Valproic Acid as a Promising Co-Treatment With Paclitaxel and Doxorubicin in Different Ovarian Carcinoma Cell Lines.

OBJECTIVE: The current preferred treatment of ovarian cancer is combination chemotherapy, usually a platinum-based drug coupled with paclitaxel (PTX). Here, we investigated whether co-treatment with valproic acid (VPA) could increase the efficiency of various ovarian cancer drugs-PTX, doxorubicin (DOX), carboplatin (CBP), and cyclophosphamide (CP)-in different ovarian cancer cell lines. METHODS: Three different ovarian cancer cell lines (OVCAR-3, TOV-21G, and TOV-112D) were treated with chemotherapeutic drugs, alone or in combination with VPA. Cell viability (XTT assay), caspase-3 activity, and the expression of cell cycle- and apoptosis-related genes and proteins were assessed. Furthermore, the effects of these drugs on α-tubulin acetylation and DNA fragmentation were investigated. RESULTS: Paclitaxel and DOX decreased cell viability and increased caspase-3 activity, and co-treatment with VPA enhanced this effect. Carboplatin and CP had no effect. Responses to treatment with PAX and DOX together with VPA on gene expression profile were highly variable and depended on the cell line investigated. However, a common feature in all cell lines was an increased expression of CDKN1A, CCNE1, PARP1, and PARP3. Co-treatment with VPA enhanced the effect of DOX and PAX on most protein expressions investigated in TOV-21G and TOV-112D cell lines, whereas in OVCAR-3, the most effect was seen with DOX with VPA. Valproic acid did not increase PTX-induced α-tubulin acetylation. An additive effect of DOX with VPA on DNA fragmentation was observed in TOV-21G and TOV-112D cell lines but not in the OVCAR-3. CONCLUSIONS: Our results indicate that VPA could be a promising agent in combined anticancer therapy for ovarian cancer, with the combination of VPA and DOX being the most effective. Certainly, additional in vivo and ex vivo experiments are necessary to investigate the molecular mechanisms of action underlying the cellular effects reported here and to study possible clinically relevant effects in ovarian cancer explants.

[Epilepsy, antiepileptic drugs and disorders of reproductive functions of women]. / Padaczka, stosowane leki a zaburzenia funkcji rozrodczych kobiet.

Epilepsy is one of the commonest chronic neurological disorders in developing countries. The disease itself and applied antiepileptic drugs cause fertility problems. As a result of seizures changes in hypothalamic and pituitary hormone secretion occur, resulting in hyperprolactinemia, menstrual disorders, premature ovarian failure as well as occurrence of polycystic ovary syndrome (PCOS). PCOS is the main problem in women with epilepsy caused by both the disease itself as well as treatment, mainly with valproic acid. Antiepileptic drugs exert an effect mainly on the level of active hormones, their synthesis in the ovaries and binding with sex hormone binding globulin. Due to impaired reproductive function, the probability of pregnancy in women with epilepsy is up to 2-fold lower than in healthy ones. It should be, however, consider that antiepileptic drugs cross the placenta, therefore it is very important to choose the appropriate treatment, not only to prevent epileptic seizures during pregnancy, but also not harmful to the developing fetus.