PHENYLBUTYRATE INDUCES APOPTOSIS IN HUMAN PROSTATE-CANCER AND IS MOREPOTENT THAN PHENYLACETATE

Phenylbutyrate (PB), a novel lead compound for prostate cancer therapy , has molecular activities distinct from its metabolite, phenylacetate (PA), Both PB and PA promote differentiation in human prostate cancer cell lines, Set little data exist comparing the cytotoxic effects of each drug, We found that PB is more potent than PA in vitro; PB is 1.5 -2.5 times more active at inhibiting growth and inducing programmed ce ll death than PA at clinically achievable doses against each human pro state cancer line studied, PB is equipotent to sodium butyrate, which induces apoptosis and differentiation through multiple mechanisms, Exp osure of prostate cancer cell lines to PB reduces their DNA synthesis, leads to fragmentation of genomic DNA, and causes 50-60% of cells to undergo apoptosis, These PB-induced effects are 2-10 times greater tha n those of the control or PA, The stereotypical changes of apoptosis c an be seen with sodium butyrate at similar concentrations, but not wit h PA, Prostate cancer cell lines overexpressing P-glycoprotein or poss essing heterogeneous molecular alterations, including p53 mutations, a re also sensitive to the effects of PB. In vivo, Copenhagen rats treat ed with oral PB had delayed growth of the androgen refractory Dunning R-3327 MAT-LyLu prostate cancer subline by 30-45% in a dose-dependent manner, These results demonstrate that PB induces cytotoxicity via apo ptosis in human prostate cancer, in addition to its differentiating pr operties.