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 cytotoxicity of a commonly used material to alleviate the symptoms of benign prostatic hyperplasia (BPH), Saw Palmetto Berry Extract (SPBE), was examined as neat oil using a set of prostatic cell lines; 267B-1, BRFF-41T and LNCaP. Proliferation of these prostatic derived cell lines is inhibited to different degrees when dosed for 3 days with SPBE. The amount of SPBE required to inhibit 50% growth (IC50) of these cell lines was 20-30 nl equivalents of SPBE per ml of medium for cell lines 267B-1 and BRFF-41T and approximately 10-fold more for the LNCaP cell line. The effect of SPBE dosing on these cell lines is not irreversible, since a 30 min treatment with SPBE at an IC50 concentration does not inhibit their growth. Normal prostate cells were inhibited by 20-25% when grown in the presence of 200 nl SPBE equivalent per ml media. Growth of other non-prostatic cancer cell lines, i.e. Jurkat and HT-29, was affected by approx. 50% and 40%, respectively. When LNCaP cells were grown in the presence of dihydrotestosterone and SPBE, the IC50 concentration decreased significantly compared to LNCaP cells grown in the presence of serum and SPBE. Reduced cellular growth after SPBE treatment of these cell lines may relate to decreased expression of Cox-2 and may be due to changes observed in the expression of Bcl-2. Expression of Cox-1 under similar conditions is not affected because of its constitutive expression. Since increased Cox-2 expression is associated with an increased incidence of prostate cancer, and decrease in its expression by SPBE would provide a basis for further investigation of its use against BPH and in prostatic cancer chemoprevention.
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PMID:Saw palmetto berry extract inhibits cell growth and Cox-2 expression in prostatic cancer cells. 1191 55

The principle of promoter-targeted gene delivery was used to direct the expression of reporter genes and inducible caspases to Cox-2-overexpressing cancer cells. The polycation poly(ethylenimine) was used in unmodified form to nonvirally deliver genes into cells, and targeting was achieved at the transcriptional level. Results demonstrated that reporter expression was reduced by an average of 89.8% in normal cells and cell lines not overexpressing Cox-2 when the strong cytomegalovirus promoter was replaced with the human Cox-2 promoter in delivered plasmids. Cocultures of normal and Cox-2-overexpressing cancer cells showed less than 0.5% reporter expression in normal fibroblast cells but over 35% reporter expression in PC3 prostate cancer cells. This targeting method was then used to direct the expression of inducible forms of caspases 3 and 9 to Cox-2-overexpressing cancer cells of the bladder and prostate. Following activation of the resulting caspase pro-forms, cells underwent apoptosis as evidenced by DNA fragmentation and cytoskeletal degradation. This result was also observed in cells resistant to apoptosis in terms of TNF-alpha initiation. Such directed apoptosis could eventually serve as a treatment for an entire class of Cox-2-overexpressing carcinomas.
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PMID:Directed apoptosis in Cox-2-overexpressing cancer cells through expression-targeted gene delivery. 1290 Jul 68

Nonsteroidal anti-inflammatory drugs (NSAIDs) play potential roles in cancer chemoprevention. In this study, we investigated the effects of NSAIDs on androgen receptor (AR)-mediated functions in prostate cancer cells. We found that two cyclooxygenase 2-specific NSAIDs, celecoxib and nimesulide, dramatically reduced the expression of androgen-inducible genes, such as prostate-specific antigen, hK2, and the FK506-binding protein 51 (FKBP51). We demonstrated that both NSAIDs repressed AR-mediated activation of prostate-specific antigen and hK2 promoter activity as well as AR protein expression. Finally, our findings suggested that overexpressed c-Jun by the NSAIDs not only inhibited the function of AR but also directly repressed AR expression at the transcription level. Our findings provide a strong rationale for celecoxib and nimesulide as potential agents for prostate cancer prevention and/or treatment.
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PMID:The cyclooxygenase 2-specific nonsteroidal anti-inflammatory drugs celecoxib and nimesulide inhibit androgen receptor activity via induction of c-Jun in prostate cancer cells. 1291 9

For the past 60 years, dietary intake of essential fatty acids has increased. Moreover, the omega-6 fatty acids have recently been found to play an important role in regulation of gene expression. Proliferation of human prostate cells was significantly increased 48 h after arachidonic acid (AA) addition. We have analyzed initial uptake using nile red fluorescence and we found that the albumin conjugated AA is endocytosed into the cells followed by the induction of RNA within minutes, protein and PGE2 synthesis within hours. Here we describe that AA induces expression of cytosolic phospholipase A2 (cPLA2) in a dose-dependent manner and that this upregulation is dependent upon downstream synthesis of PGE2. The upregulation of cox-2 and cPLA2 was inhibited by flurbiprofen, a cyclooxygenase (COX) inhibitor, making this a second feed-forward enzyme in the eicosanoid pathway. Cox-2 specific inhibitors are known to inhibit colon and prostate cancer growth in humans; however, recent findings show that some of these have cardiovascular complications. Since cPLA2 is upstream in the eicosanoid pathway, it may be a good alternative for a pharmaceutical target for the treatment of cancer.
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PMID:Arachidonic acid, an omega-6 fatty acid, induces cytoplasmic phospholipase A2 in prostate carcinoma cells. 1587 13

