Effects of the 5 alpha-reductase inhibitor dutasteride on gene expression in prostate cancer xenografts

Lucy J. Schmidt, Kevin M. Regan, S. Keith Anderson, Zhifu D Sun, Karla V. Ballman, Donald J. Tindall

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

BACKGROUND. In the prostate, androgens play a crucial role in normal and cancerous growth; hence the androgenic pathway has become a target of therapeutic intervention. Dutasteride is a 5 alpha-reductase (5AR) inhibitor currently being evaluated both for chemoprevention and treatment of prostate cancer. Dutasteride inhibits both 5AR I and II enzymes, effectively blocking conversion of testosterone to dihydrotestosterone (DHT) in the prostate. This greatly reduces the amount of the active ligand DHT available for binding to the androgen receptor (AR) and stimulating proliferation, making this a good candidate for chemoprevention of prostate cancer. In this study, we sought to determine how dutasteride is functioning at the molecular level, using a prostate cancer xenograft model. METHODS. Androgen-responsive LuCaP 35 xenograft tumors were grown in Balb/c mice. Subcutaneously implanted time-release pellets were used for drug delivery. Microarray analysis was performed using the Affymetrix HG-U133Av2 platform to examine changes in gene expression in tumors following dutasteride treatment. RESULTS. Dutasteride significantly reduced tumor growth in LuCaP 35 xenografts by affecting genes involved in apoptotic, cytoskeletal remodeling, and cell cycle pathways among others. Notably, genes in the Rho GTPase signaling pathway, shown to be important in androgen-deprivation conditions, were significantly up-regulated. CONCLUSION. We have identified multiple pathways outside of the androgenic pathway in prostate cancer xenografts affected by treatment with dutasteride. These findings provide insights into the function of dutasteride within the tumor microenvironment, potentially allowing for development of agents that can be used in combination with this drug to further enhance its effectiveness.

Original languageEnglish (US)
Pages (from-to)1730-1743
Number of pages14
JournalProstate
Volume69
Issue number16
DOIs
StatePublished - Dec 1 2009

Fingerprint

5-alpha Reductase Inhibitors
Heterografts
Prostatic Neoplasms
Gene Expression
Androgens
Dihydrotestosterone
Chemoprevention
Prostate
Cholestenone 5 alpha-Reductase
Neoplasms
rho GTP-Binding Proteins
Tumor Microenvironment
Androgen Receptors
Drug Combinations
Therapeutics
Microarray Analysis
Growth
Dutasteride
Genes
Testosterone

Keywords

  • Dutasteride
  • Prostate
  • Xenograft

ASJC Scopus subject areas

  • Urology
  • Oncology

Cite this

Schmidt, L. J., Regan, K. M., Anderson, S. K., Sun, Z. D., Ballman, K. V., & Tindall, D. J. (2009). Effects of the 5 alpha-reductase inhibitor dutasteride on gene expression in prostate cancer xenografts. Prostate, 69(16), 1730-1743. https://doi.org/10.1002/pros.21022

Effects of the 5 alpha-reductase inhibitor dutasteride on gene expression in prostate cancer xenografts. / Schmidt, Lucy J.; Regan, Kevin M.; Anderson, S. Keith; Sun, Zhifu D; Ballman, Karla V.; Tindall, Donald J.

In: Prostate, Vol. 69, No. 16, 01.12.2009, p. 1730-1743.

Research output: Contribution to journalArticle

Schmidt, LJ, Regan, KM, Anderson, SK, Sun, ZD, Ballman, KV & Tindall, DJ 2009, 'Effects of the 5 alpha-reductase inhibitor dutasteride on gene expression in prostate cancer xenografts', Prostate, vol. 69, no. 16, pp. 1730-1743. https://doi.org/10.1002/pros.21022
Schmidt, Lucy J. ; Regan, Kevin M. ; Anderson, S. Keith ; Sun, Zhifu D ; Ballman, Karla V. ; Tindall, Donald J. / Effects of the 5 alpha-reductase inhibitor dutasteride on gene expression in prostate cancer xenografts. In: Prostate. 2009 ; Vol. 69, No. 16. pp. 1730-1743.
@article{959bd8b62c8540879c6011494344817b,
title = "Effects of the 5 alpha-reductase inhibitor dutasteride on gene expression in prostate cancer xenografts",
abstract = "BACKGROUND. In the prostate, androgens play a crucial role in normal and cancerous growth; hence the androgenic pathway has become a target of therapeutic intervention. Dutasteride is a 5 alpha-reductase (5AR) inhibitor currently being evaluated both for chemoprevention and treatment of prostate cancer. Dutasteride inhibits both 5AR I and II enzymes, effectively blocking conversion of testosterone to dihydrotestosterone (DHT) in the prostate. This greatly reduces the amount of the active ligand DHT available for binding to the androgen receptor (AR) and stimulating proliferation, making this a good candidate for chemoprevention of prostate cancer. In this study, we sought to determine how dutasteride is functioning at the molecular level, using a prostate cancer xenograft model. METHODS. Androgen-responsive LuCaP 35 xenograft tumors were grown in Balb/c mice. Subcutaneously implanted time-release pellets were used for drug delivery. Microarray analysis was performed using the Affymetrix HG-U133Av2 platform to examine changes in gene expression in tumors following dutasteride treatment. RESULTS. Dutasteride significantly reduced tumor growth in LuCaP 35 xenografts by affecting genes involved in apoptotic, cytoskeletal remodeling, and cell cycle pathways among others. Notably, genes in the Rho GTPase signaling pathway, shown to be important in androgen-deprivation conditions, were significantly up-regulated. CONCLUSION. We have identified multiple pathways outside of the androgenic pathway in prostate cancer xenografts affected by treatment with dutasteride. These findings provide insights into the function of dutasteride within the tumor microenvironment, potentially allowing for development of agents that can be used in combination with this drug to further enhance its effectiveness.",
keywords = "Dutasteride, Prostate, Xenograft",
author = "Schmidt, {Lucy J.} and Regan, {Kevin M.} and Anderson, {S. Keith} and Sun, {Zhifu D} and Ballman, {Karla V.} and Tindall, {Donald J.}",
year = "2009",
month = "12",
day = "1",
doi = "10.1002/pros.21022",
language = "English (US)",
volume = "69",
pages = "1730--1743",
journal = "Prostate",
issn = "0270-4137",
publisher = "Wiley-Liss Inc.",
number = "16",

