title: Antiepileptic drugs inhibit cell growth in the human breast cancer cell line MCF7.
abstract: Several antiepileptic drugs (AEDs) are associated with anti-cancer activity. At the same time, many AEDs alter endocrine function with phenytoin (PHT) and phenobarbital (PB) causing-reduced free fractions of sex-steroid hormones, while VPA induces hyperandrogenism. Changes in sex-steroid hormone levels are known to affect apoptosis in endocrine tissue. The aim of the study was to investigate the influence of the antiepileptic drugs PHT, PB, VPA and lamotrigine (LTG) on estrogen-stimulated cell growth of human breast cancer cells (MCF-7), and to evaluate whether this effect could be related to a direct estrogen receptor (ER) binding. VPA reduced cell growth at therapeutically relevant concentrations; half-maximum effect of VPA on cell growth was 230 microM. PHT (100 microM) and PB (10 microM) reduced cell growth by 47 and 21%, respectively. None of the drugs had affinity to isolated estrogen receptors, and excess of estrogen was not able to abolish the growth inhibition provoked by VPA. However, sub-therapeutic concentrations of VPA (100 microM) mimicked estrogen by inducing cell growth (11%) in an estrogen-depleted medium, an effect that was abolished by adding an estrogen receptor antagonist. In conclusion; the estrogen receptor appear to be indirectly activated by sub-therapeutic concentrations of VPA, but therapeutic concentrations of VPA inhibits cell growth by mechanisms that do not seem to involve the estrogen receptor or estrogen stimulation.
authors.affiliation: Division of Environmental Medicine, Norwegian Institute of Public Health, PO Box 4404, Nydalen, Oslo 0403, Norway. christel.olsen@fhi.no
authors.forename: Christel M
authors.initials: CM
authors.lastname: Olsen
authors.forename: Elise T M
authors.initials: ET
authors.lastname: Meussen-Elholm
authors.forename: Line S
authors.initials: LS
authors.lastname: Røste
authors.forename: Erik
authors.initials: E
authors.lastname: Taubøll
mesh_terms: D000927:Anticonvulsants / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004967:Estrogens; D005260:Female; D006801:Humans; D000077213:Lamotrigine; D010634:Phenobarbital / Q000494:pharmacology; D010672:Phenytoin / Q000494:pharmacology; D011485:Protein Binding; D011960:Receptors, Estrogen / Q000378:metabolism; D014227:Triazines / Q000494:pharmacology; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: D000927:Anticonvulsants; D004967:Estrogens; D011960:Receptors, Estrogen; D014227:Triazines; D014635:Valproic Acid; D010672:Phenytoin; D000077213:Lamotrigine; D010634:Phenobarbital