UMLS:C0376358 - FACTA Search

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Query: UMLS:C0376358 (prostate cancer)
59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prostate cancer (CaP), the most common malignancy in American men, presents its greatest challenge to clinicians when the cancer progresses to the hormone-refractory state. In the present investigation, we studied the combined effects of interferon (IFN) and onconase, each of which has reported antitumor activity, on growth and specific protein expression in JCA-1 cells. Cells were treated for up to 3 days with 1 and 5 microg/ml onconase, with and without concurrent addition of IFN-beta(ser) (10(3) IU/ml). Cell count and viability, and de novo RNA and protein synthesis were determined. Expression and subcellular distribution of STAT-1 were also assessed by immunoblot analysis. JCA-1 cells treated for 3 days with IFN or onconase showed a 15-30% reduction in cell proliferation, which was increased to 42-51% with both agents. Analysis of [35S]methionine incorporation into cells confirmed a more pronounced inhibitory effect elicited by IFN-beta and onconase; IFN-beta and 1 microg/ml onconase each decreased de novo protein synthesis by 23-25%, while the combination resulted in 59% suppression. Similar studies using incorporation of [3H]uridine into RNA yielded less significant effects. Further investigation using pre-labeled cellular RNA and proteins showed that either agent or their combination did not affect the turnover of macromolecules. To test whether the antiproliferative effects of IFN-beta and onconase were correlated with one or more specific gene changes, expression of an IFN-modulated protein, STAT-1, was determined. Both phosphorylated and unphosphorylated forms of STAT-1 and its subcellular distribution in the nucleus and cytoplasm, were increased 3-fold by IFN-beta. The IFN-elicited elevation of STAT-1 was not additionally augmented by onconase but was reduced 20-25% when onconase was simultaneously present as IFN-beta. These data show that the overall changes in STAT-1 did not correlate with the reduction in cell growth and the suppression of de novo protein/RNA synthesis elicited by these two agents, and imply that other target proteins are likely to be involved in the combined effects of IFN-beta and onconase in JCA-1 cells.
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PMID:Combined effects of onconase and IFN-beta on proliferation, macromolecular syntheses and expression of STAT-1 in JCA-1 cancer cells. 1195 80

Cytotoxicity evaluation of gnidilatimonoein, the most active isolated diterpene ester from Daphne mucronata [Sadeghi H, Mianabadi M, Yazdanparast R, (2002) Journal of Tropical. Medicinal Plant1 3: 169-173], revealed the strong antiproliferative activity among several different human cancer cell lines (K562, CCRF-CEM, HL-60 and MOLT-4 leukemia cell lines, LNCaP-FGC-10 a prostate cancer cell line) and a mouse BALB/C fibrosarcoma cell line (WEHI-164). Using flow cytometry technique, it was found that treatment of the most responsive cells (K562) with gnidilatimonoein inhibited the progression of cells through G1 phase by almost 15% compared to the untreated cells. The population of the treated cells in the S and G2 phases also reduced by 8.3% and 5.4%, respectively. Based on the extent of [3H]-thymidine and [3H]-uridine incorporation into DNA and RNA, respectively, the major metabolic effects of gnidilatimonoein were found to be mainly on DNA and to a less extent on RNA synthesis. Additionally, the activity of inosine-5'-monophosphate dehydrogenase (IMPDH), under the effects of genidilatimonoein, was reduced in the treated cells by 44%. These data strongly suggest that the purine biosynthetic pathway is significantly affected by gnidilatimonoein.
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PMID:Nucleic acid synthesis in cancerous cells under the effect of gnidilatimonoein from Daphne mucronata. 1476 68

