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)

A novel pulse sequence strategy uses sodium magnetic resonance imaging to monitor the response to chemotherapy of mouse xenograft tumors propagated from human prostate cancer cell lines. An inversion pulse suppresses sodium with long longitudinal relaxation times, weighting the image toward intracellular sodium nuclei. Comparing these weighted sodium images before and 24 h after administration of antineoplastics, we measured a 36 +/- 4% (P < 0.001; n = 16) increase in signal intensity. Experiments with these same drugs and cells, treated in culture, detected a significant intracellular sodium elevation (10-20 mM) using a ratiometric fluorescent dye. Flow cytometry studies showed that this elevation preceded cell death by apoptosis, as determined by fluorescent end-labeling of apoptotic nuclei or Annexin V binding. Histopathology on formalin-fixed sections of explanted tumors confirmed that drug administration reduces proliferation (2.2 versus 8.6 mitotic figures per high power field; P < 0.0001), an effect that inversely correlates with the sodium magnetic resonance image response on a tumor-to-tumor basis (P < 0.02; n = 10). Morphological features, such as central zones of nonviable cells, rims of active apoptosis, and areas of viable tumor, could be distinguished by comparing weighted and unweighted images. Advantages of this sodium imaging technique include rapid determination of drug efficacy, improved diagnosis of lesions, ease of coregistration with high resolution proton magnetic resonance imaging, and absence of costly or toxic reagents.
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PMID:Rapid in vivo monitoring of chemotherapeutic response using weighted sodium magnetic resonance imaging. 1087 63

A study was initiated to test whether the FM1-43 dye technique could be applied to the study of endocytic membrane activity in two rodent prostate cancer (MAT-LyLu and AT-2) cell lines of markedly different metastatic ability. The lipophilic dye FM1-43, which has frequently been used to monitor endo/exocytic activity in excitable cells was employed. We found, as in excitable tissues, that both strongly metastatic (MAT-LyLu) and weakly metastatic (AT-2) cells in culture take up FM1-43 to give vesicular staining of a variable pattern, which appeared to differ between the two cell lines. However, unlike excitable tissues, neither cell line subsequently released the dye. Indeed, both cell lines retained the dye through several rounds of cell division suggesting that dye incorporated by cells does not enter the endo/exocytotic cycle. Uptake of dye was independent of temperature, Na+/K+ gradients, pH or metabolism. We suggest that passive accumulation of FM1-43 can occur in cancer cells and should not, automatically, be interpreted as evidence of endocytosis.
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PMID:A study of membrane activity in rat prostate cancer cells: an evaluation of the FM1-43 dye technique. 1088 9

Cardiac glycosides are used clinically to increase contractile force in patients with cardiac disorders. Their mechanism of action is well established and involves inhibition of the plasma membrane Na+/K+-ATPase, leading to alterations in intracellular K+ and Ca(2+) levels. Here, we report that the cardiac glycosides oleandrin, ouabain, and digoxin induce apoptosis in androgen-independent human prostate cancer cell lines in vitro. Cell death was associated with early release of cytochrome c from mitochondria, followed by proteolytic processing of caspases 8 and 3. Oleandrin also promoted caspase activation, detected by cleavage poly(ADP-ribose) polymerase and hydrolysis of a peptide substrate (DEVD-pNA). Comparison of the rates of apoptosis in poorly metastatic PC3 M-Pro4 and highly metastatic PC3 M-LN4 subclones demonstrated that cell death was delayed in the latter because of a delay in mitochondrial cytochrome c release. Single-cell imaging of intracellular Ca(2+) fluxes demonstrated that the proapoptotic effects of the cardiac glycosides were linked to their abilities to induce sustained Ca(2+) increases in the cells. Our results define a novel activity for cardiac glycosides that could prove relevant to the treatment of metastatic prostate cancer.
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PMID:Cardiac glycosides stimulate Ca2+ increases and apoptosis in androgen-independent, metastatic human prostate adenocarcinoma cells. 1091 54

