title: Direct antiproliferative effect of nonsteroidal 17β-hydroxysteroid dehydrogenase type 1 inhibitors in vitro.
abstract: Inhibition of the local formation of estrogens seems to be an attractive strategy for pharmacological intervention in hormone-dependent disorders. The direct antiproliferative properties of ten nonsteroidal 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) inhibitors were investigated on human cancer cell lines of gynecological origin. The mechanism of the antiproliferative action was approximated by cell cycle analysis, fluorescent microscopy, BrdU assay, determination of caspase-3 activity and quantification of the expression of cell cycle regulators at mRNA level. Treatment of HeLa cells with some of the compounds resulted in a concentration-dependent inhibition of the G1-S transition and an increase in the apoptotic population. The most effective agents increased the expression of tumor suppressors p21 and p53, while CDK2 and Rb were down-regulated. The reported anticancer actions of the tested compounds are independent of the 17β-HSD1-inhibiting capacity. These results indicate that it is possible to combine direct antiproliferative activity and 17β-HSD1 inhibition resulting in novel agents with dual mode of action.
authors.affiliation: Department of Pharmacodynamics and Biopharmacy, University of Szeged, Szeged, Hungary.
authors.forename: Ágnes
authors.initials: Á
authors.lastname: Berényi
authors.forename: Martin
authors.initials: M
authors.lastname: Frotscher
authors.forename: Sandrine
authors.initials: S
authors.lastname: Marchais-Oberwinkler
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
authors.forename: Renáta
authors.initials: R
authors.lastname: Minorics
authors.forename: Imre
authors.initials: I
authors.lastname: Ocsovszki
authors.forename: George
authors.initials: G
authors.lastname: Falkay
authors.forename: István
authors.initials: I
authors.lastname: Zupkó
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D015067:17-Hydroxysteroid Dehydrogenases