Anti-Androgen Receptor Signaling and Prostate Cancer Inhibitory Effects of Sucrose- and Benzophenone-Compounds

Abstract

Novel agents that target multiple aspects of androgen receptor (AR) signaling are desirable for chemoprevention and treatment of prostate cancer (PCa). We aimed to identify compounds isolated from medicinal herbs as such drug candidates. In the LNCaP human androgen sensitive PCa cell model, we tested five compounds purified from Lindera fruticosa Hemsley in the range of 10-50 microM for growth inhibition and AR-prostate specific antigen (PSA) suppressing potency. We determined the relationship between these activities and P53 tumor suppressor protein activation and apoptotic cleavage of PARP. We compared these compounds to the anti-androgen drug Casodex/bicalutamide to identify mechanistic novelty. Among 3 sucrose compounds, beta-D-(3,4-di-sinapoyl)fructofuranosyl-alpha-D-(6-sinapoyl)glucopyranoside decreased AR and PSA mRNA and protein levels in LNCaP cells and inhibited androgen-stimulated AR translocation from the cytosol to the nucleus. This compound also increased P53 Ser(15) phosphorylation and PARP cleavage in LNCaP cells, but required higher dosage than for suppressing AR-PSA. Interestingly, this compound did not inhibit the growth of RWPE-1 non-transformed prostate epithelial cells. The benzophenone compound 2-methoxy-3,4-(methylenedioxy)benzophenone suppressed PSA and AR in LNCaP cells without apoptosis. Our data support novel anti-AR actions of these herbal compounds distinct from Casodex and merit further investigation as drug candidates.