Abstracts

Several antiepileptic drugs (AEDs) are associated with anti-cancer activity. At the same time, many AEDs alter endocrine function with VPA inducing hyperandrogenism. Changes in sex steroid hormone levels are known to affect apoptosis in endocrine tissue and androgens are pro-apoptotic in the ovary. It has also been shown recently that VPA reduces estrogen induced cell growth in human breast cancer cells. Do VPA affect cell proliferation and apoptosis in the ovary?
Small and medium sized ovarian follicles were obtained from pig ovaries on days 8-10 and 14-16 of the oestrus cycle. Co-cultures of theca and granulosa cells were prepared and cultured for 48 hrs in control medium or VPA (100 or 250 [micro]g/ml). Cell apoptosis was studied by measuring caspase-3 activity while cell viability was estimated by the Alamar Blue test.
VPA significantly and dose-dependently increased caspase-3 activity in both small and medium follicles, suggesting an apoptotic effect of the drug. In small follicles, caspase-3 activity increased with approx. 50% at 100 and 200% at 250 [micro]g/ml of VPA. In medium follicles, caspase-3 activity increased with approx. 40% at 100 and 115% after 250 [micro]g/ml. VPA had no effect on follicular cell proliferation and viability evaluated by the Alamar Blue test.
VPA increased caspase-3 activity in a dose dependent manner and at therapeutic drug concentrations, suggesting an apoptotic effect of the drug. Our previous animal experiments have shown a disruption of follicular steroidogenesis induced by VPA, resulting in an increased androgen to estrogen ratio and low estradiol levels. The possibility exists that an apoptotic action of VPA in the ovary might be linked to the steroidogenic effects of the drug. This will have wide clinical implications, possibly also for the treatment of cancer in endocrine tissue