Inhibition of fatty acid synthase activity in prostate cancer cells by dutasteride (original) (raw)
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Journal of andrology
We sought preclinical data on the cellular and molecular effects of dutasteride in androgen-responsive, human prostate cancer (PCa) cells to better understand the mechanisms of action of 5 alpha-reductase inhibition in these cells. We used the human prostate cancer cell line LNCaP, which exhibits most features of PCa cells including androgen responsiveness. Our findings show that dutasteride kills PCa cells in vitro; it dramatically reduced viability and proliferation and disrupted genes and cellular pathways involved in metabolic, cell cycle, and apoptotic responses besides those expected in androgen-signaling pathways. Microchip gene array expression analysis revealed activation of genes in the FasL/tumor necrosis factor alpha (TNF-alpha) apoptotic and cell-survival pathways, correlating with the growth and survival effects in the LNCaP cells. Real-time polymerase chain reaction confirmed expression level changes seen by microarray analysis of candidate genes such as PLA2G2A, CDK8...
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.
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, 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.
Cancer Reports, 2021
BackgroundDutasteride has been shown to increase expression of the prostate‐specific membrane antigen (PSMA) in prostate cancer cells in previous in vitro studies. This 5‐alpha‐reductase inhibitor is commonly used for the treatment of symptomatic benign prostatic enlargement. The modulation of PSMA expression might affect PSMA‐based prostate cancer imaging and therapy.AimThe purpose of this work was to further analyze concentration‐dependent effects of Dutasteride on PSMA expression in a mouse xenograft model.Methods and resultsFour groups of mice bearing LNCaP xenografts were treated for 14 days with daily intraperitoneal injections of either vehicle control or different concentrations of Dutasteride (0.1, 1, 10 mg/kg). Total expression of PSMA, androgen receptor (AR), and caspase‐3 protein was analyzed using immunoblotting (WES). In addition, PSMA, cleaved caspase‐3 and Ki‐67 expression was assessed and quantified by immunohistochemistry. Tumor size was measured by caliper on day ...
Effect of Dutasteride on the Risk of Prostate Cancer
New England Journal of Medicine, 2010
We conducted a study to determine whether dutasteride reduces the risk of incident prostate cancer, as detected on biopsy, among men who are at increased risk for the disease.
Role of dutasteride in pre-clinical ETS fusion-positive prostate cancer models
The Prostate, 2012
BACKGROUND. Androgens play a crucial role in prostate cancer, hence the androgenic pathway has become an important target of therapeutic intervention. Previously we discovered that gene fusions between the 5 0-untranslated region of androgen regulated gene TMPRSS2 and the ETS transcription factor family members were present in a majority of the prostate cancer cases. The resulting aberrant overexpression of ETS genes drives tumor progression. METHODS. Here, we evaluated the expression levels of 5a-reductase isoenzymes in prostate cancer cell lines and tissues. We tested the effect of dutasteride, a 5a-reductase inhibitor, in TMPRSS2-ERG fusion-positive VCaP cell proliferation and cell invasion. We also evaluated the effect of dutasteride on the TMPRSS2-ERG fusion gene expression. Finally, we tested dutasteride alone or in combination with an anti-androgen in VCaP cell xenografts tumor model. RESULTS. Our data showed that 5a-reductase SRD5A1 and SRD5A3 isoenzymes that are responsible for the conversion of testosterone to DHT, are highly expressed in metastatic prostate cancer compared to benign and localized prostate cancer. Dutasteride treatment attenuated VCaP cell proliferation and invasion. VCaP cells pre-treated with dutasteride showed a reduction in ERG and PSA expression. In vivo studies demonstrated that dutasteride in combination with the anti-androgen bicalutamide significantly decreased tumor burden in VCaP cell xenograft model. CONCLUSIONS. Our findings suggest that dutasteride can inhibit ERG fusion-positive cell growth and in combination with anti-androgen, significantly reduce the tumor burden. Our study suggests that anti-androgens used in combination with dutasteride could synergistically augment the therapeutic efficacy in the treatment of ETS-positive prostate cancer.
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.