title: Effect of small molecules modulating androgen receptor (SARMs) in human prostate cancer models.
abstract: 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.
authors.affiliation: Biosciences Laboratory, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori-IRST, Meldola, Italy. anna.tesei@irst.emr.it
authors.forename: Anna
authors.initials: A
authors.lastname: Tesei
authors.forename: Carlo
authors.initials: C
authors.lastname: Leonetti
authors.forename: Marzia
authors.initials: M
authors.lastname: Di Donato
authors.forename: Elisa
authors.initials: E
authors.lastname: Gabucci
authors.forename: Manuela
authors.initials: M
authors.lastname: Porru
authors.forename: Greta
authors.initials: G
authors.lastname: Varchi
authors.forename: Andrea
authors.initials: A
authors.lastname: Guerrini
authors.forename: Dino
authors.initials: D
authors.lastname: Amadori
authors.forename: Chiara
authors.initials: C
authors.lastname: Arienti
authors.forename: Sara
authors.initials: S
authors.lastname: Pignatta
authors.forename: Giulia
authors.initials: G
authors.lastname: Paganelli
authors.forename: Michele
authors.initials: M
authors.lastname: Caraglia
authors.forename: Gabriella
authors.initials: G
authors.lastname: Castoria
authors.forename: Wainer
authors.initials: W
authors.lastname: Zoli
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000704:Analysis of Variance; D059002:Androgen Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D015153:Blotting, Western; D001973:Bromodeoxyuridine; D019556:COS Cells; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D017931:DNA Primers / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008156:Luciferases; D008297:Male; D051379:Mice; D016513:Mice, SCID; D017430:Prostate-Specific Antigen / Q000378:metabolism; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy*; D011485:Protein Binding; D060888:Real-Time Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015533:Transcriptional Activation; D014162:Transfection
chemical_list: D059002:Androgen Receptor Antagonists; D017931:DNA Primers; D011944:Receptors, Androgen; D008156:Luciferases; D017430:Prostate-Specific Antigen; D001973:Bromodeoxyuridine