Olsen Christel M, Meussen-Elholm Elise T M, Røste Line S, Taubøll Erik
Division of Environmental Medicine, Norwegian Institute of Public Health, PO Box 4404, Nydalen, Oslo 0403, Norway.
Mol Cell Endocrinol. 2004 Jan 15;213(2):173-9. doi: 10.1016/j.mce.2003.10.032.
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.
几种抗癫痫药物（AEDs）具有抗癌活性。同时，许多AEDs会改变内分泌功能，苯妥英（PHT）和苯巴比妥（PB）会导致性甾体激素的游离部分减少，而丙戊酸（VPA）会诱发高雄激素血症。已知性甾体激素水平的变化会影响内分泌组织中的细胞凋亡。本研究的目的是调查抗癫痫药物PHT、PB、VPA和拉莫三嗪（LTG）对雌激素刺激的人乳腺癌细胞（MCF-7）生长的影响，并评估这种影响是否与直接的雌激素受体（ER）结合有关。VPA在治疗相关浓度下可降低细胞生长；VPA对细胞生长的半数最大效应为230微摩尔。PHT（100微摩尔）和PB（10微摩尔）分别使细胞生长降低了47%和21%。这些药物均对分离的雌激素受体没有亲和力，且过量的雌激素也无法消除VPA引起的生长抑制。然而，亚治疗浓度的VPA（100微摩尔）在雌激素缺乏的培养基中通过诱导细胞生长（11%）模拟了雌激素的作用，添加雌激素受体拮抗剂可消除这种作用。总之，亚治疗浓度的VPA似乎可间接激活雌激素受体，但治疗浓度的VPA通过似乎不涉及雌激素受体或雌激素刺激的机制抑制细胞生长。