}

TY - JOUR

T1 - Effects of the 5 alpha-reductase inhibitor dutasteride on gene expression in prostate cancer xenografts

AU - Schmidt, Lucy J.

AU - Regan, Kevin M.

AU - Anderson, S. Keith

AU - Sun, Zhifu D

AU - Ballman, Karla V.

AU - Tindall, Donald J.

PY - 2009/12/1

Y1 - 2009/12/1

N2 - BACKGROUND. In the prostate, androgens play a crucial role in normal and cancerous growth; hence the androgenic pathway has become a target of therapeutic intervention. Dutasteride is a 5 alpha-reductase (5AR) inhibitor currently being evaluated both for chemoprevention and treatment of prostate cancer. Dutasteride inhibits both 5AR I and II enzymes, effectively blocking conversion of testosterone to dihydrotestosterone (DHT) in the prostate. This greatly reduces the amount of the active ligand DHT available for binding to the androgen receptor (AR) and stimulating proliferation, making this a good candidate for chemoprevention of prostate cancer. In this study, we sought to determine how dutasteride is functioning at the molecular level, using a prostate cancer xenograft model. METHODS. Androgen-responsive LuCaP 35 xenograft tumors were grown in Balb/c mice. Subcutaneously implanted time-release pellets were used for drug delivery. Microarray analysis was performed using the Affymetrix HG-U133Av2 platform to examine changes in gene expression in tumors following dutasteride treatment. RESULTS. Dutasteride significantly reduced tumor growth in LuCaP 35 xenografts by affecting genes involved in apoptotic, cytoskeletal remodeling, and cell cycle pathways among others. Notably, genes in the Rho GTPase signaling pathway, shown to be important in androgen-deprivation conditions, were significantly up-regulated. CONCLUSION. We have identified multiple pathways outside of the androgenic pathway in prostate cancer xenografts affected by treatment with dutasteride. These findings provide insights into the function of dutasteride within the tumor microenvironment, potentially allowing for development of agents that can be used in combination with this drug to further enhance its effectiveness.

AB - BACKGROUND. In the prostate, androgens play a crucial role in normal and cancerous growth; hence the androgenic pathway has become a target of therapeutic intervention. Dutasteride is a 5 alpha-reductase (5AR) inhibitor currently being evaluated both for chemoprevention and treatment of prostate cancer. Dutasteride inhibits both 5AR I and II enzymes, effectively blocking conversion of testosterone to dihydrotestosterone (DHT) in the prostate. This greatly reduces the amount of the active ligand DHT available for binding to the androgen receptor (AR) and stimulating proliferation, making this a good candidate for chemoprevention of prostate cancer. In this study, we sought to determine how dutasteride is functioning at the molecular level, using a prostate cancer xenograft model. METHODS. Androgen-responsive LuCaP 35 xenograft tumors were grown in Balb/c mice. Subcutaneously implanted time-release pellets were used for drug delivery. Microarray analysis was performed using the Affymetrix HG-U133Av2 platform to examine changes in gene expression in tumors following dutasteride treatment. RESULTS. Dutasteride significantly reduced tumor growth in LuCaP 35 xenografts by affecting genes involved in apoptotic, cytoskeletal remodeling, and cell cycle pathways among others. Notably, genes in the Rho GTPase signaling pathway, shown to be important in androgen-deprivation conditions, were significantly up-regulated. CONCLUSION. We have identified multiple pathways outside of the androgenic pathway in prostate cancer xenografts affected by treatment with dutasteride. These findings provide insights into the function of dutasteride within the tumor microenvironment, potentially allowing for development of agents that can be used in combination with this drug to further enhance its effectiveness.

KW - Dutasteride

KW - Prostate

KW - Xenograft

UR - http://www.scopus.com/inward/record.url?scp=70350441994&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=70350441994&partnerID=8YFLogxK

U2 - 10.1002/pros.21022

DO - 10.1002/pros.21022

M3 - Article

C2 - 19676081

AN - SCOPUS:70350441994

VL - 69

SP - 1730

EP - 1743

JO - Prostate

JF - Prostate

SN - 0270-4137

IS - 16

ER -