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)

In 36 men with prostatic cancer, the following findings were obtained: intravenous administration of 12.0 g diethylstilboestrol diphosphate (DSDP) induced a relatively slight decrease of the LH plasma level from 22.7 +/- 11.8 to 7.7 +/- 3.6 mIU/ml (34%), whereas the total testosterone plasma level decreased from 435.3 +/- 187.8 to 29.9 +/- 16.4 ng/100 ml (6.7%) suggesting a direct inhibitory effect of the oestrogen on testicular testosterone secretion. The apparently free, biologically active testosterone plasma level even decreased from 6.2 +/- 3.7 to 0.21 +/- 0.16 ng/100 ml (3.4%), due to the oestrogen-induced increase of the concentration of testosterone-binding beta-globulin (from 9.6 +/- 4.4 to 20.6 +/- 10.7-10(-8) M). 3--7 days after additional orchidectomy plus subcutaneous implantation of 100 mg dienoestrol diacetate a further decrease of the apparently free testosterone plasma level from 0.21 +/- 0.16 to 0.14 +/- 0.07 ng/100 ml was found. In contrast, 6 weeks after orchidectomy without oestrogen implantation a significant increase of th- apparently free testosterone plasma level -rom 0.21 %/- 0.16 to 0.34 +/- 0.15 ng/100 ml was observed (p less than 0.01). In view of these findings the biologically active free testosterone plasma level appears to be even more suppressed by intravenous administration of high DSDP than by orchidectomy. The most effective suppression of apparently free testosterone was achieved, however, by oestrogen treatment combined with orchidectomy.
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PMID:Endocrine effects of oestrogen treatment in patients with prostatic cancer. 97 78

We investigated the role of androgen-induced oxidative stress in prostate cancer using the androgen-responsive LNCaP human prostate cancer cell line exposed to a 1-nM concentration of the synthetic androgen R1881 (which correlates with serum androgen levels). Such exposure, which decreases growth rate and increases oxidative stress in LNCaP cells, induced statistically significant mitochondrial changes. A 40% increase in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) reduction, indicative of mitochondrial dehydrogenase activity, occurred 24 hr after androgen treatment. This change preceded 50-110% increases, 40-96 hr after R1881 exposure, in levels of cellular peroxides and hydroxyl radicals as measured by 2'7'-dicholorofluorescin diacetate (DCF) fluorescence. On the basis of electron microscopy measurements, R1881 treatment increased the area fraction of mitochondria per cell by approximately 100% at 72 hr. In agreement, mitochondrial mass at 96 hr, evaluated by the fluorescent dye nonyl acridine orange (NAO), was 80% higher in treated cells. R1881 exposure for 24 hr lowered the activities of electron transport system (ETS) complexes, I, II, and IV by 17-27% and ATP levels by 50%. The ETS inhibitors, rotenone and antimycin A, lowered androgen-induced DCF fluorescence readings to control levels thereby suggesting ETS involvement in androgen-induced oxidant production. Addition of alpha-tocopherol succinate abrogated R1881-induced elevations in MTT reduction. In sum, androgens may, directly or indirectly, contribute to oxidative stress in LNCaP cells by regulating mitochondrial number, activity, and oxidant production by mechanisms that are, at least in part, sensitive to an antioxidant.
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PMID:Androgen-induced oxidative stress in human LNCaP prostate cancer cells is associated with multiple mitochondrial modifications. 1122 34

