Effects of the Anti-Androgen Bicalutamide on Prostate Cancer Cells

The use of anti-androgen therapy for the treatment of invasive and metastatic prostate cancer is common practice. However, after an initial response, the tumor frequently progresses to 'castrate resistant prostate cancer' (CRPC), and becomes very difficult to treat. This progression has been attributed to mutations in the androgen receptor. However, despite its widespread use, the mechanisms and effects of anti-androgen therapy on prostate cancer cells are poorly understood. Utilizing flow cytometry, gene array, qPCR and western blotting we have compared the response of two androgen receptor positive cell lines LNCaP (which harbors a mutated androgen receptor and the PC-346C (which expresses the wild type receptor) to bicalutamide, the most commonly used anti-androgen in the clinic. Bicalutamide induces dose dependent effects on cell cycle and cell death in both cell lines. Whole genome expression profiling indicates that bicalutamide exerts similar, but not identical effects on the two cell lines, suggesting that the transition to CRPC is not due to somatic mutations in response to treatment. However these experiments identified a distinct threshold response to bicalutamide: at low doses of bicalutamide both cell lines induce cell cycle arrest but no significant level of cell death, while at higher doses both cell lines exhibit extensive cell death. This threshold response appears to involve the p53 axis, since many of the affected genes are downstream of this central mediator of cellular stress. The overview of gene expression changes and cellular responses to higher concentrations of bicalutamide indicates that increased doses of the anti-androgen may have clinical benefits.