ABSTRACT
Extracts from Pygeum africanum are used in the treatment of prostatitis, benign prostatic hyperplasia (BPH) and prostate cancer (PCa). The ligand-activated human androgen receptor (AR) is known to control the growth of the prostate gland. Inhibition of human AR is therefore a major goal in treatment of patients. Here, we characterize the compound N-butylbenzene-sulfonamide (NBBS) isolated from P. africanum as a specific AR antagonist. This antihormonal activity inhibits AR- and progesterone receptor- (PR) mediated transactivation, but not the related human glucocorticoid receptor (GR) or the estrogen receptors (ERα or ERß). Importantly, NBBS inhibits both endogenous PSA expression and growth of human PCa cells. Mechanistically, NBBS binds to AR and inhibits its translocation to the cell nucleus. Furthermore, using a battery of chemically synthesized derivatives of NBBS we revealed important structural aspects for androgen antagonism and have identified more potent AR antagonistic compounds. Our data suggest that NBBS is one of the active compounds of P. africanum bark and may serve as a naturally occurring, novel therapeutic agent for treatment of prostatic diseases. Thus, NBBS and its derivatives may serve as novel chemical platform for treatment prostatitis, BPH and PCa.
Subject(s)
Androgen Antagonists/pharmacology , Cell Nucleus/metabolism , Plant Bark/chemistry , Prostatic Neoplasms/pathology , Prunus africana/chemistry , Receptors, Androgen/metabolism , Sulfonamides/pharmacology , Androgen Antagonists/chemistry , Androgen Antagonists/therapeutic use , Cell Line, Tumor , Cell Nucleus/drug effects , Cell Proliferation/drug effects , Humans , Ligands , Male , Phytotherapy , Plant Extracts/chemistry , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , Prostate-Specific Antigen/metabolism , Prostatic Neoplasms/genetics , Protein Binding/drug effects , Protein Structure, Tertiary , Protein Transport/drug effects , Receptors, Androgen/chemistry , Receptors, Androgen/genetics , Receptors, Progesterone/metabolism , Sulfonamides/chemistry , Sulfonamides/isolation & purification , Transcription, Genetic/drug effectsABSTRACT
Extracts from Pygeum africanum are used in the treatment of prostatitis, benign prostatic hyperplasia and prostate cancer (Pca), major health problems of men in Western countries. The ligand-activated human androgen receptor (AR) supports the growth of the prostate gland. Inhibition of human AR by androgen ablation therapy and by applying synthetic anti-androgens is therefore the primary goal in treatment of patients. Here, we show that atraric acid (AA) isolated from bark material of Pygeum africanum has anti-androgenic activity, inhibiting the transactivation mediated by the ligand-activated human AR. This androgen antagonistic activity is receptor specific and does not inhibit the closely related glucocorticoid or progesterone receptors. Mechanistically, AA inhibits nuclear transport of AR. Importantly, AA is able to efficiently repress the growth of both the androgen-dependent LNCaP and also the androgen-independent C4-2 Pca cells but not that of PC3 or CV1 cells lacking AR. In line with this, AA inhibits the expression of the endogenous prostate specific antigen gene in both LNCaP und C4-2 cells. Analyses of cell invasion revealed that AA inhibits the invasiveness of LNCaP cells through extracellular matrix. Thus, this study provides a molecular insight for AA as a natural anti-androgenic compound and may serve as a basis for AA derivatives as a new chemical lead structure for novel therapeutic compounds as AR antagonists, that can be used for prophylaxis or treatment of prostatic diseases.
Subject(s)
Androgen Antagonists/pharmacology , Androgen Receptor Antagonists , Cell Division/drug effects , Hydroxybenzoates/pharmacology , Neoplasm Invasiveness , Prostatic Neoplasms/pathology , Base Sequence , Cell Line, Tumor , DNA Primers , Humans , Male , Polymerase Chain ReactionABSTRACT
Inactivation of the androgen receptor (AR) through androgen ablation and treatment with antiandrogens is a major goal in the therapy for prostate hyperplasia and prostate cancer. Bioactivity-directed fractionation of a selective dichloromethane extract from the stem bark of Pygeum africanum led to the isolation of the antiandrogenic compound atraric acid. Its activity was examined by an androgen receptor responsive reporter gene assay. For lead structure optimization we transformed the natural occurring compound atraric acid into its ethyl, N-propyl and N-butyl esters and their antiandrogenic activities were examined as well. In addition, benzoic acid was isolated. The structures of all compounds were determined and characterized by means of 1H- and 13C-NMR, HR-EI-mass, IR and UV spectroscopy.
Subject(s)
Androgen Antagonists/pharmacology , Phytotherapy , Plant Extracts/pharmacology , Prunus africana , Receptors, Androgen/drug effects , Androgen Antagonists/administration & dosage , Androgen Antagonists/chemistry , Androgen Antagonists/therapeutic use , Dose-Response Relationship, Drug , Humans , Hydroxybenzoates/administration & dosage , Hydroxybenzoates/chemistry , Hydroxybenzoates/pharmacology , Hydroxybenzoates/therapeutic use , Male , Plant Bark , Plant Extracts/administration & dosage , Plant Extracts/chemistry , Plant Extracts/therapeutic use , Prostatic Neoplasms/drug therapy , Structure-Activity RelationshipABSTRACT
Extracts from Pygeum africanum, Serenoa repens and Cucurbita pepo are used in the treatment of benign prostatic hyperplasia (BPH) and prostate cancer (PCa). The activity of the androgen receptor (AR) is known to control growth of the prostate. Here, we examined extracts of these plants for their antiandrogenic activity using an AR responsive reporter gene assay for drug discovery. A selective dichloromethane extract from the stem barks of Pygeum africanum revealed the highest antiandrogenic effect. Bioactivity-directed fractionation of this extract led to the isolation of N-butylbenzenesulfonamide (NBBS) indicating that extracts of the stem bark of P. africanum harbour androgen antagonistic activity. This compound may provide a novel approach for the prevention and treatment of BPH and human PCa.
