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

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.

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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

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Acknowledgements

We greatly thank Dr. O. Jänne, University of Helsinki, Finland, for providing the GFP-hAR expression plasmid.

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Correspondence to Aria Baniahmad.

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Papaioannou, M., Schleich, S., Roell, D. et al. NBBS isolated from Pygeum africanum bark exhibits androgen antagonistic activity, inhibits AR nuclear translocation and prostate cancer cell growth. Invest New Drugs 28, 729–743 (2010). https://doi.org/10.1007/s10637-009-9304-y

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Keywords

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