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


CONCLUSIONS
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.
Schmidt
Lucy J
LJ
Department of Urology Research, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
Regan
Kevin M
KM
Anderson
S Keith
SK
Sun
Zhifu
Z
Ballman
Karla V
KV
Tindall
Donald J
DJ
D000728:Androgens / Q000172:deficiency; D000818:Animals; D001378:Azasteroids / Q000008:administration & dosage*; D002455:Cell Division / Q000187:drug effects; D042944:Cholestenone 5 alpha-Reductase / Q000037:antagonists & inhibitors*; D003692:Delayed-Action Preparations; D004343:Drug Implants; D000068538:Dutasteride; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D015870:Gene Expression / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D046228:Microarray Analysis; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D014183:Transplantation, Heterologous; D015854:Up-Regulation; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D000728:Androgens; D001378:Azasteroids; D003692:Delayed-Action Preparations; D004343:Drug Implants; D004791:Enzyme Inhibitors; D042944:Cholestenone 5 alpha-Reductase; D020741:rho GTP-Binding Proteins; D000068538:Dutasteride
Clin Cancer Res. 2002 Nov;8(11):3419-26
12429629
Mol Endocrinol. 2006 May;20(5):1061-72
16384856
J Urol. 2007 Oct;178(4 Pt 1):1521-7
17707058
Prostate. 2003 Jun 1;55(4):239-46
12712403
Invest New Drugs. 2007 Oct;25(5):491-7
17636412
Clin Cancer Res. 2007 Jul 15;13(14):4130-8
17634540
Clin Cancer Res. 2006 Jul 1;12(13):4072-9
16818707
J Urol. 2004 Oct;172(4 Pt 1):1314-7
15371831
Mol Endocrinol. 2008 Mar;22(3):597-608
18079321
Contemp Clin Trials. 2007 Nov;28(6):763-9
17573244
Bioinformatics. 2004 Nov 1;20(16):2778-86
15166021
Biostatistics. 2003 Apr;4(2):249-64
12925520
J Steroid Biochem Mol Biol. 2005 Sep;96(5):355-65
16043352
J Androl. 2004 Nov-Dec;25(6):944-53
15477368
Prostate. 2004 Feb 1;58(2):130-44
14716738
Mol Endocrinol. 2009 Apr;23(4):572-83
19164447
Leukemia. 1997 Apr;11 Suppl 3:363-6
9209391
Prostate. 2007 Jul 1;67(10):1111-20
17477363