Receptor protein tyrosine phosphatase alpha (RPTPalpha) is a transmembrane protein phosphatase, and has been proposed to be involved in the differentiation of the neuronal system. In the present study, we demonstrated the expression of RPTPalpha mRNA in several normal human tissues. We further investigated the regulation of expression of RPTPalpha mRNA in epithelial cells utilizing three commercially available human prostate cancer cell lines LNCaP, PC-3 and DU145. This is because these cells exhibit different levels of differentiation, defined by the expression of a tissue-specific differentiation antigen, prostatic acid phosphatase (PAcP), and their androgen sensitivity. LNCaP cells express PAcP and are androgen-sensitive cells, while PC-3 and DU145 cells do not express PAcP and are androgen-insensitive cells. Northern blot analyses revealed that, in LNCaP cells, fetal bovine serum (FBS) and 5alpha-dihydrotestosterone (DHT) down-regulates RPTPalpha mRNA expression, similar to the effect on PAcP. Contrarily, FBS up-regulated the RPTPalpha mRNA level in PC-3 and DU145 cells. In LNCaP cells, sodium butyrate inhibited cell growth and up-regulated RPTPalpha as well as PAcP mRNA expression. Although, sodium butyrate also inhibited the growth of PC-3 and DU145 cells, the level of RPTPalpha mRNA was decreased in PC-3, while increased in DU145 cells. Thus, data taken together indicate that the expression of RPTPalpha is apparently regulated by a similar mechanism to that of PAcP in LNCaP cells.
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PMID:Expression of receptor protein tyrosine phosphatase alpha mRNA in human prostate cancer cell lines. 1093 23

Patch-clamp recordings were used to study ion currents induced by cell swelling caused by hypotonicity in human prostate cancer epithelial cells, LNCaP. The reversal potential of the swelling-evoked current suggested that Cl(-) was the primary charge carrier (termed I(Cl,swell)). The selectivity sequence of the underlying volume-regulated anion channels (VRACs) for different anions was Br(-) approximately I(-) > Cl(-) > F(-) > methanesulfonate >> glutamate, with relative permeability numbers of 1.26, 1.20, 1.0, 0.77, 0.49, and 0.036, respectively. The current-voltage patterns of the whole cell currents as well as single-channel currents showed moderate outward rectification. Unitary VRAC conductance was determined at 9.6 +/- 1.8 pS. Conventional Cl(-) channel blockers 5-nitro-2-(3-phenylpropylamino)benzoic acid (100 microM) and DIDS (100 microM) inhibited whole cell I(Cl,swell) in a voltage-dependent manner, with the block decreasing from 39.6 +/- 9.7% and 71.0 +/- 11. 0% at +50 mV to 26.2 +/- 7.2% and 14.5 +/- 6.6% at -100 mV, respectively. Verapamil (50 microM), a standard Ca(2+) antagonist and P-glycoprotein function inhibitor, depressed the current by a maximum of 15%. Protein tyrosine kinase inhibitors downregulated I(Cl,swell) (genistein with an IC(50) of 2.6 microM and lavendustin A by 60 +/- 14% at 1 microM). The protein tyrosine phosphatase inhibitor sodium orthovanadate (500 microM) stimulated I(Cl,swell) by 54 +/- 11%. We conclude that VRACs in human prostate cancer epithelial cells are modulated via protein tyrosine phosphorylation.
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PMID:Volume-regulated chloride conductance in the LNCaP human prostate cancer cell line. 1100 95