Collective evidence suggests that cyclooxygenase 2 (COX2) plays a role in prostate cancer risk. Cyclooxygenase 2 is the major enzyme that converts arachidonic acid to prostaglandins, which are potent mediators of inflammation. Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the enzymatic activity of COX2 and long-term use of NSAIDs appears to modestly lower the risk of prostate cancer. We investigated whether common genetic variation in COX2 influences the risk of advanced prostate cancer. Nine single-nucleotide polymorphisms (SNPs) in COX2 were genotyped among 1012 men in our case-control study of advanced prostate cancer. Gene-environment interactions between COX2 polymorphisms and NSAID use were also evaluated. Information on NSAID use was obtained by questionnaire. Three SNPs demonstrated nominally statistically significant associations with prostate cancer risk, with the most compelling polymorphism (rs2745557) associated with a lower risk of disease (odds ratio (OR) GC vs GG=0.64; 95% confidence interval (CI): 0.49-0.84; P=0.002). We estimated through permutation analysis that a similarly strong result would occur by chance 2.7% of the time. Nonsteroidal anti-inflammatory drug use was associated with a lower risk of disease in comparison to no use (OR=0.67; 95% CI: 0.52-0.87). No significant statistical interaction between NSAID use and rs2745557 was observed (P=0.12). Our findings suggest that variation in COX2 is associated with prostate cancer risk.
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PMID:COX2 genetic variation, NSAIDs, and advanced prostate cancer risk. 1760 63

Chronic inflammation has been hypothesized to increase prostate cancer risk. Prostaglandin-endoperoxide synthase 2 (PTGS2) encodes the proinflammatory cyclooxygenase 2 enzyme believed to be the rate-limiting step in the synthesis of prostaglandins, important mediators of inflammation. We investigated associations between PTGS2 polymorphisms and prostate cancer risk among 2321 prostate cancer cases and 2560 controls in two large case-control studies nested within the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and the Cancer Prevention Study II Nutrition Cohort. Five single nucleotide polymorphisms (SNPs) (rs5277, rs20432, rs4648276, rs5275 and rs689470) were examined in SNP and haplotype analyses (five SNPs in PLCO and four SNPs in the Nutrition Cohort). In PLCO, the Ex10 +837 T>C marker (rs5275) was initially associated with prostate cancer risk (P-trend = 0.02) but became non-significant after adjustment for multiple comparisons (P = 0.08); this SNP showed no association with prostate cancer risk in the Nutrition Cohort (P-trend = 0.54) or in an analysis pooling the two cohorts (P-trend = 0.20). No other SNP was associated with prostate cancer risk in PLCO or the Nutrition Cohort individually or combined. Haplotype analyses suggested an association between PTGS2 variants in PLCO alone (global P = 0.007), but not in the Nutrition Cohort (global P = 0.78) or pooled analysis (global P = 0.18). In conclusion, despite the potential importance of inflammation in prostate carcinogenesis, results from our large study of five PTGS2 SNPs does not support a strong association between PTGS2 variants and prostate cancer risk in non-Hispanic white men.
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PMID:Polymorphic variants in PTGS2 and prostate cancer risk: results from two large nested case-control studies. 1799 89

We recently showed that Nexrutine, a Phellodendron amurense bark extract, suppresses proliferation of prostate cancer cell lines and tumor development in the transgenic adenocarcinoma of mouse prostate (TRAMP) model. Our data also indicate that the anti-proliferative effects of Nexrutine are emediated in part by Akt and Cyclic AMP response element binding protein (CREB). Cyclooxygenase (Cox-2), a pro-inflammatory mediator, is a CREB target that induces prostaglandin E(2) (PGE(2)) and suppresses apoptosis. Treatment of LNCaP cells with Nexrutine reduced tumor necrosis factor alpha-induced enzymatic as well as promoter activities of Cox-2. Nexrutine also reduced the expression and promoter activity of Cox-2 in PC-3 cells that express high constitutive levels of Cox-2. Deletion analysis coupled with mutational analysis of the Cox-2 promoter identified CRE as being sufficient for mediating Nexrutine response. Immunohistochemical analysis of human prostate tumors show increased expression of CREB and DNA binding activity in high-grade tumors (three-fold higher in human prostate tumors compared to normal prostate; P = .01). We have identified CREB-mediated activation of Cox-2 as a potential signaling pathway in prostate cancer which can be blocked with a nontoxic, cost-effective dietary supplement like Nexrutine, demonstrating a prospective for development of Nexrutine for prostate cancer management.
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PMID:Regulation of Cox-2 by cyclic AMP response element binding protein in prostate cancer: potential role for nexrutine. 1803 Mar 57

