Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The benign hypertrophy of prostate (BPH) is a progressive disease which can assign all the men to various degrees, involving an unquestionable repercussion on the quality of life. The two types of drugs commonly used for the treatment of the symptomatic BPH are the inhibitors of 5-alpha-reductase and the alpha-blockers. They last one relatively long action, making it possible to prevent occurred of complications like the acute urinary retention or the prostatic recourse to the surgery. A risk of progression and development of urinary complications can require an association of these two therapeutic agents in order to obtain a faster and durable improvement of symptomatology. The results of various studies are reported which highlight the interest of this therapeutic combination and underline the contribution of an inhibitor of 5-alpha-reductase among patients presenting a significant prostatic volume and a high PSA. Taking into account the risk of bad compliance and side effects with the long course, after a treatment combined for six months by tamsulosine and dutasteride, the stop of the alpha-blocker allows a maintenance of the situation obtained. Lastly, several clinical studies made it possible to draw the attention to the potentially preventive action of the inhibitors of 5-alpha-reductase in the development of the prostate cancer by its action to the DHT. These observational studies left the place to the PCPT study which made it possible to confirm a reduction in the prevalence of the cancer of prostate in a group of patients treated by finasteride compared with a placebo group. Currently, the preventive potential role of the dutasteride is also the subject of a study (REDUCE). These results are necessary in order to better define the interest and the role of the inhibition of 5-alpha-reductase in a strategic attitude of prostate cancer prevention.
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PMID:[Novel therapeutics strategies in benign hypertrophy of prostate management]. 1624 Aug 94

Human type 10 17beta-hydroxysteroid dehydrogenase (HSD) is a homotetrameric protein located in mitochondria. This enzyme was alternatively named short chain L-3-hydroxyacyl-CoA dehydrogenase (SCHSD). This NAD(H)-dependent dehydrogenase is essential for the metabolism of branched-chain fatty acids and isoleucine, and is expressed in a variety of tissues, e.g., prostate, brain, liver, and heart. This enzyme inactivates 17beta-estradiol and exhibits a strong oxidative 3alpha-HSD activity to convert 5alpha-androstanediol and allopregnanolone into 5alpha-dihydrotestosterone (5alpha-DHT) and 5alpha-dihydroprogesterone, respectively, in living cells. Certain malignant prostatic epithelial cells and activated astrocytes in Alzheimer's disease patient's brain contain extraordinarily high levels of this enzyme. This mitochondrial dehydrogenase enables prostate cancer cells to generate 5alpha-DHT in the absence of testosterone. Its inactivation of allopregnanolone is important to the modulation of GABA(A) receptor. Among steroidogenic enzymes 17beta-HSD10 plays a significant part in the intracrinology. Although this protein has an affinity for amyloid-beta peptide, its role in the pathogenesis of Alzheimer's disease is far from clear. Additional knowledge of this versatile enzyme would provide the foundation for designing new drugs aimed at treating some neurological diseases and certain types of cancers.
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PMID:Roles of type 10 17beta-hydroxysteroid dehydrogenase in intracrinology and metabolism of isoleucine and fatty acids. 1661 Nov 67

In order to select a better prostate cancer cell model for androgen receptor (AR)-mediated reporter gene assays, we assessed the androgen response characteristics of three cell lines, LNCaP, PC3/AR(+) and 22Rv1, in this study. Both the mRNA and the proteins of AR and glucocorticoid receptor (GR) were expressed in all three cell lines. Among the three cell lines, only in LNCaP cells, DHT concentration-dependently stimulated proliferation. DHT induced the luciferase activity in three cell lines which were transiently transfected with pMMTV-Luc, in a concentration-dependent manner. The maximum induction was 24.0-fold and 13.4-fold in 22Rv1 and in the LNCaP respectively. PC3/AR(+) were more sensitive to respond to DHT at a minimal concentration of 10(-12)M by 14.0-fold induction. The transcriptional activity induced with 10(-8)M DHT was inhibited about 50-75% in the PC3/AR(+) and 22Rv1, and 98% in the LNCaP, by vinclozolin. Dexamethasone concentration-dependently induced the luciferase activity in PC3 and 22Rv1, but not in the LNCaP. However, the response to dexamethasone in 22Rv1 was very weak compared to DHT. The (anti)androgencity of seven pyrethroids was assessed via an AR-mediated luciferase reporter assay. None of them showed the androgenic action in all three cell lines. Permethrin inhibited the DHT induced luciferase activity about 22%, 35.8% and 75.5% in 22Rv1, PC3/AR(+) and LNCaP, respectively. Based on results from in this study and cell line character, 22Rv1 cells seemed to be an appropriate model for the screening of androgenic endocrine disruptors, although it needs further studies with other steroid receptor and thyroid receptor.
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PMID:Comparison of prostate cancer cell lines for androgen receptor-mediated reporter gene assays. 1662 34