Progression to androgen independence remains the main problem that impacts on survival and quality of life in prostate cancer patients. We have investigated the potency of tributyrin, an orally available prodrug of butyrate, to induce growth arrest, differentiation and apoptosis in LNCaP, PC-3 and TSU-PR1 human prostate cancer cell lines. Cells were treated with 0.1 to 5 mM tributyrin or sodium butyrate. Growth inhibition, cell cycle arrest and apoptosis induction was assessed using standard methods. Both agents induced a more differentiated, fibroblast-like phenotype in androgen-sensitive as well as androgen-resistant cell lines. Expression of prostate-specific antigen was increased in LNCaP cells by tributyrin as a indicator of differentiation. The IC(50) for sodium butyrate was 2.5 mM in PC-3 and TSU-PR1 cells. LNCaP cells exhibited <50% growth inhibition at 5 mM sodium butyrate. However, the IC(50) for tributyrin was 0.8 mM in PC-3 cells, 1.2 mM in TSU-PR1 cells and 3.1 mM in LNCaP cells. Flow cytometry revealed a strong G1-arrest after exposure to tributyrin or sodium butyrate. Both agents resulted in a strong increase of apoptosis rates compared with mock-treated cells. Overall, tributyrin had a 2.5- to 3-fold growth inhibitory and apoptosis-inducing potency compared with equimolar concentrations of sodium butyrate. Our results demonstrate that tributyrin is more potent than butyrate in regard to cell growth inhibition and apoptosis induction at pharmacologically relevant concentrations. Hence, tributyrin may be a promising candidate for clinical protocols in prostate cancer.
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PMID:Tributyrin induces differentiation, growth arrest and apoptosis in androgen-sensitive and androgen-resistant human prostate cancer cell lines. 1100 76

Epidemiological and clinical data suggest that selenium may prevent prostate cancer, but the biological effects of selenium on normal or malignant prostate cells are not well known. We evaluated the effects of sodium selenite (Na2SeO3) or l-selenomethionine (SeMet) on monolayer and anchorage-independent growth in a series of normal primary prostate cultures (epithelial, stromal, and smooth muscle) and prostate cancer cell lines (LNCaP, PC-3, and DU145). We observed differential, dose-dependent growth inhibition and apoptosis within prostate cancer cells (compared with normal prostate cells) treated with 1-500 microM of Na2SeO3 or SeMet. Na2SeO3 more potently inhibited growth at any given concentration. The androgen-responsive LNCaP cells were the most sensitive to selenium growth suppression (IC50s at 72 h for Na2SeO3 and SeMet were 0.2 and 1.0 microM, respectively). Growth of the primary prostate cells virtually was not suppressed (IC50s at 72 h for Na2SeO3 and SeMet were 22-38 and >500 microM, respectively). We also observed that DNA condensation and DNA fragmentation (terminal deoxynucleotidyltransferase dUTP nick end labeling/fluorescence-activated cell sorting) were elevated in selenium-treated cells and that activated caspase-3 colocalized with terminal deoxynucleotidyltransferase dUTP nick end labeling-stained cells by immunofluorescence. Higher basal poly(ADP-ribose) polymerase (PARP) expression levels and PARP cleavage (a substrate for caspase-3) were observed during apoptosis in tumor cells, compared with normal cells. Selective tumor cell death was associated with an increase in sub-G0-G1 cells after propidium iodide staining and fluorescence-activated cell sorting analysis. SeMet caused an increase in arrest in the G2-M phase of the cell cycle selectively in cancer cells. Inhibition of cancer cell growth by SeMet was associated with phosphorylation of P-Tyr15-p34/cdc2, which caused growth arrest in the G2-M phase. Anchorage-independent growth of prostate cancer cells in soft agar was sensitive to selenium. Our results suggest that Na2SeO3 is the more potent inducer of apoptosis in normal and cancer prostate cells. Our SeMet results involving PARP and G2-M cell-cycle arrest (cited above) indicate that SeMet selectively induces apoptosis in cancer but not primary cells of the human prostate. Our overall findings are relevant to the molecular mechanisms of selenium actions on prostate carcinogenesis and help demonstrate the selective, dose-dependent effects of selenium (especially SeMet) on prostate cancer cell death and growth inhibition.
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PMID:Selenium effects on prostate cell growth. 1109 24

