Advanced prostate cancer (PrC) is the second leading cause of death from cancer in US males. Advanced PrC cells are initially androgen-sensitive and thus androgen ablation therapy causes tumors to undergo regression and fall into a remission phase where residual cells remain dormant while androgen levels remain very low. Unfortunately, this phase usually lasts 3 to 5 years prior to tumor relapse, where the tumor cells re-grow in the absence of androgens. This form of the disease is aggressive and invariably fatal. In this study, we investigated the effects of a combination of herbal extracts on various stages of PrC, androgen-dependent and castrate-resistant, using CWR22 and CWR22Rv1 cells, respectively. Zyflamend, a commercially available product consisting of 10 different herbal extracts, had been shown to reduce pre-malignant forms of PrC in clinical trials. We expanded these earlier experiments by using Zyflamend in a model of advanced PrC. Our initial results indicated that Zyflamend could repress androgen-sensitive and castrate-resistant (androgen-insensitive) prostate tumor growth. Using a cell model for castrate-resistant PrC, Zyflamend inhibited the growth of CWR22Rv1 cells by increasing the expression of the cell cycle inhibitors p21 and p27. These effects were mediated via hyperacetylation of histone 3 through the suppression of class I and II histone deacetylases (HDACs) and an induction of CBP/p300 histone acetyl transferase activity. The latter effect was mediated by the upregulation/activation of Erk-1/-2 and Elk-1. Zyflamend also inhibited androgen receptor expression, its downstream gene target, prostate specific antigen (PSA), and increased cell death by inducing apoptosis as indicated by caspase 3 activity and PARP cleavage. The reduction of androgen receptor was confirmed in CWR22Rv1 xenograft tissues. Our results suggest the extracts of this herbal combination inhibits castrate-resistant prostate cancer cell growth epigenetically and by coordinately affecting androgen receptor signaling pathways involved in cell growth/death. In an androgen-dependent PrC tumor xenograft model, Zyflamend reduced the growth of CWR22-derived tumors and enhanced the responsiveness of tumor cells to hormone ablation. Zyflamend potentiated the regression of PrC cells and their sensitivity to androgen deprivation. These results suggest that Zyflamend may be an effective adjuvant when used with hormone ablation therapy.