title: The cytotoxic effects of estradiol-17 beta, catecholestradiols and methoxyestradiols on dividing MCF-7 and HeLa cells.
abstract: In this study the cytotoxic effects of high concentrations (greater than or equal to 1 x 10(-6) M) of estradiol-17 beta (E2), 2-/4-hydroxyestradiol-17 beta (2-/4-OHE2) and 2-/3-/4-methoxyestradiol-17 beta (2-/3-/4-MeOE2) were determined on dividing MCF-7 and HeLa cells. The 2-MeOE2 metabolite followed by 2-OHE2 and E2 (in this order) proved to be extremely toxic to dividing MCF-7 and HeLa cells. The cytotoxic effect on these cells comprised uneven chromosome distribution. Indirect immunofluorescent studies, in which monoclonal anti-alpha-tubulin antibodies were used, showed that these compounds (2-MeOE2 greater than 2-OHE2 greater than E2) at high concentrations caused abnormal and fragmented polar formations as well as disorientated microtubule arrangement in the dividing MCF-7 and HeLa cells. The 4-OHE2 and 3-/4-MeOE2 metabolites had little or no cytotoxic effects on dividing cells. The large number of abnormal metaphases seen in HeLa cells exposed to 2-MeOE2 suggested that this metabolite may be the ultimate cytotoxic compound. The reduction in the number of HeLa cells with abnormal metaphase configurations after exposure to 2-OHE2 plus quinalizarin (an inhibitor of catechol-O-methyltransferase) indicated that the production of 2-MeOE2 is necessary for the formation of abnormal spindles in metaphase. Quinalizarin treatment in the presence of 2-MeOE2 had no effect on the large number of abnormal metaphases. We therefore conclude that neither E2 nor 2-OHE2, but a high concentration of 2-MeOE2 is responsible for abnormal spindle formation. In additional experiments the number of normal and abnormal dividing HeLa cells were greatly reduced when simultaneously exposed to E2 and 2-/4-hydroxylase-inhibitor alpha-naphthoflavone.
authors.affiliation: Department of Physiology, Medical School, University of Pretoria, South Africa.
authors.forename: J C
authors.initials: JC
authors.lastname: Seegers
authors.forename: M L
authors.initials: ML
authors.lastname: Aveling
authors.forename: C H
authors.initials: CH
authors.lastname: Van Aswegen
authors.forename: M
authors.initials: M
authors.lastname: Cross
authors.forename: F
authors.initials: F
authors.lastname: Koch
authors.forename: W S
authors.initials: WS
authors.lastname: Joubert
mesh_terms: D001571:Benzoflavones / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002393:Estrogens, Catechol / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D006900:Hydroxylation; D007150:Immunohistochemistry; D008677:Metaphase; D008940:Mitotic Index; D014404:Tubulin / Q000032:analysis
chemical_list: D001571:Benzoflavones; D002393:Estrogens, Catechol; D014404:Tubulin; D004958:Estradiol; C011512:alpha-naphthoflavone