Deregulation of apoptosis is involved in prostate cancer development and progression. This study involved an immunohistochemical "profiling" of prostate tissue specimens from patients who underwent prostatectomy for localized prostate cancer, to identify apoptosis-specific alterations associated with premalignant precursor lesions. Prostate tissue was pathologically evaluated, and areas of benign acini, high-grade prostate intraepithelial neoplasia (HGPIN), and prostate cancer were identified. Immunohistochemical analysis was performed to determine the expression of p27Kip1, a key cell cycle regulator, transforming growth factor (TGF)-beta receptor II (TbetaRII), a critical signaling effector of TGF-beta; Smad4, a downstream intracellular effector of TGF-beta signaling; p53, a key apoptosis regulator; and prostate-specific antigen (PSA), a clinical marker of prostate cancer. The apoptotic index of the same cell populations was determined using the transferase-mediated digoxigenin-tagged 16-desoxy-uridine-triphosphate nick end labeling assay. Our findings indicate a significant reduction in p27Kip1 immunoreactivity in HGPIN (P<0.0001) and prostate cancer (P<0.0001) compared with the benign tissue. A significant down-regulation was detected in TbetaRII expression in HGPIN and prostate cancer compared with benign prostatic hyperplasia (BPH)(P<0.001). A significant decrease was also observed in Smad4 levels in HGPIN and prostate cancer compared with BPH (P<0.001). Evaluation of the incidence of apoptosis revealed a significant decrease in the apoptotic index among the epithelial cell populations in HGPIN and a further decrease in prostate carcinoma (P<0.01). This reduced apoptotic index correlated with a significant increase in p53 immunoreactivity in the prostatic carcinoma foci. Prostate cancer cells exhibited strong nuclear staining for p53 compared with adjacent HGPIN (P<0.05) and the benign lesions of the same prostate specimens (P<0.05). A significant reduction in PSA immunostaining was detected in HGPIN and prostate carcinoma foci compared with the benign glandular epithelia (P<0.001). These results further define deregulation of TGF-beta signaling effectors as a molecular basis for loss of apoptotic control contributing to the development of prostate tumors. Identification of apoptotic regulators in precursor premalignant lesions may have prognostic significance in disease progression as well as therapeutic value for targeting prostate cancer.
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PMID:Apoptosis incidence and protein expression of p53, TGF-beta receptor II, p27Kip1, and Smad4 in benign, premalignant, and malignant human prostate. 1571 23

Neuroendocrine (NE)-like cells are hypothesized to contribute to the progression of prostate cancer by producing factors that enhance the growth, survival or metastatic capabilities of surrounding tumor cells. Many of the factors known to be secreted by NE-like cells, such as neurotensin (NT), parathyroid hormone-related peptide, serotonin, bombesin, etc., are agonists for G-protein-coupled receptors, but the signaling pathways activated by these agonists in prostate tumor cells are not fully defined. Identification of such pathways could provide insights into novel methods of treating late-stage disease. Using conditioned culture medium (CM) from LNCaP-derived NE-like cells (as a source of these agonists) or NT (a prototypical component of CM) to treat PC3 cells, we found that the epidermal growth factor (EGF) receptor (EGFR) was transactivated and that such activation was required for maximal PC3 cell mitogenesis, as measured by 5-bromo-2'-deoxy-uridine incorporation or cell number. NT also induced a time-dependent increase in EGFR Tyr(845) phosphorylation and phosphorylation of c-Src and signal transducer and activator of transcription 5b (Stat5b) (a downstream effector of Tyr(845)), events that were blocked by specific inhibition of c-Src (which mediates Tyr(845) phosphorylation of EGFR) or of EGFR. Introduction of mutant forms of EGFR (Tyr(845)) or Stat5b in PC3 cells, or treatment with selective, catalytic inhibitors of EGFR, c-Src and matrix metalloproteinases (MMPs) resulted in the loss of NT-induced stimulation of DNA synthesis, relative to wild-type controls. These data indicate that the mitogenic effect of NT on prostate cancer cells requires transactivation of the EGFR by MMPs and a novel downstream pathway involving c-Src, phosphorylation of EGFR Tyr(845) and activation of Stat5b.
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PMID:Neurotensin stimulates mitogenesis of prostate cancer cells through a novel c-Src/Stat5b pathway. 1686 79

