Novel oligomeric proanthocyanidin derivatives interact with membrane androgen sites and induce regression of hormone-independent prostate cancer

Prostate cancer is the commonest male malignancy in Western societies and current therapeutic approaches are evolving to manage growth, recurrence and mortality neoplasia. Recently, membrane androgen receptors (mAR) were characterized in human prostate cancer, being preferentially expressed in tumor than in benign gland areas. Furthermore, mAR agonists (protein-conjugated testosterone) decrease in vitro prostate cancer cell growth and induce apoptosis, while in vivo they regress growth of tumor xenografts, alone or in combination with taxane drugs. In this respect, targeting mARs might be a novel therapeutic approach in prostate cancer. Seeking for new small molecules ligands of mAR, we report that flavanol dimers B1-B4 (oligomeric procyanidins, OPC) decrease in vitro growth of the androgen-sensitive (LnCaP) and resistant (DU145) human prostate cancer cell lines, in the following order: B3=B4>B2>>B1 (LnCaP) and B2>>B3=B4>>B1 (DU145). Some of these analogs were previously shown to trigger signaling cascades similar to testosterone-BSA conjugate. Galloylation does not confer an additional advantage; however, oleylation increases their antiproliferative potency by a factor of 100. In addition, we report that B2, oleylated or not, displaces testosterone from mAR with an IC50 at the nM range and induces DU145 tumor xenograft regression by 50% (testosterone-BSA 40%). In this respect, oleylated B2 is a potent small molecule agonist of mAR and could be a novel therapeutic agent for advanced prostate cancer, especially taking into account the absence of androgenic actions and (liver) toxicity.