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.
Angelucci
Adriano
A
Department of Basic and Applied Biology, Science School, University of L'Aquila, and Bambino Gesù Hospital-IRCCS, Rome, Italy. adriano.angelucci@gmail.com
Valentini
Alessandra
A
Millimaggi
Danilo
D
Gravina
Giovanni L
GL
Miano
Roberto
R
Dolo
Vincenza
V
Vicentini
Carlo
C
Bologna
Mauro
M
Federici
Giorgio
G
Bernardini
Sergio
S
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002277:Carcinoma / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D053222:Fas Ligand Protein / Q000378:metabolism; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects*; D014158:Transcription, Genetic / Q000502:physiology; D014635:Valproic Acid / Q000494:pharmacology*; D019014:fas Receptor / Q000378:metabolism
D000970:Antineoplastic Agents; D053222:Fas Ligand Protein; D019014:fas Receptor; D014635:Valproic Acid