The natural compound atraric acid is an antagonist  of the human androgen receptor inhibiting cellular  invasiveness and prostate cancer cell growth.
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.
Papaioannou
Maria
M
Institute of Human Genetics and Anthropology, Friedrich-Schiller-University, Kollegiengasse, Jena, Germany.
Schleich
Sonja
S
Institute for Pharmaceutical Chemistry, Philipps-University Marburg, Marbacher Weg, Marburg, Germany.
Prade
Ina
I
Institute of Human Genetics and Anthropology, Friedrich-Schiller-University, Kollegiengasse, Jena, Germany.
Degen
Stephanie
S
Institute of Human Genetics and Anthropology, Friedrich-Schiller-University, Kollegiengasse, Jena, Germany.
Roell
Daniela
D
Institute of Human Genetics and Anthropology, Friedrich-Schiller-University, Kollegiengasse, Jena, Germany.
Schubert
Undine
U
Institute of Human Genetics and Anthropology, Friedrich-Schiller-University, Kollegiengasse, Jena, Germany.
Tanner
Tamzin
T
Department of Molecular Cell Biology, University of Leuven, Heresraat, Leuven, Belgium.
Claessens
Frank
F
Department of Molecular Cell Biology, University of Leuven, Heresraat, Leuven, Belgium.
Matusch
Rudolf
R
Institute for Pharmaceutical Chemistry, Philipps-University Marburg, Marbacher Weg, Marburg, Germany.
Baniahmad
Aria
A
Institute of Human Genetics and Anthropology, Friedrich-Schiller-University, Kollegiengasse, Jena, Germany.|Department of Molecular Cell Biology, University of Leuven, Heresraat, Leuven, Belgium.
D000726:Androgen Antagonists / Q000494:pharmacology*; D059002:Androgen Receptor Antagonists; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D017931:DNA Primers; D006801:Humans; D062385:Hydroxybenzoates / Q000494:pharmacology*; D008297:Male; D009361:Neoplasm Invasiveness; D016133:Polymerase Chain Reaction; D011471:Prostatic Neoplasms / Q000473:pathology*
D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D017931:DNA Primers; D062385:Hydroxybenzoates; C480398:atraric acid