Prevention trials showed that selenium reduced prostate cancer incidence by 50%, establishing selenium as a promising chemopreventive agent for prostate cancer. Selenium inhibited human prostate cancer cell growth, blocked cell cycle progression at multiple transition points, and induced apoptotic cell death. Previous studies showed a novel mechanism of selenium anticancer action in which selenium markedly reduces androgen signaling and androgen receptor (AR)-mediated gene expression, including prostate-specific antigen (PSA), in human prostate cancer cells. The molecular mechanisms of selenium-mediated down-regulation of AR signaling are not clear. In this study, a systemic approach was taken to examine the modification of androgen signaling by selenium in human prostate cancer cells. In addition to reduced AR mRNA expression, selenium was found to initially increase the stability of AR mRNA within 6 hours while decreasing the stability of AR mRNA after 8 hours. Selenium increased AR protein degradation and reduced AR nuclear localization. Scatchard analysis indicated that selenium did not affect ligand binding to AR in LNCaP cells. Chromatin immunoprecipitation analyses showed that DHT increased the recruitment of AR and coactivators, such as SRC-1 and TIF-2, to the promoter of the PSA gene, and that recruitment was greatly diminished in the presence of 5 micromol/L selenium. On the other hand, selenium enhanced the recruitment of corepressors, such as SMRT, to the promoter of the PSA gene. Taken together, these results suggest that selenium disrupts AR signaling at multiple stages, including AR mRNA expression, mRNA stability, protein degradation, nuclear translocation, and recruitment of coregulators.
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PMID:Mechanisms of selenium down-regulation of androgen receptor signaling in prostate cancer. 1664 61

Androgen-regulated genes (ARG) are implicated in normal and neoplastic growth of the prostate. Recently, we reported genomic amplification and/or overexpression of a previously known neurotrophic factor, prosaposin, in androgen-independent (AI) or metastatic prostate cancer (PCa) cells and tissues. Prosaposin and/or its known active molecular derivatives (e.g., saposin C) function as a pluripotent growth factor with diverse biological activities that favor malignant phenotypes in PCa cells. In addition, prosaposin or saposin C upregulates androgen receptor (AR) and AR-target genes (i.e., prostate-specific antigen, Probasin) expression and activity in LNCaP cells. Here, we examined prosaposin as an ARG. We report that DHT treatment of LNCaP cells increases prosaposin expression. In addition, we demonstrate androgen-responsiveness of prosaposin promoter and AR occupancy to a hormone-responsive element located in the proximal region of the prosaposin promoter. Our data for the first time identify prosaposin as an ARG. This observation, together with the pleiotropic growth factor activity of prosaposin, might suggest a role for this molecule in AR-dependent progression of prostate cancer at its early or late AI-state.
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PMID:Prosaposin is a novel androgen-regulated gene in prostate cancer cell line LNCaP. 1717 40

Osteoprotegerin (OPG), a key regulator of bone resorption, is hypothesized to have a role in prostate cancer (CaP) bone metastasis. As advanced CaP is treated by androgen ablation, we examined if androgen modulates OPG expression by CaP cell lines in vitro. Basal levels of secreted OPG protein were significantly greater in androgen-independent PC-3 cells compared with androgen-responsive LNCaP-FGC cells (P<0.001); OPG was not detected in the androgen-responsive CaP cell lines LAPC-4 or DuCaP. Treatment with 5alpha-dihydrotestosterone (5alpha-DHT) significantly decreased OPG protein levels in both PC-3 and LNCaP-FGC, with maximal suppression using 10(-9)-10(-7) M 5alpha-DHT in PC-3 (P<0.01; day 3), and using 10(-10)-10(-9) M 5alpha-DHT in LNCaP-FGC cells (P<0.01; day 6). OPG messenger RNA levels were not significantly altered by this 5alpha-DHT treatment. Co-treatment with 10(-6) M flutamide blocked 5alpha-DHT inhibition of OPG protein expression in LNCaP-FGC cells. These data suggest that androgen may modulate OPG protein levels in CaP cell lines in vitro using a post-transcriptional mechanism.
Prostate Cancer Prostatic Dis 2007
PMID:Androgen decreases osteoprotegerin expression in prostate cancer cells. 1718 57

