Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In human prostate cancer PC3 cells, the effect of Y-24180, a presumed specific platelet activation factor (PAF) receptor antagonist, on intracellular Ca2+ concentration ([Ca2+]i) was measured by using fura-2 as a Ca2+-sensitive fluorescent probe. Y-24180 (1-10 microM) caused a rapid and sustained [Ca2+]i rise in a concentration-dependent manner. The [Ca2+]i rise was prevented by 40% by removal of extracellular Ca2+, but was not changed by dihydropyridines, verapamil and diltiazem. In Ca2+-free medium, thapsigargin, an inhibitor of the endoplasmic reticulum Ca2+-ATPase, caused a monophasic [Ca2+]i rise, after which the increasing effect of 10 microM Y-24180 on [Ca2+]i was reduced by 67%; conversely, depletion of Ca2+ stores with 10 microM Y-24180 abolished thapsigargin-induced [Ca2+]i rise. U73122, an inhibitor of phospholipase C, inhibited ATP-, but not Y-24180-induced [Ca2+]i rise. Activation of protein kinase C with phorbol-12-myristate-13-acetate (PMA) enhanced Y-24180-induced [Ca2+]i rise by 70%. Overnight treatment with 0.1-10 microM Y-24180 inhibited cell proliferation in a concentration-dependent manner. Collectively, these results suggest that Y-24180 acts as a potent and cytotoxic Ca2+ mobilizer in prostate cancer cells, by stimulating both extracellular Ca2+ influx and intracellular Ca2+ release. Since alterations in Ca2+ movement may interfere with many cellular signalling processes unrelated to modulation of PAF receptors, caution must be applied in using this reagent as a selective PAF receptor antagonist.
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PMID:Novel effect of Y-24180, a presumed specific platelet activation factor receptor antagonist, on Ca2+ levels and growth of human prostate cancer cells. 1515 75

The blockade of Akt activation through the inhibition of 3-phosphoinositide-dependent kinase-1 (PDK-1) represents a major signaling mechanism whereby celecoxib mediates apoptosis. Celecoxib, however, is a weak PDK-1 inhibitor (IC(50), 48 microM), requiring at least 30 microM to exhibit discernable effects on the growth of tumor cells in vitro. Here, we report the structure-based optimization of celecoxib to develop PDK-1 inhibitors with greater potency in enzyme inhibition and growth inhibition. Kinetics of PDK-1 inhibition by celecoxib with respect to ATP suggest that celecoxib derivatives inhibit PDK-1 by competing with ATP for binding, a mechanism reminiscent to that of many kinase inhibitors. Structure-activity analysis together with molecular modeling was used to generate compounds that were tested for their potency in inhibiting PDK-1 kinase activity and in inducing apoptosis in PC-3 prostate cancer cells. Docking of potent compounds into the ATP-binding site of PDK-1 was performed for lead optimization, leading to two compounds, OSU-03012 and OSU-03013, with IC(50) values in PDK-1 inhibition and apoptosis induction in the low microM range. Exposure of PC-3 cells to these agents led to Akt dephosphorylation and inhibition of p70 S6 kinase activity. Moreover, overexpression of constitutively active forms of PDK-1 and Akt partially protected OSU-03012-induced apoptosis. Screening in a panel of 60 cell lines and more extensive testing in PC-3 cells indicated that the mean concentration for total growth inhibition was approximately 3 microM for both agents. Considering the conserved role of PDK-1/Akt signaling in promoting tumorigenesis, these celecoxib analogs are of translational relevance for cancer prevention and therapy.
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PMID:From the cyclooxygenase-2 inhibitor celecoxib to a novel class of 3-phosphoinositide-dependent protein kinase-1 inhibitors. 3093 80

