Adenoviral neutral endopeptidase gene delivery in combination with paclitaxel for the treatment of prostate cancer

Neutral endopeptidase (NEP) is a cell-surface peptidase that inhibits prostate cancer cell growth partly via inhibition of Akt kinase. We investigated the antitumor effects of an adenovirus gene delivery system (AdNEP) to restore NEP expression in DU145 prostate cancer cells in combination with paclitaxel chemotherapy. DU145 cells were infected with adenovirus expressing NEP or LacZ, treated with paclitaxel, and assessed for cell viability, Akt activation and induction of apoptosis. Athymic mice with established DU145 xenografts were injected intratumorally with AdNEP or AdLacZ and intraperitoneally with paclitaxel and monitored for tumor growth over 28 days. Compared to AdLacZ plus paclitaxel, AdNEP plus paclitaxel significantly inhibited DU145 cell growth and increased apoptosis as determined by increased caspase-3 and PARP-1 proteolytic fragments. In a xenograft model, tumor volume was reduced in mice treated with AdNEP plus paclitaxel (122.85±89.5 mm(3); P<0.01) compared with mice treated with AdNEP plus saline (653.9±230.3 mm(3)), AdLacZ plus paclitaxel (575.9±176.6 mm(3)) or AdLacZ plus saline (920.2±238.2 mm(3)). In conclusion, these data suggest that NEP can augment taxane-induced apoptosis through inhibition of Akt/Bad signaling, and that the combination of NEP plus paclitaxel may be an effective strategy to inhibit castration-resistant prostate cancer growth.