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)

Endostatin is a 20-kDa endogenous angiogenesis inhibitor that has recently been shown to inhibit the expression of vascular endothelial growth factor (VEGF), an angiogenic growth factor that is up-regulated by hypoxia via the HIF-1 transcription factor complex. To determine if the anti-angiogenic activity of endostatin involves a modulation of the HIF-1/VEGF pathway in cancer cells, experiments were conducted to establish what effect endostatin has on HIF-1 activity, HIF-1alpha protein production, and cellular localization in prostate cancer cells and endothelial cells. Endothelial cell tube formation was inhibited by endostatin purchased from Calbiochem (San Diego, CA) but not endostatin obtained from EntreMed (Rockville, MD). Subsequent experiments using Calbiochem endostatin showed that it did not alter HIF-1alpha protein production or cellular localization in any of the cell lines tested, nor did it alter HIF-1 transactivational activity in hypoxia. Whether or not this is also true in vivo remains to be determined. Nevertheless, these data suggest that the anti-angiogenic activity of endostatin is independent of the HIF-1/VEGF pathway. Immunocytochemical staining results do not indicate a decreased production of VEGF in Calbiochem endostatin-treated LNCaP or human umbilical vein endothelial cells (HUVEC). Treatment of rat aortic cross sections with human endostatin from Calbiochem resulted in a dose-dependent inhibition of microvessel outgrowth. Importantly, inhibition of vessel outgrowth by Calbiochem endostatin in a human saphenous vein angiogenesis assay required early treatment. In view of this in vitro data, we suggest that clinical trials involving endostatin treatment of late-stage disease may not adequately represent the efficacy of this drug in early-stage cancer.
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PMID:Anti-angiogenic activity of human endostatin is HIF-1-independent in vitro and sensitive to timing of treatment in a human saphenous vein assay. 1455 3

Dietary intake of many fruits and vegetables has been shown to be associated with reduced risk of cancer. We investigated the in vivo efficacy of grape seed extract (GSE, patented as Traconol) against prostate cancer (PCA) and associated molecular events. Athymic nude mice were implanted with hormone-refractory human prostate carcinoma DU145 cells and fed with 100 and 200 mg/kg/day (5 days/week) doses of GSE for 7 weeks. At the end of experiment, tumors were immunohistochemically analyzed for cell proliferation, apoptosis and angiogenesis. Our data show that GSE feeding strongly inhibited tumor growth that accounted for 59-73% (p < 0.001) inhibition in tumor volume and 37-47% (p < 0.05) decrease in tumor weight at the end of the experiment. It did not show any significant change in body weight gain profile and diet consumption. Immunohistochemical analysis of tumors showed that GSE decreases proliferation index by 51-66% (p < 0.001) and increases apoptotic index by 3-4-fold (p < 0.001). CD31 staining for endothelial cells, showed decrease in intratumoral microvasculature in GSE-fed group of mice. Control tumors showed 64.0 +/- 1.6 CD31 positive cells/400x field compared to 23.2 +/- 0.9 and 15.7 +/- 0.08 (p < 0.001) CD31 positive cells in 100 and 200 mg/kg doses of GSE-treated tumors, respectively. GSE strongly inhibited (47-70%, p < 0.05) vascular endothelial growth factor (VEGF) secretion in conditioned medium by DU145 cells. Recently, the circulating level of insulin-like growth factor binding protein (IGFBP)-3 is shown to inversely related with PCA risk, growth and prognosis. Consistent with this, we observed 6-7-fold (p < 0.001) increase in tumor-secreted levels of IGFBP-3 after GSE feeding. In other immunohistochemical studies, compared to controls, tumor xenografts from GSE-fed groups of mice showed a moderate decrease in VEGF but an increase in IGFBP-3 levels. These findings suggest that GSE possesses in vivo anticancer efficacy against hormone-refractory human PCA, which is associated with its antiproliferative, proapoptotic and antiangiogenic activities together with upregulation of IGFBP-3.
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PMID:Grape seed extract inhibits advanced human prostate tumor growth and angiogenesis and upregulates insulin-like growth factor binding protein-3. 1469

