Therapeutic Potential of Bipolar Androgen Therapy for Castration-Resistant Prostate Cancer: In Vitro and In Vivo Studies

Androgen deprivation therapy (ADT) is a primary treatment for advanced prostate cancer (PCa), but resistance often leads to castration-resistant PCa (CRPC). CRPC remains androgen receptor (AR)-dependent, and AR overexpression causes vulnerability to high doses of androgen in CRPC. Bipolar androgen therapy (BAT) refers to the periodic administration of testosterone, resulting in oscillation between supraphysiologic and near-castrate serum testosterone levels. In this study, we evaluated the efficacy of BAT against CRPC in a preclinical setting. To emulate CRPC characteristics, PCa cell lines (LNCaP, VCaP, and 22Rv1) were cultured in phenol red-free RPMI-1640 medium supplemented with 10% dextran-coated charcoal treated FBS (A- cell line). Cell viability, AR, and AR-V7 expression were evaluated using the Cell Counting Kit-8 and Western blotting. In vivo studies involved 12 castrated NOG mice injected with LNCaP/A- cells, treated with testosterone pellets or controls in 2-week cycles. Tumor sizes were measured post a 6-week treatment cycle. Bicalutamide inhibited PCa cell viability but not in the adapted cell lines. Supraphysiologic androgen levels suppressed AR-expressing PCa cell growth in vitro. In vivo, high AR-expressing LNCaP cells proliferated under castrate conditions, while BAT-treated xenografts exhibited significant growth inhibition with low Ki-67 and mitotic indexes and a high cell death index. This study provides preliminary evidence that BAT is effective for the treatment of CRPC through rapid cycling between supraphysiologic and near-castrate serum testosterone levels, inducing an anti-tumor effect.