Investigational New Drugs

, Volume 28, Issue 6, pp 729–743

NBBS isolated from Pygeum africanum bark exhibits androgen antagonistic activity, inhibits AR nuclear translocation and prostate cancer cell growth

  • Maria Papaioannou
  • Sonja Schleich
  • Daniela Roell
  • Undine Schubert
  • Tamzin Tanner
  • Frank Claessens
  • Rudolf Matusch
  • Aria Baniahmad
PRECLINICAL STUDIES

Summary

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 ERβ). 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.

Keywords

Antihormone Prostate cancer N-butylbenzene-sulfonamide Natural compound Pygeum africanum Androgen receptor 

Abbreviations

AR

Human androgen receptor

BPH

Benign prostate hyperplasia

CPA

Cyproterone acetate

C4-2

a LNCaP derivative cell line that exhibits androgen-independent growth

CV1

Kidney cell line from green monkey, lacking endogenously expressed functional AR, GR, ER, PR and TR

DHT

Dihydrotestosterone, androgen agonist

E2

Estradiol

ER

Human estrogen receptor

GAPDH

Glyceraldehyde-3-phosphate dehydrogenase

GFP

Green fluorescent protein

GR

Human glucocorticoid receptor

HBD

Hormone binding domain

LNCaP

a human prostate cancer cell line, exhibits hormone-dependent growth

LacZ

β-galactosidase expression vector used for normalization of transfection efficiency

Luc

Luciferase

MMTV

Mouse mammary tumor virus

NBBS

N-butylbenzene-sulfonamide

OH-F

Hydroxyflutamide, androgen antagonist

PCa

Prostate cancer

PC3

a human prostate cancer cell line, lacking endogenously expressed functional AR

PC3-ARwt

stable transfected PC3 cell line, expressing human wild type AR

PSA

Prostate specific antigen

PR

Human progesterone receptor

qRT-PCR

Real time reverse transcription polymerase chain reaction

R1881

Methyltrienolone, androgen agonist

RLU

Relative light units (normalized to internal control)

T3

Thyroid hormone (3,5,3′-triiodothyronine)

TR

Thyroid hormone receptor

(DR4)2

Two direct repeats as known TR response elements

Supplementary material

10637_2009_9304_MOESM1_ESM.ppt (326 kb)
Supplemental data(PPT 325 kb)

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Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Maria Papaioannou
    • 1
  • Sonja Schleich
    • 2
  • Daniela Roell
    • 1
  • Undine Schubert
    • 1
  • Tamzin Tanner
    • 3
  • Frank Claessens
    • 3
  • Rudolf Matusch
    • 2
  • Aria Baniahmad
    • 1
    • 4
  1. 1.Institute of Human GeneticsJena University HospitalJenaGermany
  2. 2.Institute for Pharmaceutical ChemistryPhilipps-University MarburgMarburgGermany
  3. 3.Division of Biochemistry, Faculty of MedicineUniversity of LeuvenLeuvenBelgium
  4. 4.Department of BiosciencesUniversity of KuopioKuopioFinland

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