Gene expression in prostate cancer cells treated with the dual 5 alpha-reductase inhibitor dutasteride (original) (raw)
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The Prostate, 2009
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 alphareductase (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.
The Journal of Urology, 2004
Purpose: In the prostate testosterone is converted to dihydrotestosterone (DHT) by the enzymes 5␣-reductase (5␣R) types 1 and 2 (5␣R1 and 5␣R2). Suppression of DHT formation by 5␣R inhibition may be beneficial in early treatment or prevention of prostate cancer. Although 5␣R2 is the dominant enzyme in the prostate, evidence indicates that 5␣R1 may be up-regulated in some prostate cancers. This suggests that dual inhibition of both isoenzymes may be more effective than suppression of 5␣R2 alone in prostate cancer treatment or prevention. In this short-term pilot study we examined the effect of the dual 5␣R inhibitor dutasteride on markers of tumor regression.
Growth of LAPC4 prostate cancer xenograft tumor is insensitive to 5α-reductase inhibitor dutasteride
American journal of clinical and experimental urology, 2014
Intermittent androgen deprivation therapy (IADT) allows prostate cancer patients a break from the side-effects of continuous androgen deprivation therapy (ADT). Although clinical studies suggest that IADT can significantly improve patient quality of life over ADT, it has not been demonstrated to improve patient survival. Recently, increased survival has been demonstrated when 5α-reductase inhibitors have been used during the off-cycle of IADT in animal xenograft tumor models LNCaP and LuCaP35. In the current study, the sensitivity of LAPC4 xenograft tumor regrowth to the 5ARI dutasteride was determined. Tumor regrowth and gene expression changes in LAPC4 tumors were compared to the previously determined response of LNCaP and LuCaP35 xenograft tumors to 5ARI treatment during the off-cycle of IADT, LAPC4, LNCaP and LuCaP35 tumors were sensitive to androgen manipulation. However, in contrast to LNCaP and LuCaP35, dutasteride treatment during testosterone-stimulated prostate regrowth di...
Cancer Research, 2010
Androgens and the androgen receptor (AR) influence prostate carcinogenesis. Lowering intraprostatic dihydrotestosterone (DHT) by inhibiting 5-alpha-reductase (SRD5A) reduces prostate cancer (PCa) incidence, but is not uniformly effective. Mechanisms by which SRD5A inhibition influences PCa initiation and/or progression among different individuals have not been established. We sought to identify molecular alterations underlying the differential chemo-preventive activity of SRD5A inhibition. Men with clinically-localized PCa were randomized to prostatectomy alone (n=25) or 4 months treatment with the SRD5A-inhibitor dutasteride (0.5mg (n=26) or 3.5mg (n=24)) preceding prostatectomy. Serum and prostate androgens were measured using mass spectrometry. We evaluated benign epithelial gene expression using expression profiling and immunohistochemistry, and characterized tumor TMPRSS2-ERG fusion status using FISH. Dutasteride at 0.5 or 3.5mg decreased prostatic DHT by 93% (0.23ng/g; p<0.001) and 98.8% (0.04ng/ g; p<0.001) vs. untreated patients (3.33ng/g). Despite significant and uniform suppression of tissue DHT, unsupervised clustering based on prostatic gene expression did not allow us to discriminate dutasteride-treated from untreated individuals. However, we could resolve subjects into distinct cohorts characterized by high or low expression of AR-regulated genes (irrespective of treatment dose) based solely on AR transcript expression. The high-dose dutasteride treatment group comprised significantly fewer cancers with TMPRSS2-ERG fusions. Despite substantial and uniform reductions in prostatic DHT, dutasteride was associated with highly variable alterations in benign epithelial gene expression. Segregation of subjects based on AR and androgen-regulated gene expression indicates patients are differentially sensitive to SRD5A inhibition. Tissue AR levels may serve as a pretreatment predictor of SRD5A chemo-preventive efficacy.
The Prostate, 2006
BACKGROUND. As dihydrotestosterone (DHT) is the most potent androgen in the prostate, inhibition of the 5a-reductase isoenzymes, which convert testosterone to DHT, could be an appropriate target for the treatment of prostate cancer. METHODS. Eighty-one men with clinically localized prostate cancer received daily dutasteride 3.5 or 0.5 mg, or no therapy for 4 months before radical prostatectomy. Histopathological assessments were conducted on prostatectomy specimens. RESULTS. Treatment with dutasteride was associated with reductions in serum and intraprostatic DHT of !90%, and a decrease in total prostate and tumor volumes. No effect of dutasteride was noted on Gleason grade. Histopathological effects on benign tissue were similar but less prominent than those seen with androgen ablation, whereas there was no significant difference in cancer histology among the groups. CONCLUSIONS. Dutasteride treatment results in similar but less marked changes compared with androgen ablation.
Inhibition of fatty acid synthase activity in prostate cancer cells by dutasteride
Prostate, 2007
PURPOSE. With malignant progression to androgen independence, prostate cancer cells develop resistance to apoptosis and exhibit a variety of gene expression changes, including increased fatty acid synthase (FASN) expression. Increased FASN expression has been shown to correlate with poor prognosis, and correspondingly, the FASN gene has been proposed as a therapeutic target. Because FASN is an androgen regulated gene in the prostate, we have examined the effects of dutasteride on FASN in prostate cancer cells in vitro. Dutasteride is a novel dual inhibitor of the 5 alpha-reductase enzymes and is currently in use both for treatment of benign prostate hyperplasia (BPH) and in the reduction by dutasteride of prostate cancer events (REDUCE) prostate cancer prevention trial. METHODS. Microarray analysis was used to identify genes affected by treatment with dutasteride, followed by real time PCR confirmation. FASN expression at the protein level was examined using Western blotting and immunocytochemistry. Enzymatic activity of FASN was assayed by 14 C-labeled malonyl-CoA incorporation. Viability after dutasteride treatment was assayed by MTS (Promega) and apoptosis via caspase 3/7 by DEVD cleavage assay. RESULTS. We have demonstrated that the 5 alpha-reductase inhibitor dutasteride, at clinically relevant levels, inhibits FASN mRNA, protein expression and enzymatic activity in prostate cancer cells. CONCLUSIONS. This is the first study to examine the effects of clinically relevant levels of dutasteride on prostate cancer cells at the molecular level and specifically, demonstrating the inhibition of FASN in these cells.
The Journal of Urology, 2007
We evaluated the effects of dutasteride for preventing or delaying prostate growth and neoplastic changes in a transgenic model of prostate cancer. Materials and Methods: Large probasin-large T antigen mice were treated for 4 or 8 weeks with dutasteride. The prostate and seminal vesicles were compared with those from intact and castrated large probasin-large T antigen mice and WT mice. Results: Dutasteride greatly decreased the transgene induced increase in prostate weight but castration caused greater reduction. Dutasteride inhibited type 1 and 2, 5alpha-reductase activities, decreased DNA and protein, and increased apoptotic bodies and TUNEL staining in the dorsolateral prostate. No evidence of poorly differentiated cancer was seen. Dutasteride did not decrease the weight of the androgen dependent levator ani or bulbocavernosus muscle. Conclusions: Dutasteride inhibited type 1 and 2, 5alpha-reductase activities, and decreased DNA and protein content of the dorsolateral prostate without affecting androgen responsive muscle weight in large probasin-large T antigen mice. These studies provide support for the hypothesis that a 5alpha-reductase inhibitor inhibits the initiation and/or progression of clinical prostate cancers.