Prostate specific antigen, the clinical marker for prostate cancer, is a neutral serine protease whose function is to lyse seminal proteins. Recent work by our laboratory has suggested that prostate specific antigen stimulates the generation of reactive oxygen species in prostate cancer cells. Using 2',7'-dichlorofluorescin diacetate, a dye that fluoresces in the presence of hydrogen peroxide or hydroxyl radicals, we found that prostate specific antigen markedly stimulated reactive oxygen species generation in LNCaP cells. The effect was concentration dependent and its specificity was supported by the fact that anti-prostate specific antigen antibodies abolished the response. Since testosterone stimulates the production of prostate specific antigen, we considered that the reactive oxygen species response to testosterone may be linked to prostate specific antigen. We found that the testosterone effect on reactive oxygen species was blocked by flutamide and by anti-prostate specific antigen antibody. Additionally, though PC3 and DU145 could not respond to testosterone, they readily increased reactive oxygen species in response to prostate specific antigen. Focusing on the mechanism of the prostate specific antigen effect, we tested two other serine proteases, trypsin and chymotrypsin, but found no effect on reactive oxygen species in LNCaP cells. Nevertheless, serine protease inhibitors, alpha(1)-antichymotrypsin, alpha(2)-macroglobulin and Bowman-Birk inhibitor, blocked reactive oxygen species generation stimulated by prostate specific antigen. This apparent paradox was investigated with the use of a specific anti-'prostate specific antigen' antibody which recognizes an epitope away from the catalytic site and which does not inhibit protease activity. Despite the lack of inhibition of proteolytic activity, this antibody blocked the effect of prostate specific antigen on reactive oxygen species generation. These findings suggest that although the integrity of the prostate specific antigen molecule is necessary for stimulating reactive oxygen species generation, its proteolytic activity is not. The underlying mechanism is currently under investigation.
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PMID:Testosterone and prostate specific antigen stimulate generation of reactive oxygen species in prostate cancer cells. 1169 38

Reactive oxygen species (ROS) appear to play an important role in regulating growth and survival of prostate cancer. However, the sources for ROS production in prostate cancer cells have not been determined. We report that ROS are generated by intact American Type Culture Collection DU 145 cells and by their membranes through a mechanism blocked by NAD(P)H oxidase inhibitors. ROS are critical for growth in these cells, because NAD(P)H oxidase inhibitors and antioxidants blocked proliferation. Components of the human phagocyte NAD(P)H oxidase, p22phox and gp91phox, as well as the Ca2+ concentration-responsive gp91phox homolog NOX5 were demonstrated in DU 145 cells by RT-PCR and sequencing. Although the protein product for p22phox was not detectable, both gp91phox and NOX5 were identified throughout the cell by immunostaining and confocal microscopy and NOX5 immunostaining was enhanced in a perinuclear location, corresponding to enhanced ROS production adjacent to the nuclear membrane imaged by 2',7'-dichlorofluorescin diacetate oxidation. The calcium ionophore ionomycin dramatically stimulated ferricytochrome c reduction in cell media, further supporting the importance of NOX5 for ROS production. Antisense oligonucleotides for NOX5 inhibited ROS production and cell proliferation in DU 145 cells. In contrast, antisense oligonucleotides to p22phox or gp91phox did not impair cell growth. Inhibition of ROS generation with antioxidants or NAD(P)H oxidase inhibitors increased apoptosis in cells. These results indicate that ROS generated by the newly described NOX5 oxidase are essential for prostate cancer growth, possibly by providing trophic intracellular oxidant tone that retards programmed cell death.
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PMID:NOX5 NAD(P)H oxidase regulates growth and apoptosis in DU 145 prostate cancer cells. 1268 16

The purpose of this study was to determine in vitro the relationship between ionizing radiation (IR) treatment, reactive oxygen species (ROS) production, lipid peroxidation, glutathione (GSH) levels, and DNA damage of the human benign prostate hyperplasia BPH-1 cell line, and two prostate cancer cell lines, LNCaP, which is androgen-sensitive, and DU-145, which is androgen non-responsive. The cells were analysed after exposure to 1.0 or 2.0 Gy of X-ray radiations. The response to IR treatment was evaluated by examining: ROS production by quantitative analysis with fluorescent probe 5 and 6-carboxy-2'7'-dichlorodihydrofluorescein diacetate bis acetomethyl ester (DCFH-DA), GSH levels by 2,2'-dinitro-5,5'-dithio-benzoic acid (DTNB), and lipoperoxidation by thiobarbituric acid reactive substances (TBARS) analysis. To study IR-induced DNA damage, Single Cell Gel Electrophoresis or comet assay was performed. DU-145 cells were characterized by higher DNA damage, more evident extent of lipid peroxidation, and slighter levels of ROS and GSH compared to BPH-1 or LNCaP. Human benign BPH-1 and cancer LNCaP and DU-145 cell lines are not equal regarding their capability of IR resistance in terms of ROS production, antioxidant potential, IR-induced lipid peroxidation and DNA damage.
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PMID:Distinct response to ionizing radiation of human prostate cell lines. 1614 61