Onconase (Onc) is a ribonuclease from amphibian oocytes that is cytostatic and cytotoxic to many tumour lines. It shows in vivo antitumour activity in mouse tumour models and is currently in Phase III clinical trials. The present study was designed to test whether cytotoxic effects of ONC can be modulated by differentiating agents. Human leukaemic HL-60 and prostate cancer LNCaP and JCA-1 cells were treated with Onc in the absence and presence of several inducers of differentiation and frequency of apoptosis was assessed using three different cytometric methods and confirmed by analysis of cell morphology. A moderate degree of apoptosis observed after 48-72 h incubation of HL-60 cells in the presence of 0.42 microM Onc alone was markedly potentiated by administration of retinoic acid (all trans), sodium butyrate or dimethylsulfoxide at concentrations known to induce differentiation but be minimally cytotoxic. Likewise, the frequency of apoptosis of LNCaP and JCA-1 cells treated with Onc was increased in the cultures to which phenylbutyrate was added. Although cell treatment with Onc alone, with each of the differentiating agents alone or with Onc in combination with the differentiating agents led to an increase in the proportion of G1 cells, no specific cell cycle phase preference in induction of apoptosis was observed. The data suggest that cells undergoing differentiation are particularly vulnerable to Onc; a combination of Onc and differentiating agents should be considered for further in vivo tests to assess its possible usefulness in the clinic.
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PMID:Induction of differentiation of leukaemic (HL-60) or prostate cancer (LNCaP, JCA-1) cells potentiates apoptosis triggered by onconase. 1110 Oct 12

The objective of this study was twofold: (1) to determine if a cellular digestion process can facilitate examination of the morphology of the connective tissue framework of the prostate, and (2) to examine the connective tissue framework in normal prostate tissue, benign prostatic hyperplasia (BPH) and prostate cancer. Ten prostate glands were examined. Using the Ohtani method of digestion, the cellular elements were removed. This enabled scanning electron microscopy analysis of the connective tissue framework within the prostatic tissue. Light microscopy of tissue blocks determined the histology of specimens. The prostate is supported by a highly structured network of collagen fibres. This network of fibres varies in normal and diseased states. In benign prostatic hyperplasia, the collagen network is dense, with an increased number of fibres. In prostatic adenocarcinoma, there is non-uniform swelling with a loss and disintegration of collagen fibres. In conclusion, sodium hydroxide cellular digestion provides an excellent method for demonstrating the connective tissue framework of prostatic tissue. The morphological changes in collagen fibres in normal prostate, benign prostatic hyperplasia and prostatic adenocarcinoma have implications for prostate growth in normal and diseased states.
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PMID:The connective tissue framework in the normal prostate, BPH and prostate cancer: analysis by scanning electron microscopy after cellular digestion. 1112 7

We have reported previously that among human prostate cancer cell lines LNCaP but not PC-3 cells undergo apoptosis after treatment with the protein kinase inhibitor staurosporine (STS). We have now further investigated this model to uncover the molecular mechanism causing resistance to STS-induced apoptosis in PC-3 cells. S-100 lysates of both cell lines showed biochemical changes typical of apoptosis after the addition of cytochrome c and dATP, suggesting that the postmitochondrial phase of apoptosis was intact. Upon addition of STS, the proapoptotic molecules Bax and Bad became predominantly mitochondrial in both cell lines. This, in turn, was followed by loss of mitochondrial transmembrane potential, translocation of cytochrome c to the cytosol, activation of caspase-9, -3, and -7, and cleavage of the apoptotic targets, DNA fragmentation factor and poly(ADP-ribose) polymerase, in LNCaP but not in PC-3 cells. Components of the mitochondrial permeability transition pore, adenine nucleotide transporter and voltage-dependent anion channel, were normally expressed in the correct subcellular fraction of both cell lines. Overexpression of the proapoptotic proteins Bax and Bad, fused to a green fluorescent protein but not of green fluorescent protein alone, induced apoptosis in >80% of PC-3 cells. These experiments suggested that a factor protecting the mitochondria of PC-3 cells mediates resistance to STS-induced apoptosis. A wide search among the antiapoptotic Bcl-2 family members was performed, and Bcl-X(L) was found to be overexpressed in PC-3 cells. Experiments down-regulating Bcl-X(L) expression by using the tyrosine kinase inhibitor genistein, sodium butyrate, or an antisense Bcl-X(L) oligonucleotide restored sensitivity to apoptosis in PC-3 cells. Thus, Bcl-X(L) overexpression is one of the mediators of resistance to STS-induced apoptosis in the prostate cancer cell line PC-3.
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PMID:Overexpression of BCL-X(L) underlies the molecular basis for resistance to staurosporine-induced apoptosis in PC-3 cells. 1124 86


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