Valproic acid induces apoptosis in prostate carcinoma cell lines by activation of multiple death pathways

Valproic acid is a well-known antiepileptic drug that was recently discovered to have a wide-spectrum antitumoral action in several tumors. In our work, we tested the proapoptotic activity of valproic acid in prostate cancer. Valproic acid-induced apoptosis was described by several in-vitro assays in three prostate cancer cell lines: two representing the prototype of advanced, clinically untreatable stages of prostate progression, PC3 and DU145, and one resembling a more differentiated androgen-sensitive tumor, LNCaP. We observed that valproic acid was a potent and early apoptotic inducer, mainly in less-differentiated prostate cancer cell lines. The molecular analysis of the apoptotic machinery involved in valproic acid action revealed a central role in Bcl-2 downmodulation. When prostate cancer cells were treated for a longer time with valproic acid, we detected an enhancement of Fas-dependent apoptosis associated with an overexpression in Fas and Fas ligand. Our data indicate that the use of valproic acid may be a suitable therapeutic agent in the control of prostate cancer progression and its action appears particularly relevant in the control of refractory stages of prostate cancer.