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. Copyright 2009 Wiley-Liss, Inc.
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. Copyright 2009 Wiley-Liss, Inc.
Authors: Hannelore V Heemers; Kevin M Regan; Lucy J Schmidt; S Keith Anderson; Karla V Ballman; Donald J Tindall Journal: Mol Endocrinol Date: 2009-01-22
Authors: F Fina; X Muracciole; P Rocchi; I Nanni-Métellus; C Delfino; L Daniel; C Dussert; L 'H Ouafik; P M Martin Journal: J Steroid Biochem Mol Biol Date: 2005-07-25 Impact factor: 4.292
Authors: Neil Fleshner; Leonard G Gomella; Michael S Cookson; Antonio Finelli; Andrew Evans; Samir S Taneja; M Scott Lucia; Eric Wolford; Matthew C Somerville; Roger Rittmaster Journal: Contemp Clin Trials Date: 2007-05-29 Impact factor: 2.226
Authors: Anders S Bjartell; Hikmat Al-Ahmadie; Angel M Serio; James A Eastham; Scott E Eggener; Samson W Fine; Lene Udby; William L Gerald; Andrew J Vickers; Hans Lilja; Victor E Reuter; Peter T Scardino Journal: Clin Cancer Res Date: 2007-07-15 Impact factor: 12.531
Authors: Mark A Titus; Yun Li; Olga G Kozyreva; Varun Maher; Alejandro Godoy; Gary J Smith; James L Mohler Journal: Prostate Date: 2013-10-22 Impact factor: 4.104
Authors: Lucy J Schmidt; Kelly Duncan; Neelu Yadav; Kevin M Regan; Alissa R Verone; Christine M Lohse; Elena A Pop; Kristopher Attwood; Gregory Wilding; James L Mohler; Thomas J Sebo; Donald J Tindall; Hannelore V Heemers Journal: Mol Endocrinol Date: 2012-03-28
Authors: Alexander B Opoku-Acheampong; Dave Unis; Jamie N Henningson; Amanda P Beck; Brian L Lindshield Journal: PLoS One Date: 2013-10-18 Impact factor: 3.240
Authors: Kathrin Bohn-Wippert; Erin N Tevonian; Yiyang Lu; Meng-Yao Huang; Melina R Megaridis; Roy D Dar Journal: Cell Rep Date: 2018-12-26 Impact factor: 9.423