We previously reported that our novel compound
3beta-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene (VN/124-1) is a potent 17alpha-
hydroxylase/
17,20-lyase (
CYP17) inhibitor/
antiandrogen and strongly inhibits the formation and proliferation of human
prostate cancer LAPC4
tumor xenografts in severe combined immunodeficient mice. In this study, we report that VN/124-1 and other novel
CYP17 inhibitors also cause down-regulation of
androgen receptor (AR)
protein expression in vitro and in vivo. This mechanism of action seems to contribute to their antitumor efficacy. We compared the in vivo antitumor efficacy of VN/124-1 with that of
castration and a clinically used
antiandrogen,
Casodex, and show that VN/124-1 is more potent than
castration in the LAPC4 xenograft model. Treatment with VN/124-1 (0.13 mmol/kg twice daily) was also very effective in preventing the formation of LAPC4
tumors (6.94 versus 2410.28 mm(3) in control group). VN/124-1 (0.13 mmol/kg twice daily) and VN/124-1 (0.13 mmol/kg twice daily) +
castration induced regression of LAPC4
tumor xenografts by 26.55% and 60.67%, respectively. Treatments with
Casodex (0.13 mmol/kg twice daily) or
castration caused significant
tumor suppression compared with control. Furthermore, treatment with VN/124-1 caused marked down-regulation of AR
protein expression, in contrast to treatments with
Casodex or
castration that caused significant up-regulation of AR
protein expression. The results suggest that VN/124-1 acts by several mechanisms (
CYP17 inhibition, competitive inhibition, and down-regulation of the AR). These actions contribute to inhibition of the formation of LAPC4
tumors and cause regression of growth of established
tumors. VN/124-1 is more efficacious than
castration in the LAPC4 xenograft model, suggesting that the compound has potential for the treatment of
prostate cancer.