Genitourinary Oncology Research Laboratory, Department of Medicine, Weill Cornell Medical College and Weill Cornell Cancer Center, New York, NY, USA.
Int J Oncol. 2012 Oct;41(4):1192-8. doi: 10.3892/ijo.2012.1586. Epub 2012 Aug 8.
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 mm3; P<0.01) compared with mice treated with AdNEP plus saline (653.9±230.3 mm3), AdLacZ plus paclitaxel (575.9±176.6 mm3) or AdLacZ plus saline (920.2±238.2 mm3). 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.
中性内肽酶（NEP）是一种细胞表面肽酶，通过抑制 Akt 激酶来部分抑制前列腺癌细胞生长。我们研究了腺病毒基因传递系统（AdNEP）恢复 DU145 前列腺癌细胞中 NEP 表达，与紫杉醇化疗联合治疗的抗肿瘤作用。将表达 NEP 或 LacZ 的腺病毒感染 DU145 细胞，用紫杉醇处理，并评估细胞活力、Akt 激活和诱导凋亡。将已建立的 DU145 异种移植物的裸鼠瘤内注射 AdNEP 或 AdLacZ，并腹腔内注射紫杉醇，并在 28 天内监测肿瘤生长。与 AdLacZ 加紫杉醇相比，AdNEP 加紫杉醇显着抑制 DU145 细胞生长并增加凋亡，这是通过增加 caspase-3 和 PARP-1 蛋白水解片段来确定的。在异种移植模型中，与 AdNEP 加生理盐水（653.9±230.3 mm3）、AdLacZ 加紫杉醇（575.9±176.6 mm3）或 AdLacZ 加生理盐水（920.2±238.2 mm3）相比，用 AdNEP 加紫杉醇治疗的小鼠肿瘤体积减少（122.85±89.5 mm3；P<0.01）。综上所述，这些数据表明 NEP 可以通过抑制 Akt/Bad 信号转导增强紫杉烷诱导的凋亡，并且 NEP 加紫杉醇的组合可能是抑制去势抵抗性前列腺癌生长的有效策略。
