The direct inhibitory effect of dutasteride or finasteride on androgen receptor activity is cell line specific

Rishi Raj Chhipa, Danny Halim, Jinrong Cheng, Huan Yi Zhang, James L. Mohler, Clement Ip, Yue Wu

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

BACKGROUND Finasteride and dutasteride were developed originally as 5α-reductase inhibitors to block the conversion of testosterone to dihydrotestosterone (DHT). These drugs may possess off-target effects on the androgen receptor (AR) due to their structural similarity to DHT. METHODS A total of four human prostate cancer cell models were examined: LNCaP (T877A mutant AR), 22Rv1 (H874Y mutant AR), LAPC4 (wild-type AR), and VCaP (wild-type AR). Cells were cultured in 10% charcoal-stripped fetal bovine serum, either with or without DHT added to the medium. AR activity was evaluated using the ARE-luciferase assay or the expression of AR regulated genes. RESULTS Dutasteride was more potent than finasteride in interfering with DHT-stimulated AR signaling. Disruption of AR function was accompanied by decreased cell growth. Cells that rely on DHT for protection against death were particularly vulnerable to dutasteride. Different prostate cancer cell models exhibited different sensitivities to dutasteride and finasteride. LNCaP was most sensitive, LAPC4 and VCaP were intermediate, while 22Rv1 was least sensitive. Regardless of the AR genotype, if AR was transfected into drug-sensitive cells, AR was inhibited by drug treatment; and if AR was transfected into drug-resistant cells, AR was not inhibited. CONCLUSIONS The direct inhibitory effect of dutasteride or finasteride on AR signaling is cell line specific. Mutations in the ligand binding domain of AR do not appear to play a significant role in influencing the AR antagonistic effect of these drugs. Subcellular constituent is an important factor in determining the drug effect on AR function.

Original languageEnglish (US)
Pages (from-to)1483-1494
Number of pages12
JournalProstate
Volume73
Issue number14
DOIs
StatePublished - Oct 1 2013
Externally publishedYes

Fingerprint

Finasteride
Androgen Receptors
Cell Line
Dihydrotestosterone
Pharmaceutical Preparations
Dutasteride
Prostatic Neoplasms

Keywords

  • androgen receptor signaling
  • antiandrogen
  • dutasteride
  • finasteride
  • prostate cancer

ASJC Scopus subject areas

  • Oncology
  • Urology

Cite this

The direct inhibitory effect of dutasteride or finasteride on androgen receptor activity is cell line specific. / Chhipa, Rishi Raj; Halim, Danny; Cheng, Jinrong; Zhang, Huan Yi; Mohler, James L.; Ip, Clement; Wu, Yue.

In: Prostate, Vol. 73, No. 14, 01.10.2013, p. 1483-1494.

Research output: Contribution to journalArticle

Chhipa, Rishi Raj ; Halim, Danny ; Cheng, Jinrong ; Zhang, Huan Yi ; Mohler, James L. ; Ip, Clement ; Wu, Yue. / The direct inhibitory effect of dutasteride or finasteride on androgen receptor activity is cell line specific. In: Prostate. 2013 ; Vol. 73, No. 14. pp. 1483-1494.
@article{9d47a602ac154824ae1c1f058f276355,
title = "The direct inhibitory effect of dutasteride or finasteride on androgen receptor activity is cell line specific",
abstract = "BACKGROUND Finasteride and dutasteride were developed originally as 5α-reductase inhibitors to block the conversion of testosterone to dihydrotestosterone (DHT). These drugs may possess off-target effects on the androgen receptor (AR) due to their structural similarity to DHT. METHODS A total of four human prostate cancer cell models were examined: LNCaP (T877A mutant AR), 22Rv1 (H874Y mutant AR), LAPC4 (wild-type AR), and VCaP (wild-type AR). Cells were cultured in 10{\%} charcoal-stripped fetal bovine serum, either with or without DHT added to the medium. AR activity was evaluated using the ARE-luciferase assay or the expression of AR regulated genes. RESULTS Dutasteride was more potent than finasteride in interfering with DHT-stimulated AR signaling. Disruption of AR function was accompanied by decreased cell growth. Cells that rely on DHT for protection against death were particularly vulnerable to dutasteride. Different prostate cancer cell models exhibited different sensitivities to dutasteride and finasteride. LNCaP was most sensitive, LAPC4 and VCaP were intermediate, while 22Rv1 was least sensitive. Regardless of the AR genotype, if AR was transfected into drug-sensitive cells, AR was inhibited by drug treatment; and if AR was transfected into drug-resistant cells, AR was not inhibited. CONCLUSIONS The direct inhibitory effect of dutasteride or finasteride on AR signaling is cell line specific. Mutations in the ligand binding domain of AR do not appear to play a significant role in influencing the AR antagonistic effect of these drugs. Subcellular constituent is an important factor in determining the drug effect on AR function.",
keywords = "androgen receptor signaling, antiandrogen, dutasteride, finasteride, prostate cancer",
author = "Chhipa, {Rishi Raj} and Danny Halim and Jinrong Cheng and Zhang, {Huan Yi} and Mohler, {James L.} and Clement Ip and Yue Wu",
year = "2013",
month = "10",
day = "1",
doi = "10.1002/pros.22696",
language = "English (US)",
volume = "73",
pages = "1483--1494",
journal = "Prostate",
issn = "0270-4137",
publisher = "Wiley-Liss Inc.",
number = "14",

