title: High-throughput cell-based compound screen identifies pinosylvin methyl ether and tanshinone IIA as inhibitors of castration-resistant prostate cancer.
abstract: Current treatment options for castration-resistant prostate cancer (CRPC) are limited. In this study, a high-throughput screen of 4910 drugs and drug-like molecules was performed to identify antiproliferative compounds in androgen ablated prostate cancer cells. The effect of compounds on cell viability was compared in androgen ablated LNCaP prostate cancer cells and in LNCaP cells grown in presence of androgens as well as in two non-malignant prostate epithelial cells (RWPE-1 and EP156T). Validation experiments of cancer specific anti-proliferative compounds indicated pinosylvin methyl ether (PSME) and tanshinone IIA as potent inhibitors of androgen ablated LNCaP cell proliferation. PSME is a stilbene compound with no previously described anti-neoplastic activity whereas tanshinone IIA is currently used in cardiovascular disorders and proposed as a cancer drug. To gain insights into growth inhibitory mechanisms in CRPC, genome-wide gene expression analysis was performed in PSME- and tanshinone IIA-exposed cells. Both compounds altered the expression of genes involved in cell cycle and steroid and cholesterol biosynthesis in androgen ablated LNCaP cells. Decrease in androgen signalling was confirmed by reduced expression of androgen receptor and prostate specific antigen in PSME- or tanshinone IIA-exposed cells. Taken together, this systematic screen identified a novel anti-proliferative agent, PSME, for CRPC. Moreover, our screen confirmed tanshinone IIA as well as several other compounds as potential prostate cancer growth inhibitors also in androgen ablated prostate cancer cells. These results provide valuable starting points for preclinical and clinical studies for CRPC treatment.
authors.affiliation: Turku Centre for Biotechnology, University of Turku, Finland.
authors.forename: Kirsi
authors.initials: K
authors.lastname: Ketola
authors.affiliation: Turku Centre for Biotechnology, University of Turku, Finland.
authors.forename: Miro
authors.initials: M
authors.lastname: Viitala
authors.affiliation: Medical Biotechnology, VTT Technical Research Centre of Finland, Finland.
authors.forename: Pekka
authors.initials: P
authors.lastname: Kohonen
authors.affiliation: Medical Biotechnology, VTT Technical Research Centre of Finland, Finland.
authors.forename: Vidal
authors.initials: V
authors.lastname: Fey
authors.affiliation: Division of Experimental Urology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Zoran
authors.initials: Z
authors.lastname: Culig
authors.affiliation: Turku Centre for Biotechnology, University of Turku, Finland; Medical Biotechnology, VTT Technical Research Centre of Finland, Finland; Division of Experimental Urology, Innsbruck Medical University, Innsbruck, Austria; Institute for Molecular Medicine, Finland (FIMM), University of Helsinki, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Kallioniemi
authors.affiliation: Turku Centre for Biotechnology, University of Turku, Finland; Medical Biotechnology, VTT Technical Research Centre of Finland, Finland.
authors.forename: Kristiina
authors.initials: K
authors.lastname: Iljin