title: Novel oligomeric proanthocyanidin derivatives interact with membrane androgen sites and induce regression of hormone-independent prostate cancer.
abstract: Prostate cancer is the most common malignancy among men in Western societies, and current therapeutic approaches are evolving to manage growth, recurrence, and mortality neoplasia. Membrane androgen receptors (mARs) have been characterized in human prostate cancer, being preferentially expressed in tumor rather than benign gland areas. Furthermore, mAR agonists (protein-conjugated testosterone) decrease in vitro prostate cancer cell growth and induce apoptosis, whereas 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. In our search for new small-molecule ligands of mAR, we report that flavanol dimers B1-B4 (oligomeric procyanidins) decrease in vitro growth of the androgen-sensitive (LnCaP) and androgen-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-bovine serum albumin (BSA) conjugate. Galloylation does not confer an additional advantage; however, oleylation increases the dimers' antiproliferative potency by a factor of 100. In addition, we report that B2, oleylated or not, displaces testosterone from mARs with an IC(50) value at the nanomolar 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 when taking into account the absence of androgenic actions and (liver) toxicity.
authors.affiliation: Laboratory of Experimental Endocrinology, University of Crete, School of Medicine, Heraklion, Greece.
authors.forename: Marilena
authors.initials: M
authors.lastname: Kampa
authors.forename: Katerina
authors.initials: K
authors.lastname: Theodoropoulou
authors.forename: Fani
authors.initials: F
authors.lastname: Mavromati
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Pelekanou
authors.forename: George
authors.initials: G
authors.lastname: Notas
authors.forename: Eleni D
authors.initials: ED
authors.lastname: Lagoudaki
authors.forename: Artemissia-Phoebe
authors.initials: AP
authors.lastname: Nifli
authors.forename: Cécile
authors.initials: C
authors.lastname: Morel-Salmi
authors.forename: Efstathios N
authors.initials: EN
authors.lastname: Stathopoulos
authors.forename: Joseph
authors.initials: J
authors.lastname: Vercauteren
authors.forename: Elias
authors.initials: E
authors.lastname: Castanas
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000502:physiology; D002417:Cattle; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056604:Grape Seed Extract / Q000302:isolation & purification / Q000378:metabolism* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D044945:Proanthocyanidins / Q000302:isolation & purification / Q000378:metabolism* / Q000502:physiology / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D011944:Receptors, Androgen / Q000378:metabolism*; D013739:Testosterone / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D056604:Grape Seed Extract; C511402:Grape Seed Proanthocyanidins; D044945:Proanthocyanidins; D011944:Receptors, Androgen; C013221:proanthocyanidin; D013739:Testosterone