K. Minamiguchi, Masanao Seki, H. Aoyagi
Nov 1, 2014
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European Journal of Cancer
Abstract
Background: Recent evidence from both preclinical and clinical studies is consistent with the importance of reactivation of androgen receptor (AR) signaling in a majority of castration-resistant prostate cancer (CRPC). This knowledge has driven the clinical development of new inhibitors of androgen production (e.g., abiraterone) and AR signaling (e.g., enzalutamide). However, resistance to these new therapies has already been reported. Reactivation of AR signaling occurs by several mechanisms in CRPC. In the present study, we describe the biological characterization of TAS3681, which is a new AR antagonist with AR downregulation activity, and propose this concept as a potential new approach for the treatment of CRPC. Methods: For cell growth assay, prostate cancer cells were treated with androgen and TAS3681 in steroid depleted media for 3 days, and the living cells were determined by using wst-8 reagent. For assay of AR transactivation, COS-7 cells were transiently transfected with androgenresponsive reporter gene construct and expression vectors encoding wt or mu ARs. The transfected cells were treated with TAS3681 and androgen in steroid depleted media for 24 h, and luciferase activity was measured. For an in vivo pharmacodynamic (PD) assay to confirm AR downregulation in tumor, TAS3681 was orally dosed in CRPC tumor xenograft model. Tumor was isolated and AR level in tumor was determined by Western blot. Results: In cell growth assay, TAS3681 suppressed the growth of AR positive prostate cancer cells but did not affect that of AR-negative DU145 prostate cancer cells, indicating a dependency on AR for efficacy. TAS3681 did not stimulate AR nuclear translocation and suppressed wt and mu ARs (including F876L) transactivation in cells, indicative of its pure AR antagonist profile. In contrast to enzalutamide and bicalutamide, TAS3681 effectively suppressed androgen-independent AR transactivation by growth factors and cytokines via AR downregulation activity. Interestingly, in prostate cancer cells which express full-length and splice variant AR, TAS3681 reduced the expression of both ARs. Moreover, TAS3681 treatment effectively decreased AR level in CRPC tumors in vivo. Conclusion: Our findings suggest that TAS3681, a new type of AR antagonist with AR downregulation activity, has the potential to circumvent resistance to current and 2nd-generation therapies targeting AR signaling and could provide a new therapeutic strategy in the treatment of CRPC.