Overexpression of the tumor suppressor gene, wild-type p53 (wtp53), using adenoviral vectors (Adp53) has been suggested to kill cancer cells by hydroperoxide-mediated oxidative stress [1,2] and nutrient distress induced by the glucose analog, 2-deoxyglucose (2DG), has been suggested to enhance tumor cell killing by agents that induce oxidative stress via disrupting hydroperoxide metabolism [3,4]. In the current study clonogenic cell killing of PC-3 and DU-145 human prostate cancer cells (lacking functional p53) mediated by 4 h exposure to 50 plaque forming units (pfus)/cell of Adp53 (that caused the enforced overexpression of wtp53) was significantly enhanced by treatment with 2DG. Accumulation of glutathione disulfide was found to be significantly greater in both cell lines treated with 2DG+Adp53 and both cell lines treated with 2DG+Adp53 showed a approximately 2-fold increases in dihydroethidine (DHE) and 5-(and-6)-carboxy-2',7'-dichlorodihydrofluorescein diacetate (CDCFH(2)) oxidation, indicative of increased steady-state levels of O(2)(.-) and hydroperoxides, respectively. Finally, overexpression of catalase or glutathione peroxidase using adenoviral vectors partially, but significantly, protected DU-145 cells from the toxicity induced by 2DG+Adp53 treatment. These results show that treatment of human prostate cancer cells with the combination of 2DG (a nutrient stress) and overexpression of the tumor suppressor gene, wtp53, enhances clonogenic cell killing by a mechanism that involves oxidative stress as well as allowing for the speculation that inhibitors of glucose and hydroperoxide metabolism can be used in combination with Adp53 gene therapy to enhance therapeutic responses.
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PMID:2-Deoxyglucose combined with wild-type p53 overexpression enhances cytotoxicity in human prostate cancer cells via oxidative stress. 1815 76

1. Isoliquiritigenin (ISL) is a simple chalcone-type flavonoid derived from liquorice compounds. It has been reported to have anti-oxidative and antitumour activities. The aim of the present study was to investigate the antitumour effect of ISL on prostate cancer cells and to explore the possible signalling mechanisms involved. 2. Cell viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The fluorescent probe 2',7'-dichlorofluorescein diacetate (H(2)DCF-DA) was used to measure intracellular levels of reactive oxygen species (ROS). Mitochondrial membrane potential (Psi(m)) was measured using the mitochondrial probe 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethyl-benzimidazolylcarbocyanine iodide (JC-1). 3. Isoliquiritigenin treatment (10-100 micromol/L for 24 h) markedly inhibited the proliferation of both C4-2 and LNCaP prostate cancer cells in a dose-dependent manner. Intriguingly, ISL treatment (10-100 micromol/L for 24 h) had no effect on the viability of IEC-6 normal epithelial cells. Treatment of C4-2 and IEC-6 cells with 87.0 micromol/L ISL significantly decreased ROS levels and the Psi(m) of C4-2 cells, but had no effect on either parameter in IEC-6 cells. Furthermore, AMP-activated protein kinase (AMPK) and extracellular-signal regulated kinase (ERK) levels were three to fourfold higher in IEC-6 cells than in C4-2 cells (P < 0.05). 4. The results of the present study suggest that ISL, a natural anti-oxidant, selectively inhibits the proliferation of prostate cancer C4-2 cells, which may be attributed, in part, to defective AMPK and ERK signalling pathways in C4-2 compared with IEC-6 cells.
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PMID:Isoliquiritigenin, a natural anti-oxidant, selectively inhibits the proliferation of prostate cancer cells. 2045 27

