MP83-20 ENZALUTAMIDE AS AN ANDROGEN RECEPTOR INHIBITOR PREVENTS UROTHELIAL TUMORIGENESIS

Emerging preclinical evidence suggests the critical role of androgen-mediated androgen receptor (AR) signals in the development of bladder cancer. However, little is known about the efficacy of enzalutamide, an AR signaling inhibitor, in androgen-induced urothelial tumorigenesis. We therefore aimed to assess the effects of enzalutamide on neoplastic transformation of urothelial cells. An immortalized normal urothelial cell line SVHUC stably expressing wild-type AR (SVHUC-AR) was exposed to a chemical carcinogen 3-methylcholanthrene (MCA) to induce neoplastic transformation, and subsequently cultured for 6 weeks in the presence of anti-androgens, including enzalutamide, hydroxyflutamide, and bicalutamide. Tumorigenesis was then monitored, using plate and soft agar colony formation assays as well as mouse xenograft models. In SVHUC-AR cells exposed to MCA, each anti-androgen inhibited AR-mediated transcriptional activity, but only enzalutamide prevented AR nuclear translocation. In vitro transformation showed that treatment with each anti-androgen during the process of neoplastic transformation reduced the efficiency of colony formation in vitro. Compared with mock treatment, culture with enzalutamide (P = 0.028), hydroxyflutamide (P = 0.033), or bicalutamide (P = 0.038) also resulted in prevention/retardation of tumor formation in male NOD-SCID mice. In addition, anti-androgens up-regulated the expression of several molecules that play a protective role in bladder tumorigenesis, including p53, p21, and PTEN, and down-regulated that of several oncogenic genes, such as c-myc, cyclin D1, and cyclin E, in MCA-exposed SVHUC-AR cells. Thus, enzalutamide, flutamide, and bicalutamide were found to similarly prevent neoplastic transformation of urothelial cells. These findings offer a potential chemopreventive approach for urothelial tumors using AR antagonists.