The natural compound atraric acid is an antagonist of the human androgen receptor inhibiting cellular invasiveness and prostate cancer cell growth

Abstract

IntroductionThe prostate gland is a part of the male reproductive system and is, normally, about the size of a walnut. Aging men will eventually develop a prostate disease at some stage of life. The most common of them are benign prostatic hyperplasia (BPH)

The natural compounds atraric acid and N-butylbenzene-sulfonamide as antagonists of the human androgen receptor and inhibitors of prostate cancer cell growth

“…The endogenous PSA expression in the androgen-dependent human PCa cell line LNCaP harbouring an AR mutant, was significantly repressed by AA and NBBS (Papaioannou et al, 2009a;2009b). Similar results were observed, performing real-time PCR with the androgen-independent growing PCa cell line C4-2, also containing the AR-T877A mutant.…”

“…In line with this AA inhibited the androgen-induced invasion of human LNCaP cells (Papaioannou et al, 2009a) while AA alone had no influence on the cell invasion. Thus, AA inhibits the agonist-induced invasion of LNCaP cells through the extracellular matrix and therefore could be a potential inhibitor also for PCa metastasis.…”

“…AA and NBBS decreased the cell proliferation of several human prostate cancer cell lines either growing androgen dependently and containing the wild type AR or the AR-T877A mutant or growing androgen independently and containing the AR-T877A mutant (C4-2). In contrast, growth of PC3 cells lacking expression of the AR or non PCa cells also lacking AR expression were not effected by AA and NBBS, suggesting an AR-dependent growth inhibitory mechanism imposed by AA and NBBS (Papaioannou et al, 2009a;2009b). Also, neither toxicity nor apoptosis could be observed during the treatment.…”

“…Neither AA nor NBBS had any measurable effect on the ligand-induced transactivation of GR, PR-A, TRβ, or one of the ER receptors in the concentrations used for 90% of AR inhibition (Papaioannou et al, 2009a;2009b). NBBS as well as AA showed an inhibitory effect at high concentrations for the PR-B form and AA additionally had estrogenic potential at high concentration of 100 µM (Papaioannou et al, 2009a;2009b). This slight repression and activation of other nuclear hormone receptors only at high employed concentrations suggest that AA and NBBS are AR specific antiandrogens.…”

“…This point mutation in the ligand binding domain (LBD) of the AR renders the antiandrogenic metabolite OH-Fl of the recently used antihormone flutamide into an AR agonist. Notably, AA and NBBS exhibit repression of the AR-T877A mutant and therefore seem to have another molecular mechanism to mediate inhibition of AR compared to OH-Fl (Papaioannou et al, 2009a;2009b).…”