This paper focuses on the synthesis, characterization and biological activity of new N,N'-methylene modified cyclohexyl ethylenediamine-N,N'-diacetate (edda)-type ligands and their Pt(IV) complexes. Both the ligands and complexes were characterized by infrared, UV-vis, ESI-MS, 1D ((1)H, (13)C, (195)Pt) and 2D (COSY, HSQC, HMBC) NMR spectroscopy and elemental analysis. The possible correlation between the reduction potentials and the cytotoxicity of the complexes was examined. The potential antitumoral activity of all compounds was tested in vitro on human melanoma A375, human glioblastoma U251, human prostate cancer PC3, human colon cancer HCT116, mouse melanoma B16 and mouse colon cancer CT26CL25 cells, as well as primary fibroblasts and keratinocytes. The results obtained revealed strong antitumor potential of the newly synthesized drugs with preserved efficacy against cisplatin resistant lines and less toxicity towards nonmalignant counterparts. The mechanism found to be responsible for the observed tumoricidal action of each synthesized compound was induction of apoptosis generally accompanied with caspase activation. Taken together, the effective response to the treatment of a wide range of different cell lines, including cisplatin resistant subclones, as well as induction of apoptosis, as the mechanism suggested to be the most desirable way of eliminating malignant cells, represents a great advantage of this novel group of drugs in comparison to other members in this metallo-drug family.
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PMID:Novel methylene modified cyclohexyl ethylenediamine-N,N'-diacetate ligands and their platinum(IV) complexes. Influence on biological activity. 2236 71

Mefloquine (MQ) is currently in clinical use as a prophylactic treatment for malaria. Previous studies have shown that MQ induces oxidative stress in vitro. The present study investigated the anticancer effects of MQ treatment in PC3 cells. The cell viability was evaluated using sulphorhodamine-B (SRB) staining, while annexin V and propidium iodide (PI) were used as an assay for cell death. Reactive oxygen species (ROS) formation was detected with 2',7'-dichlorofluorescein-diacetate (DCFH-DA), a sensitive intracellular probe, and the alteration of cellular status was defined by trypan blue staining. The results of the present study indicated that MQ has a high cytotoxicity that causes cell death in PC3 cells. MQ markedly inhibited the PC3 cells through non-apoptotic cell death. MQ also induced significant ROS production. The MQ treatment mediated G1 cell cycle arrest and cyclin D1 accumulation through p21 upregulation in the PC3 cells. Moreover, the use of MQ improved the survival of the treatment group compared with the control group in the experimental mice. The present study indicates that MQ possesses potential therapeutic efficacy for the treatment of prostate cancer (PCa) in vivo. These findings provide insights that may aid the further optimization and application of new and existing therapeutic options.
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PMID:Mefloquine induces cell death in prostate cancer cells and provides a potential novel treatment strategy in vivo. 2375 54

With the advent of (68)Ga-labeled prostate-specific membrane antigen-N,N'-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid ((68)Ga-PSMA-HBED-CC) positron emission tomography (PET) hybrid imaging in prostate cancer (PCa), even small metastatic lymph nodes (LNs) can be visualized. However, intraoperative detection of such LNs may not be easy owing to their inconspicuous morphology and/or atypical localization. The aim of our feasibility study was to evaluate PSMA-radioguided surgery for detection of metastatic LNs. One patient with primary PCa and evidence of LN metastases and four PCa patients with evidence of recurrent disease to regional LNs on (68)Ga-PSMA-HBED-CC PET hybrid imaging received an intravenous injection of an (111)In-PSMA investigation and therapy agent 24h before surgery. Metastatic LNs were tracked intraoperatively using a gamma probe with acoustic and visual feedback. All radioactive-positive LN specimens detected in vivo were confirmed by ex vivo measurements and corresponded to PSMA-avid metastatic disease according to histopathology analysis. Intraoperative use of the gamma probe detected all PSMA-positive lesions identified on preoperative (68)Ga-PSMA-HBED-CC PET. Detection of small subcentimeter metastatic LNs was facilitated, and PSMA-radioguided surgery in two patients revealed additional lesions close to known tumor deposits that were not detected by preoperative (68)Ga-PSMA-HBED-CC PET. However, greater patient numbers and long-term follow-up data are needed to determine the future role of PSMA-radioguided surgery.
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PMID:Prostate-specific membrane antigen-radioguided surgery for metastatic lymph nodes in prostate cancer. 2595 51


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