Androgens as well as monohydroxy-fatty acids are implicated in the pathogenesis of prostate cancer. Like a huge variety of endo- and xenobiotics, they are eliminated as glucuronide conjugates formed by uridine diphosphate-glucuronosyltransferase (UGT) enzymes. In the present study, we observe that treatment of the prostate cancer cells LNCaP with natural and synthetic androgens, IL-1alpha, or epidermal growth factor (EGF) differently modulates the glucuronidation of androgen and bioactive lipid metabolites. Indeed, glucuronidation of 5alpha-androstane-3alpha,17beta-diol and 13-hydroxyoctadecadienoic acid was drastically reduced, whereas 12-hydroxyeicosatetraenoic acid conjugation by UGT was increased after androgen treatment. These effects reflected the reduction of UGT2B10, -B15, and -B17 enzyme expression, and the activation of the UGT2B11 gene. In human prostate epithelial cells, only UGT2B11 and -B15 mRNAs are detected and are regulated by androgens in a similar manner as in LNCaP cells. In LNCaP cells, IL-1alpha and EGF also regulate UGT2B expression in an isoform-specific manner; IL-1alpha induced UGT2B10 and reduced UGT2B17, while having no effects on UGT2B11 mRNA levels. EGF treatment resulted in a decreased UGT2B17 expression, whereas UGT2B10 and -B11 mRNA remained at their basal levels. Overall, these results demonstrate that in the human prostate, androgens do not only affect their own inactivation but also influence the levels of monohydroxy-fatty acids by regulating the expression of UGT2B enzymes in an isoform-specific manner. These differential effects of androgens, IL-1alpha, and EGF on lipid metabolism likely constitute an additional mechanism by which these endogenous factors promote prostate cancer development.
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PMID:Isoform-specific regulation of uridine diphosphate-glucuronosyltransferase 2B enzymes in the human prostate: differential consequences for androgen and bioactive lipid inactivation. 1688 6

Sialyltransferases transfer sialic acid from cytidine 5'-monophospho-N-acetylneuraminic acid (CMP-NeuAc) to an acceptor molecule. Trans-sialidases of parasites transfer alpha2,3-linked sialic acid from one molecule to another without the involvement of CMP-NeuAc. Here we report another type of sialylation, termed reverse sialylation, catalyzed by mammalian sialyltransferase ST3Gal-II. This enzyme synthesizes CMP-NeuAc by transferring NeuAc from the NeuAcalpha2,3Galbeta1,3GalNAcalpha unit of O-glycans, 3-sialyl globo unit of glycolipids, and sialylated macromolecules to 5'-CMP. CMP-NeuAc produced in situ is utilized by the same enzyme to sialylate other O-glycans and by other sialyltransferases such as ST6Gal-I and ST6GalNAc-I, forming alpha2,6-sialylated compounds. ST3Gal-II also catalyzed the conversion of 5'-uridine monophosphate (UMP) to UMP-NeuAc, which was found to be an inactive sialyl donor. Reverse sialylation proceeded without the need for free sialic acid, divalent metal ions, or energy. Direct sialylation with CMP-NeuAc as well as the formation of CMP-NeuAc from 5'-CMP had a wide optimum range (pH 5.2-7.2 and 4.8-6.4, respectively), whereas the entire reaction comprising in situ production of CMP-NeuAc and sialylation of acceptor had a sharp optimum at pH 5.6 (activity level 50% at pH 5.2 and 6.8, 25% at pH 4.8 and 7.2). Several properties distinguish forward/conventional versus reverse sialylation: (i) sodium citrate inhibited forward sialylation but not reverse sialylation; (ii) 5'-CDP, a potent forward sialyltransferase inhibitor, did not inhibit the conversion of 5'-CMP to CMP-NeuAc; and (iii) the mucin core 2 compound 3-O-sulfoGalbeta1,4GlcNAcbeta1,6(Galbeta1,3)GalNAcalpha-O-benzyl, an efficient acceptor for ST3Gal-II, inhibited the conversion of 5'-CMP to CMP-NeuAc. A significant level of reverse sialylation activity is noted in human prostate cancer cell lines LNCaP and PC3. Overall, the study demonstrates that the sialyltransferase reaction is readily reversible in the case of ST3Gal-II and can be exploited for the enzymatic synthesis of diverse sialyl products.
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PMID:Reversible sialylation: synthesis of cytidine 5'-monophospho-N-acetylneuraminic acid from cytidine 5'-monophosphate with alpha2,3-sialyl O-glycan-, glycolipid-, and macromolecule-based donors yields diverse sialylated products. 1806 23

A cell survival assay of the four arabinosyl uridine analogs with functionalities of 5-fluoro, 5-fluorovinyl, 5-iodo, and 5-iodovinyl as potential positron-emitter tagged probe for monitoring cancer gene therapy were performed. Cytotoxicities of 5-fluoro-, 5-iodo-, 5-fluorovinyl, and 5-iodovinyl arabinosyl uridines against SR-39 thymidine kinase transfected murine prostate cancer cells have been evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. None of them showed significant bioactivity. A syn conformation derived from intra-hydrogen bonding was suggested for the unfavorable interaction and diminished bioactivity.
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PMID:Comparison of bioactivities of 5-Fluoro, 5-Iodo, 5-Iodovinyl, and 5-fluorovinyl arabinosyl uridines against SR-39 TK-transfected murine prostate cancer cells. 1817 88