The identification of agents with antiproliferative activity against endothelial cells has significant value for the treatment of many angiogenesis-dependent pathologies. Herein, we describe the discovery of a series of thalidomide analogues possessing inhibitory effects against both endothelial and prostate cancer cells. More specifically, several analogues exhibited low micromolar to mid-nanomolar potency in the inhibition of human microvascular endothelial cell (HMEC) proliferation, both in the presence and absence of vascular endothelial growth factor (VEGF), with the tetrafluorophthalimido class of compounds demonstrating the greatest potency. Additionally, all the compounds were screened against two different androgen independent prostate cancer cell lines (PC-3 and DU-145). Again, the tetrafluorophthalimido analogues exhibited the greatest effect with GI(50) values in the low micromolar range. Thalidomide was found to demonstrate selective inhibition of androgen receptor positive LNCaP prostate cancer cells. Furthermore, we showed that, as an example, tetrafluorophthalimido analogue 19 was able to completely inhibit the prostate specific antigen (PSA) secretion by the LNCaP cell line, while thalidomide demonstrated a 70% inhibition. We have also demonstrated that a correlation exists between HMEC and prostate cancer cell proliferation for this structural class. Altogether, our study suggests that these analogues may serve as promising leads for the development of agents that target both androgen dependent and independent prostate cancer and blood vessel growth.
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PMID:Thalidomide analogues demonstrate dual inhibition of both angiogenesis and prostate cancer. 1472 53

Activator protein-2alpha (AP-2) is a transcription factor that regulates proliferation and differentiation in mammalian cells. We have shown previously that although AP-2 is expressed highly in normal prostatic epithelium, its expression is lost in high-grade prostatic intraepithelial neoplasia and prostate cancer, suggesting that loss of AP-2 plays a role in prostate cancer development. We demonstrate that forced AP-2 expression in the prostate cancer cell line LNCaP-LN3 (AP-2 negative) inhibited dramatically tumor incidence in nude mice. To identify the genes that might have been responsible for this effect, we used microchip expression array. We found several genes known to be involved in malignancy were deregulated, including the vascular endothelial growth factor (VEGF) gene. Because VEGF was down-regulated by 14.7-fold in the AP-2-transfected cells and because it is a major angiogenic factor in prostate cancer development and progression, we chose to examine the AP-2-VEGF interaction. Our evidence suggests that AP-2 repressed transcriptionally the VEGF promoter by competing with the transcriptional activator Sp3. Loss of AP-2 in prostate cancer cells reduced the AP-2:Sp3 ratio and activated VEGF expression. AP-2 acts as a tumor-suppressor gene in prostate cancer. Elucidating the molecular events resulting from loss of AP-2 in the prostate epithelium has implications for the understanding and prevention of the onset of prostate cancer.
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PMID:Activator protein 2alpha inhibits tumorigenicity and represses vascular endothelial growth factor transcription in prostate cancer cells. 1474 78

The platelet-derived growth factor (PDGF) proteins are potent stimulators of cell proliferation/transformation and play a major role in cell-cell communication. For over two decades, PDGFs were thought to exist as three dimeric polypeptides (the homodimers AA and BB and the heterodimer AB). Recently, however, the PDGF C and D chains were discovered in a BLAST search of the expressed sequence tag databases. The PDGF CC and DD dimers have a unique two-domain structure with an NH(2)-terminal CUB (compliment subcomponents C1r/C1s, Uegf, and Bmp1) domain and a COOH-terminal PDGF/vascular endothelial growth factor domain. Whereas secreted PDGF AA, BB, and AB readily activate their cell surface receptors, it was suggested that extracellular proteolytic removal of the CUB domain is required for the PDGF/vascular endothelial growth factor domain of PDGF CC and DD to activate PDGF receptors. In the present study, we examined the processing of latent PDGF D into its active form and the effects of PDGF D expression on prostate cancer progression. We show that LNCaP cells auto-activate latent PDGF DD into the active PDGF domain, which can induce phosphorylation of the beta-PDGF receptor and stimulates LNCaP cell proliferation in an autocrine manner. Additionally, LNCaP-PDGF D-conditioned medium induces migration of the prostate fibroblast cell line 1532-FTX, indicating LNCaP-processed PDGF DD is active in a paracrine manner as well. In a severe combined immunodeficient mouse model, PDGF DD expression accelerates early onset of prostate tumor growth and drastically enhances prostate carcinoma cell interaction with surrounding stromal cells. These demonstrate a potential oncogenic activity of PDGF DD in the development and/or progression of prostate cancer.
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PMID:A potential oncogenic activity of platelet-derived growth factor d in prostate cancer progression. 1499 32

