imperial College, St. Mary's Hospital, London W2 1NY, UK. joanna.day@ic.ac.uk
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Day
authors.forename: Simon P
authors.initials: SP
authors.lastname: Newman
authors.forename: Alexander
authors.initials: A
authors.lastname: Comninos
authors.forename: Claire
authors.initials: C
authors.lastname: Solomon
authors.forename: Atul
authors.initials: A
authors.lastname: Purohit
authors.forename: Matthew 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; D017209:Apoptosis; D002455:Cell Division / Q000187:drug effects; D002469:Cell Separation; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology*; D004970:Estrone / Q000031:analogs & derivatives* / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D016193:G1 Phase; D016195:G2 Phase; D006801:Humans; D006894:Hydroxyestrones / Q000378:metabolism; D015151:Immunoblotting; D020128:Inhibitory Concentration 50; D008297:Male; D008938:Mitosis; D008956:Models, Chemical; D010051:Ovarian Neoplasms / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured
chemical_list: C414671:2-ethylestrone-3-O-sulfamate; D006894:Hydroxyestrones; D019253:Proto-Oncogene Proteins c-bcl-2; D004970:Estrone; D004958:Estradiol; D000077584:2-Methoxyestradiol; D017239:Paclitaxel; C003655:2-methoxyestrone