Recent preclinical evidence has indicated that both
androgen receptor (AR) inactivation and
glucocorticoid receptor (GR) transrepression are associated with suppression of urothelial
carcinogenesis. We therefore assessed the effect of a unique compound,
2-(4-acetoxyphenyl)-2-chloro-N-methylethylammonium chloride (
Compound A; CpdA), which could function as an AR antagonist as well as a GR
ligand, on urothelial
tumorigenesis. Using the in vitro system with GR-positive non-neoplastic urothelial SVHUC cells stably expressing AR (SVHUC-AR), neoplastic transformation induced by a chemical
carcinogen 3-methylcholanthrene (MCA) was inhibited similarly by an anti-
androgen hydroxyflutamide and a
glucocorticoid prednisone, and more strongly by CpdA. CpdA also prevented the neoplastic transformation of AR-negative MCA-SVHUC cells, which was diminished by a GR antagonist
RU486, but failed to prevent that of GR knockdown MCA-SVHUC cells. In MCA-SVHUC-AR cells, CpdA significantly reduced the expression levels of oncogenes (c-Fos/c-Jun/c-Myc) and induced those of
tumor suppressors (UGT1A/p21/p27/p53/PTEN). Additionally, a potent
carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine induced
bladder cancer in all of 8 mock-treated mice versus 4 (50%) of
flutamide-treated (P = 0.021), 4 (50%) of
prednisone-treated (P = 0.021), or 2 (25%) of CpdA-treated (P = 0.002) animals. Finally, CpdA was found to reduce AR transactivation and selectively induce GR transrepression (i.e. suppression of NF-κB transactivation and expression of its regulated genes), but not GR transactivation (i.e. activation of
glucocorticoid-response element-mediated transcription and expression of its targets) in SVHUC cells. These findings suggest that CpdA suppresses urothelial
tumorigenesis via both the AR and GR pathways, which may consequently provide an effective option of
chemoprevention for
bladder cancer, especially in patients with superficial disease following transurethral surgery.