Clinical, laboratory, histopathological, and pharmacological evidence support the notion that the coagulation system, which is activated in most cancer patients, plays an important role in tumor biology. Our laboratory has provided evidence that thrombin activates angiogenesis, a process which is essential in tumor growth and metastasis. This event is independent of fibrin formation. At the cellular level many actions of thrombin can contribute to activation of angiogenesis: (1). Thrombin decreases the ability of endothelial cells to attach to basement membrane proteins. (2). Thrombin greatly potentiates vascular endothelial growth factor- (VEGF-) induced endothelial cell proliferation. This potentiation is accompanied by up-regulation of the expression of VEGF receptors (kinase insert domain-containing receptor [KDR] and fms-like tyrosine kinase [Flt-1]). (3). Thrombin increases the mRNA and protein levels of alpha (v)beta (3) integrin and serves as a ligand to this receptor. Furthermore, thrombin increases the secretion of VEGF and enhances the expression and protein synthesis of matrix metalloprotease-9 and alpha (v)beta (3) integrin in human prostate cancer PC-3 cells. These results could explain the angiogenic and tumor-promoting effect of thrombin and provide the basis for development of thrombin receptor mimetics or antagonists for therapeutic application.
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PMID:Role of thrombin in angiogenesis and tumor progression. 1503 98

Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes encoding glucose transporters, glycolytic enzymes, and vascular endothelial growth factor (VEGF). HIF-1alpha is a major subunit of HIF-1 heterodimer. In this study, an immunohistochemical analysis of HIF-1alpha was focused on clinical specimens containing high-grade prostate intraepithelial neoplasia lesions since high-grade prostate intraepithelial neoplasia is considered the precursor of a majority of invasive prostate adenocarcinoma and presents the increased activity of angiogenesis. HIF-1alpha was up-regulated in 11 of 14 high-grade prostate intraepithelial neoplasia lesions identified in a total 10 prostate biopsies relative to the respective normal epithelium, stromal cells, and benign prostatic hyperplasia (BPH). Moreover, up-regulation of HIF-1alpha in adjacent prostate cancer lesions was more enhanced than in high-grade prostate intraepithelial neoplasia. The results suggest that up-regulation of HIF-1alpha is an early event in prostate carcinogenesis, and that HIF-1alpha may become a potential target for prostate cancer prevention and a surrogate biomarker for monitoring pre-malignant lesions of the prostate.
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PMID:Up-regulation of hypoxia-inducible factor 1alpha is an early event in prostate carcinogenesis. 1506 31

Neuroendocrine cells have been found in all the stages of prostate cancer, but their clinical significance is not completely understood. Neuroendocrine cells are androgen receptor- and prostate-specific antigen-negative, do not proliferate, and secrete many neuropeptides, such as chromogranin A. Neuroendocrine differentiation of prostate cancer correlates with an advancing tumour stage, poor prognosis and tumour progression after androgen deprivation. Furthermore, neuroendocrine phenotype is associated with the increased expression of neo-angiogenesis and vascular endothelial growth factor and with an over-expression of survivin, a new anti-apoptosis protein. Chromogranin A is the quantitatively major secretory protein of the vesicles inside neuroendocrine prostate cells and it is the marker most frequently used to detect neuroendocrine features, both in tissues and in general circulation. Tumours displaying neuroendocrine phenotype tend to be more aggressive and resistant to hormone-therapy. Neuroendocrine differentiation seems to be a dynamic phenomenon: in vitro and in vivo data suggest that it can be induced by androgen suppression. Moreover, the differences in the expression of somatostatin receptors between primary and hormone-refractory prostate cancer are likely to be related to the changes in neuroendocrine phenotype during androgen deprivation. Circulating chromogranin A levels seem to be scarcely affected by endocrine- and chemotherapy, while they significantly decreased after treatment with somatostatin analogs.
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PMID:Somatostatin receptors: from basic science to clinical approach. Unlabeled somatostatin analogues-1: Prostate cancer. 1507 13