Many organic compounds containing selenium have shown anticancer effects and some have been used in chemoprevention of cancers and other diseases. Though Se-containing amino acids are generally used for these purposes, the natural nucleosides may also be used as Se-carriers for these important applications. Therefore, we describe here the convenient synthesis of the new 3'-MeSe-thymidine nucleoside and the other uridine and thymidine derivatives modified with MeSe at the 2' and 5' positions, and report their anti-tumor activity against prostate cancer cell lines. Our work demonstrates for the first time anticancer activity of the methylseleno nucleosides.
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PMID:Facile synthesis and anti-tumor cell activity of Se-containing nucleosides. 1911 70

Teriflunomide (TFN) is an inhibitor of de novo pyrimidine synthesis and the active metabolite of leflunomide. Leflunomide is prescribed to patients worldwide as an immunomodulatory and anti-inflammatory disease-modifying prodrug. Leflunomide inhibited the growth of human prostate cancer xenographs in mice, and leflunomide or TFN promoted cytostasis and/or apoptosis in cultured cells. These findings suggest that TFN could be useful in prostate cancer chemoprevention. We investigated the possible mechanistic aspects of this tenet by characterizing the effects of TFN using premalignant PWR-1E and malignant DU-145 human prostate epithelial cells. TFN promoted a dose- and time-dependent cytostasis or apoptosis induction in these cells. The cytostatic effects of TFN, which were reversible but not by the presence of excess uridine in the culture medium, included diminished cellular uridine levels, an inhibition in oxygen consumption, a suppression of reactive oxygen species (ROS) generation, S-phase cell cycle arrest, and a conspicuous reduction in the size and number of the nucleoli in the nuclei of these cells. Conversely, TFN's apoptogenic effects were characteristic of catastrophic mitochondrial disruption (i.e., a dissipation of mitochondrial inner transmembrane potential, enhanced ROS production, mitochondrial cytochrome c release, and cytoplasmic vacuolization) and followed by DNA fragmentation. The respiration-deficient derivatives of the DU-145 cells, which are also uridine auxotrophs, were markedly resistant to the cytostatic and apoptotic effects of TFN, implicating de novo pyrimidine synthesis and mitochondrial bioenergetics as the primary targets for TFN in the respiration competent cells. These mechanistic findings advocate a role for TFN and mitochondrial bioenergetics in prostate cancer chemoprevention.
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PMID:Teriflunomide (leflunomide) promotes cytostatic, antioxidant, and apoptotic effects in transformed prostate epithelial cells: evidence supporting a role for teriflunomide in prostate cancer chemoprevention. 2056 49

The current study was aimed at synthesizing a glucuronide derivative of D-penicillamine (D-PA) to be used for imaging purposes. First of all, D-PA-glucuronide (D-PA-Glu) was synthesized by experimental treatments starting with uridine 5'-diphospho-glucuronosyltransferase enzyme rich microsome preparate. Then, the synthesized compound was labeled with technetium ((99m)Tc) by using a reduction method with stannous chloride. Quality controls were performed by using high-performance liquid chromatography and thin-layer radio chromatography (TLRC). Radiolabeling yield of (99m)Tc-D-PA-Glu was more than 98% according to TLRC results. In vitro evaluations of radiolabeled complexes were investigated on PC-3 human prostate cancer cells. (99m)Tc-D-PA-Glu exhibited more accumulation on PC-3 cells versus (99m)Tc-D-PA at 240 minutes. In order to determine its radiopharmaceutical potential, biodistribution studies were carried out in male Albino Wistar rats. The biodistribution results of (99m)Tc-D-PA-Glu, showed the highest uptake in prostate at 120 minutes postinjection with the main excretion route being through kidneys and bladder. (99m)Tc-D-PA-Glu and (99m)Tc-D-PA have exhibited different biodistribution results.
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PMID:99mTc-d-penicillamine-glucuronide: synthesis, radiolabeling, in vitro and in vivo evaluation. 2195 May 58

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