The management of
hormone-refractory
prostate cancer represents a major challenge in the
therapy of this
tumor, and identification of novel
androgen receptor antagonists is needed to render treatment more effective. We analyzed the activity of two novel
androgen receptor antagonists, (S)-11 and (R)-9, in in vitro and in vivo experimental models of
hormone-sensitive or
castration-resistant
prostate cancer (CRPC). In vitro experiments were performed on LNCaP, LNCaP-AR, LNCaP-Rbic and VCaP human
prostate cancer cells. Cytotoxic activity was assessed by SRB and
BrdU uptake, AR transactivation by
luciferase reporter assay and PSA levels by Real Time RT-PCR and ELISA assays. Cell cycle progression-related markers were evaluated by western blot. In vivo experiments were performed on SCID mice xenografted with cells with different sensitivity to hormonal treatment. In
hormone-sensitive LNCaP and LNCaP-AR cells, the latter expressing high
androgen receptor levels, (R)-9 and (S)-11 exhibited a higher cytotoxic effect compared to that of the reference compound ((R)-
bicalutamide), also in the presence of the
synthetic androgen R1881. Furthermore, the cytotoxic effect produced by (R)-9 was higher than that of (S)-11 in the two
hormone-resistant LNCaP-AR and VCaP cells. A significant reduction in PSA levels was observed after exposure to both molecules. Moreover, (S)-11 and (R)-9 inhibited
DNA synthesis by blocking the
androgen-induced increase in
cyclin D1 protein levels. In vivo studies on the toxicological profile of (R)-9 did not reveal the presence of adverse events. Furthermore, (R)-9 inhibited
tumor growth in various in vivo models, especially LNCaP-Rbic xenografts, representative of recurrent disease. Our in vitro results highlight the antitumor activity of the two novel molecules (R)-9 and (S)-11, making them a potentially attractive option for the treatment of CRPC.