Dietary supplements and botanical products are widely used by patients diagnosed with prostate cancer (CaP) as a primary or adjuvant form of treatment for their medical conditions in the United States. Many of the available products are complex mixtures composed of extracts from foreign plants, whose mechanism of action typically is not systematically and rigorously investigated. Laboratory studies employing precisely defined conditions and referenced methodologies are essential not only for standardization and characterization of the products, but are also important requisites for providing scientific evidence and molecular insights in regard to the clinical efficacies some of these products purportedly demonstrate. In previous studies from this laboratory, we serendipitously observed that Equiguard, a dietary supplement formulated with extracts from nine Chinese herbs for preventing decline in renal functions associated with the aging process, contain 70% ethanol-extractable ingredients that displayed potent growth inhibitory activities in androgen-dependent (AD) LNCaP and androgen-independent (AI) DU-145 and PC-3 cells. Moreover, significant reduction in expression of the androgen receptor (AR) and prostate specific antigen (PSA) also occurred in Equiguard-treated LNCaP cells. Although these results offer the possibility that Equiguard confers chemoprevention for CaP, it remains undetermined whether Equiguard functions in CaP cell types that represent the transition of AD to the AI status. Further, details of its mechanism of action have not been fully elucidated. The studies described in this report focusing on CWR22Rv1 cells are intended to fill these gaps. These cells express AR and PSA, yet show weak responsiveness to androgens and largely proliferate in an AI-independent manner - features that mimic AD --> AI in clinically advanced disease. Using the CWR22Rv1 cells, we showed that 70% ethanolic extracts of Equiguard effectively suppressed colony formation, inhibited cell proliferation, reduced expression of cell cycle regulatory proteins including cyclin D1, E2F, as well as lowered AR and PSA levels. Treatment of CWR22Rv1 cells with Equiguard also decreased cyclooxygenase 2 and led to increases in quinone reductase 1 and 2. These results provide further support that Equiguard possess multiple, chemopreventive attributes capable of disrupting the transition of AD --> AI in clinically advanced CaP.
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PMID:Ethanolic extracts of herbal supplement Equiguard suppress growth and control gene expression in CWR22Rv1 cells representing the transition of prostate cancer from androgen dependence to hormone refractory status. 1809 61

Prostate cancer is initially responsive to hormonal therapy, but cancers inevitably progress in an androgen-independent fashion with virtually all tumors evolving into more aggressive androgen refractory disease. Immunohistological comparisons of cyclooxygenase 2 (COX-2) expressions in 3 pairs of prostate cancer patients before and after the combined androgen blockade (CAB) therapy show elevated COX-2 expressions. This observation from clinical specimens is further supported by in vitro laboratory data using human prostate cancer cells in which the antiandrogen hydroxyflutamide (HF) induced COX-2 expression, and androgen suppressed COX-2 expression. By applying knockdown and overexpression strategies to modulate AR expression in prostate cancer cells, we confirmed that androgen/AR signal suppressed, and HF induced COX-2 expression at both protein and mRNA levels. COX-2 promoter reporter assay indicated that the suppression of COX-2 by androgen/AR is at the transcriptional level via modulation of NF-kappaB signals. Treatment of LNCaP and LAPC4 cells with 1 microM HF in the presence of 1 nM DHT, which mimics the CAB therapy condition, promotes cell growth, and this growth induction can be suppressed via adding the COX-2 specific inhibitor, NS398. This suggests that HF promoted prostate cancer cell growth is COX-2 dependent and this HF-COX-2 activation pathway can account for one reason of CAB therapy failure. Together, these findings provide a possible explanation how CAB with antiandrogen HF therapy might fail and provide a potential new therapeutic approach to battle prostate cancer via combination of CAB therapy with COX-2 inhibitor(s).
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PMID:A new prostate cancer therapeutic approach: combination of androgen ablation with COX-2 inhibitor. 1838 14

CpG-oligonucleotides (CpG-ODNs), mimicking bacterial DNA, have recently been shown to stimulate prostate cancer invasion in vitro via Toll-like receptor 9 (TLR9). Since cyclooxygenase 2 (COX-2), frequently overexpressed in multiple tumor types including prostate cancer, is a causal factor for tumor development, invasion and metastasis, an interesting question is raised whether TLR9 regulates COX-2 expression in prostate cancer cells. To address this question, herein we examined COX-2 expression in PC-3 cells stimulated with different doses and time courses of CpG-ODNs. The regulatory role of NF-kappaB in TLR9-mediated COX-2 expression was also investigated. CpG-ODN was found to up-regulate the expression of COX-2 in PC-3 cells in a dose- and time-dependent manner, but have little impact on COX-1 expression. Moreover, CpG-ODN also promoted nuclear translocation and activation of NF-kappaB, which appeared to be required for COX-2 induction by CpG-ODN. Overall, TLR9 up-regulates COX-2 expression in prostate cancer cells, at least partially through the activation of NF-kappaB, which may be implicated in tumor invasion and metastasis.
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PMID:Toll-like receptor 9 agonists up-regulates the expression of cyclooxygenase-2 via activation of NF-kappaB in prostate cancer cells. 1961 91


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