Although prostate cancer growth is regulated by androgens through the androgen receptor (AR), in vitro assays of AR levels in prostate tumors have limited prognostic value. This might be improved by direct measurement of tumor AR in vivo using positron emission tomography (PET) imaging with fluorine-18-labeled androgens. Most AR PET imaging agents have been designed to limit steroid binding to serum proteins, but there is evidence that binding to sex hormone binding globulin (SHBG) might enhance tumor uptake. To probe the role of SHBG in prostate tumor uptake of PET imaging agents, we have synthesized two fluoro steroids, 7alpha-(fluoromethyl)dihydrotestosterone (7alpha-FM-DHT) and 7alpha-(fluoromethyl)nortestosterone (7alpha-FM-norT), by a route amenable to their labeling with [18F]fluoride ion. Both compounds have high affinity for AR, but 7alpha-FM-norT has much lower affinity for SHBG. Thus, these two fluoro steroids are well matched in terms of their site of fluorine labeling, similarity of structure, and equivalent AR binding affinity-but contrasting SHBG binding-and therefore can be used as agents for evaluating the role of SHBG binding in the target tissue uptake of AR PET imaging agents in humans.
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PMID:Synthesis of 7alpha-(fluoromethyl)dihydrotestosterone and 7alpha-(fluoromethyl)nortestosterone, structurally paired androgens designed to probe the role of sex hormone binding globulin in imaging androgen receptors in prostate tumors by positron emission tomography. 1758 12

Vitamin D seems to be involved in the control of prostate cancer cell growth. 17beta-Hydroxysteroid dehydrogenases type 2, type 4 and type 5 are enzymes which regulate intracellular concentration of active sex steroid hormones, which in turn, regulate the development, growth, and function of the prostate and play a role in the development and progression of prostate cancer. Using quantitative real-time PCR we find that calcitriol up-regulates HSD17B type 2, type 4 and type 5 in human prostate cancer LNCaP and PC3 cells but not in stromal cells. LXR agonist, TO-901317, suppresses the expression of HSD17B2 mRNA and inhibits calcitriol induced HSD17B2 expression. TO-901317 up-regulates the expression of HSD17B5 but not that of HSD17B4. 5alpha-Dihydrotestosterone up-regulates the expression of HSD17B2 and HSD17B4 but it significantly inhibits HSD17B5 expression by 70%. Calcitriol has no effect on DHT mediated expression of the three genes. The regulation of HSD17B2, HSD17B4 and HSD17B5 by ligands of LXR and VDR as well as AR in prostate cancer cells suggests a complex interaction of these signaling systems in the prostate.
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PMID:Regulation of 17beta-hydroxysteroid dehydrogenase type 2, type 4 and type 5 by calcitriol, LXR agonist and 5alpha-dihydrotestosterone in human prostate cancer cells. 1762 17

PC-SPES is an eight-herb mixture that has an activity against prostate cancer. Recently, we purified Saw Palmetto (Serenoa repens) from PC-SPES and found that Saw Palmetto induced growth arrest of prostate cancer LNCaP, DU145, and PC3 cells with ED50s of approximately 2.0, 2.6, and 3.3 microl/ml, respectively, as measured by mitochondrial-dependent conversion of the the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Saw Palmetto induced apoptosis of LNCaP cells in a time- and dose-dependent manner as measured by TUNEL assays. Also, Saw Palmetto increased the expression of p21waf1 and p53 protein in LNCaP cells. In addition, we found that Saw Palmetto down-regulated DHT- or IL-6-induced expression of prostate specific antigen in conjunction with down-regulation of the level of androgen receptor in the nucleus as measured by Western blot analysis. Moreover, Saw Palmetto down-regulated the IL-6-induced level of the phosphorylated form of STAT 3 in LNCaP cells. Furthermore, Saw Palmetto inhibited the growth of LNCaP cells present as tumor xenografts in BALB/c nude mice without adverse effect. These results indicate that Saw Palmetto might be useful for the treatment of individuals with prostate cancer.
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PMID:Saw Palmetto induces growth arrest and apoptosis of androgen-dependent prostate cancer LNCaP cells via inactivation of STAT 3 and androgen receptor signaling. 1767 86

Intracellular reactive oxygen species (ROS) may cause oxidative DNA damage, resulting in the formation of adducts such as 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG) and the cyclic pyrimidopurinone N-1, N(2) malondialdehyde-2'-deoxyguanosine (M(1)dG). These adducts have been associated with carcinogenesis, genomic instability and clonal evolution. We tested two hypotheses in human prostate cancer cells grown in vitro and in a xenograft model: (1) treatment of androgen-sensitive cells with DHT increases levels of oxidative DNA adduct levels; (2) flutamide, a competitive androgen receptor antagonist, prevents DHT-induced changes. Levels of M(1)dG and 8-oxo-dG adducts were determined by immunoslot blot and liquid chromatography-tandem mass spectrometry. M(1)dG and 8-oxo-dG levels were significantly higher than control levels in LNCaP cells exposed to supra-physiological concentrations (25-100 nM) of DHT (both P<0.05 by ANOVA). Flutamide pre-treatment completely prevented this increase. In the xenograft model, tumour levels of M(1)dG were decreased by 46% (P=0.001 by Mann-Whitney Test) in flutamide-treated animals compared to controls. The changes demonstrated suggest that oxidative DNA adducts may serve as biomarkers of the efficacy of androgen manipulation in chemoprevention trials.
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PMID:Androgen manipulation alters oxidative DNA adduct levels in androgen-sensitive prostate cancer cells grown in vitro and in vivo. 1809 12


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