}

TY - JOUR

T1 - The direct inhibitory effect of dutasteride or finasteride on androgen receptor activity is cell line specific

AU - Chhipa, Rishi Raj

AU - Halim, Danny

AU - Cheng, Jinrong

AU - Zhang, Huan Yi

AU - Mohler, James L.

AU - Ip, Clement

AU - Wu, Yue

PY - 2013/10/1

Y1 - 2013/10/1

N2 - BACKGROUND Finasteride and dutasteride were developed originally as 5α-reductase inhibitors to block the conversion of testosterone to dihydrotestosterone (DHT). These drugs may possess off-target effects on the androgen receptor (AR) due to their structural similarity to DHT. METHODS A total of four human prostate cancer cell models were examined: LNCaP (T877A mutant AR), 22Rv1 (H874Y mutant AR), LAPC4 (wild-type AR), and VCaP (wild-type AR). Cells were cultured in 10% charcoal-stripped fetal bovine serum, either with or without DHT added to the medium. AR activity was evaluated using the ARE-luciferase assay or the expression of AR regulated genes. RESULTS Dutasteride was more potent than finasteride in interfering with DHT-stimulated AR signaling. Disruption of AR function was accompanied by decreased cell growth. Cells that rely on DHT for protection against death were particularly vulnerable to dutasteride. Different prostate cancer cell models exhibited different sensitivities to dutasteride and finasteride. LNCaP was most sensitive, LAPC4 and VCaP were intermediate, while 22Rv1 was least sensitive. Regardless of the AR genotype, if AR was transfected into drug-sensitive cells, AR was inhibited by drug treatment; and if AR was transfected into drug-resistant cells, AR was not inhibited. CONCLUSIONS The direct inhibitory effect of dutasteride or finasteride on AR signaling is cell line specific. Mutations in the ligand binding domain of AR do not appear to play a significant role in influencing the AR antagonistic effect of these drugs. Subcellular constituent is an important factor in determining the drug effect on AR function.

AB - BACKGROUND Finasteride and dutasteride were developed originally as 5α-reductase inhibitors to block the conversion of testosterone to dihydrotestosterone (DHT). These drugs may possess off-target effects on the androgen receptor (AR) due to their structural similarity to DHT. METHODS A total of four human prostate cancer cell models were examined: LNCaP (T877A mutant AR), 22Rv1 (H874Y mutant AR), LAPC4 (wild-type AR), and VCaP (wild-type AR). Cells were cultured in 10% charcoal-stripped fetal bovine serum, either with or without DHT added to the medium. AR activity was evaluated using the ARE-luciferase assay or the expression of AR regulated genes. RESULTS Dutasteride was more potent than finasteride in interfering with DHT-stimulated AR signaling. Disruption of AR function was accompanied by decreased cell growth. Cells that rely on DHT for protection against death were particularly vulnerable to dutasteride. Different prostate cancer cell models exhibited different sensitivities to dutasteride and finasteride. LNCaP was most sensitive, LAPC4 and VCaP were intermediate, while 22Rv1 was least sensitive. Regardless of the AR genotype, if AR was transfected into drug-sensitive cells, AR was inhibited by drug treatment; and if AR was transfected into drug-resistant cells, AR was not inhibited. CONCLUSIONS The direct inhibitory effect of dutasteride or finasteride on AR signaling is cell line specific. Mutations in the ligand binding domain of AR do not appear to play a significant role in influencing the AR antagonistic effect of these drugs. Subcellular constituent is an important factor in determining the drug effect on AR function.

KW - androgen receptor signaling

KW - antiandrogen

KW - dutasteride

KW - finasteride

KW - prostate cancer

UR - http://www.scopus.com/inward/record.url?scp=84883163775&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84883163775&partnerID=8YFLogxK

U2 - 10.1002/pros.22696

DO - 10.1002/pros.22696

M3 - Article

C2 - 23813737

AN - SCOPUS:84883163775

VL - 73

SP - 1483

EP - 1494

JO - Prostate

JF - Prostate

SN - 0270-4137

IS - 14

ER -