The nuclear receptor peroxisome proliferator-activated receptor delta [PPARdelta/beta (NR1C2)] has been implicated in colorectal carcinogenesis by various molecular genetic observations. These observations have recently been supported by studies of activation of PPARdelta by pharmacological agents. Here we present the first report of the stimulation of breast and prostate cancer cell growth using PPARdelta selective agonists. Activation of PPARdelta with compound F stimulated proliferation in breast (T47D, MCF7) and prostate (LNCaP, PNT1A) cell lines, which are responsive to sex hormones. Conversely, we have found that several steroid-independent cell lines, including colon lines, were unresponsive to compound F. These findings were confirmed with an additional high-affinity PPARdelta agonist, GW501516. Conditional expression of PPARdelta in MCF7 Tet-On cells resulted in a doxycycline-enhanced response to GW501516, thus providing direct genetic evidence for the role of PPARdelta in the proliferative response to this drug. Activation of PPARdelta in T47D cells resulted in increased expression of the proliferation marker Cdk2 and also vascular endothelial growth factor alpha (VEGFalpha) and its receptor, FLT-1, thus, suggesting that PPARdelta may initiate an autocrine loop for cellular proliferation and possibly angiogenesis. Consistent with this hypothesis, we demonstrated a pro-proliferative effect of GW501516 on human umbilical vein endothelial cell cultures and found that GW501516 also regulated the expression of VEGFalpha and FLT-1 in these cells. Our observations provide the first evidence that activation of PPARdelta can result in increased growth in breast and prostate cancer cell lines and primary endothelial cells and supports the possibility that PPARdelta antagonists may be of therapeutic value in the treatment of breast and prostate cancer.
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PMID:Activation of peroxisome proliferator-activated receptor delta stimulates the proliferation of human breast and prostate cancer cell lines. 1512 55

Epidemiological studies and clinical observations suggest that nonsteroidal anti-inflammatory drugs and certain selective cyclooxygenase (COX)-2 inhibitors may reduce the relative risk of clinically evident prostate cancer. This prompted us to investigate the chemopreventive potential of celecoxib, a selective COX-2 inhibitor, against prostate carcinogenesis in a transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Similar to prostate cancer in humans, prostate malignancies in TRAMP mice progress from precursor intraepithelial lesions, to invasive carcinoma that metastasizes to lymph nodes, liver, lungs, and occasionally to bone. The basal enzyme activity and protein expression of COX-2 is significantly higher (>4-fold) in the dorsolateral prostate of TRAMP mice up to 24 weeks of age compared with their nontransgenic littermates. Eight-week-old TRAMP mice were randomly divided and fed either control diet (AIN 76A) or a custom prepared AIN 76A diet containing 1500-ppm celecoxib ad libitum for 24 weeks, a dosage that would compare with the normal recommended dose for the treatment of human disease. Studies from two independent experiments, each consisting of 10 mice on test, showed that the cumulative incidence of prostate cancer development at 32 weeks of age in animals fed with AIN 76A diet was 100% (20 of 20) as observed by tumor palpation, whereas 65% (13 of 20), 35% (7 of 20), and 20% (4 of 20) of the animals exhibited distant site metastases to lymph nodes, lungs, and liver. Celecoxib supplementation to TRAMP mice from 8-32 weeks of age exhibited significant reduction in tumor development (5 of 20) with no signs of metastasis. Celecoxib feeding resulted in a significant decrease in prostate (56%; P < 0.0003) and genitourinary weight (48%; P < 0.008). Sequential magnetic resonance imaging analysis of celecoxib-fed mice documented lower prostate volume compared with the AIN 76A-fed group. Histopathological examination of celecoxib-fed animals showed reduced proliferation, and down-modulation of COX-2 and prostaglandin E2 levels in the dorsolateral prostate and plasma, respectively. These results correlated with retention of antimetastasis markers, viz E-cadherin, and alpha- and beta-catenin, along with a significant decrease in vascular endothelial growth factor protein expression. Celecoxib supplementation also resulted in enhanced in vivo apoptosis in the prostate as monitored by several techniques including a recently perfected technique of 99mTc-labeled annexin V in live animals followed by phosphor imaging. One striking observation in an additional study was that celecoxib feeding to mice with established tumors (16 weeks of age) significantly improved their overall survival (P = 0.014), compared with AIN 76A-fed group. Our findings suggest that celecoxib may be useful in chemoprevention of prostate cancer.
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PMID:Suppression of prostate carcinogenesis by dietary supplementation of celecoxib in transgenic adenocarcinoma of the mouse prostate model. 1512 78


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