Abstract B79: Xanthohumol from hops (Humulus lupulus L.) is a novel antiandrogen

Abstract

Abstract Xanthohumol (XN), a prenylated chalcone from hops, possesses a broad spectrum of chemopreventive actions, including anti-inflammatory, antioxidant, and anti-estrogenic mechanisms, and inhibits tumor growth in vitro and in vivo. This study aimed to investigate the anti-androgenic potential of XN with regard to prostate carcinogenesis. In hormone-depleted, androgen-sensitive LNCaP human prostate cancer cells, XN at a concentration of 10 µM inhibited prostate specific antigen (PSA) secretion induced by 25 nM dihydrotestosterone (DHT) by more than 90% (p<0.001) after 24, 48 and 72 h of incubation. In a concentration range of 0.4 to 50 µM, XN dose-dependently inhibited PSA secretion (p<0.001) with a halfmaximal inhibitory concentration of 3.1 ± 0.32 µM after 48 h of incubation. Also, DHT-PSA-and insulin like growth factor (IGF-1) mRNA expression was dose-dependently inhibited by increasing XN concentrations (p<0.05), measured by quantitative RT-PCR. Western Blot analyses of cytosolic and nuclear protein lysates revealed that XN inhibited DHT-induced nuclear translocation of the androgen receptor (AR). Furthermore, in a yeast AR assay, XN inhibited AR-transcription at concentrations of 10 to 100 µM. Docking calculations of XN to the AR indicate steric interactions between the prenyl moiety of XN and Trp741, which could destabilize the AR C-terminal helix 12 and thus further explain the antagonist activity of XN. To investigate anti-androgenic action of XN in vivo, a Hershberger assay with male orchiectomizedWistar rats was performed. Prostate and seminal vesicle weight gain was stimulated by subcutaneous application of 0.2 mg/kg body weight (bw) testosterone propionate (TP). After 12 days, no significant inhibitory effects of oral XN (10 and 30 mg/kg bw) on prostate weights was observed, whereas the anti-androgen flutamide used as a positive control inhibited the 1.2-fold induction of prostate weights by 78% (p<0.001). However, seminal vesicle weight gain induced by TP was significantly reduced by 56 and 29% by XN treatment (10 and 30 mg/kg bw), respectively, and by 92% by flutamide application. Quantitative RT-PCR analyses of prostate RNA confirmed the anti-androgenic effects of XN in vivo. XN and flutamide significantly reduced the expression of androgen-dependent target genes PSA, AR, IGF-1, prostate binding protein C3, myostatin and tyrosine aminotransferase (p<0.05). Taken together, in the present study XN was identified as a potent novel anti-androgen, which might be of use for future prostate cancer prevention trials. Citation Information: Cancer Prev Res 2010;3(1 Suppl):B79.