1. The effect of maprotiline, an antidepressant, on human prostate cells is unclear. In the present study, the effect of maprotiline on [Ca2+]i and growth in PC3 human prostate cancer cells was measured using the fluorescent dyes fura-2 and tetrazolium, respectively. 2. Maprotiline caused a rapid, concentration-dependent increase in [Ca2+]i (EC50 = 200 micromol/L). The maprotiline-induced [Ca2+]i increase was reduced by removal of extracellular Ca2+ or pretreatment with nicardipine. 3. The maprotiline-induced Mn2+ influx-associated fura-2 fluorescence quench directly suggests that maprotiline caused Ca2+ influx. 4. In Ca(2+)-free medium, thapsigargin, an inhibitor of the endoplasmic reticulum Ca(2+)-ATPase, caused a monophasic [Ca2+]i increase, after which the effects of maprotiline of increasing [Ca2+]i were abolished. In addition, pretreatment with maprotiline reduced a major portion of the thapsigargin-induced increase in [Ca2+]i. 5. U73122, an inhibitor of phospholipase C, abolished the ATP (but not maprotiline)-induced increase in [Ca2+]i. 6. Overnight incubation with 1-10 micromol/L maprotiline did not alter cell proliferation, although incubation with 30-50 micromol/L maprotiline decreased cell proliferation. 7, These findings suggest that maprotiline rapidly increases [Ca2+]i in human prostate cancer cells by stimulating both extracellular Ca2+ influx and intracellular Ca2+ release and that it may modulate cell proliferation in a concentration-dependent manner.
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PMID:Effect of the antidepressant maprotiline on Ca2+ movement and proliferation in human prostate cancer cells. 1523 32

In this study, we investigated ionic mechanisms involved in growth arrest induced by extracellular ATP in androgen-independent prostate cancer cells. Extracellular ATP reversibly induced a rapid and sustained intracellular pH (pH(i)) decrease from 7.41 to 7.11. Inhibition of Ca(2+) influx, lowering extracellular Ca(2+), and buffering cytoplasmic Ca(2+) inhibited ATP-induced acidification, thereby demonstrating that acidification is a consequence of Ca(2+) entry. We show that ATP induced reuptake of Ca(2+) by the mitochondria and a transient depolarization of the inner mitochondrial membrane. ATP-induced acidification was reduced after the dissipation of the mitochondrial proton gradient by rotenone and carbonyl cyanide p-trifluoromethoxyphenylhydrazone, after inhibition of Ca(2+) uptake into the mitochondria by ruthenium red, and after inhibition of the F(0)F(1)-ATPase with oligomycin. ATP-induced acidification was not induced by either stimulation of the Cl(-)/HCO(3)(-) exchanger or inhibition of the Na(+)/H(+) exchanger. In addition, intracellular acidification, induced by an ammonium prepulse method, reduced the amount of releasable Ca(2+) from the endoplasmic reticulum, assessed by measuring change in cytosolic Ca(2+) induced by thapsigargin or ATP in a Ca(2+)-free medium. This latter finding reveals cross talk between pH(i) and Ca(2+) homeostasis in which the Ca(2+)-induced intracellular acidification can in turn regulate the amount of Ca(2+) that can be released from the endoplasmic reticulum. Furthermore, pH(i) decrease was capable of reducing cell growth. Taken together, our results suggest that ATP-induced acidification in DU-145 cells results from specific effect of mitochondrial function and is one of the major mechanisms leading to growth arrest induced by ATP.
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PMID:The role of intracellular pH in cell growth arrest induced by ATP. 1535 52

The phytochemical resveratrol (trans-3,4',5-trihydroxystilbene) is a naturally occurring polyphenol with a plethora of health-beneficial properties, including a preventive role in cancer. We surmise that resveratrol may exert its diverse biological effects by interacting with specific target proteins, denoted RTPs. To test this possibility, resveratrol was immobilized on epoxy-activated agarose forming a resveratrol affinity column (RAC), which was used to detect and isolate RTPs. Distinct RTPs can be resolved on RAC by fractionation with increasing NaCl, followed by 1mM ATP, and finally, with 1-2mM resveratrol. A 22-kDa polypeptide, RTP-22, eluted with resveratrol was identified by MALDI-TOF MS and cloning/expression in Escherichia coli, as dihydronicotinamide riboside quinone reductase 2 (NQO2). The utility of RAC was additionally explored with extracts derived from different staging prostate cancer cells. NQO2 was most abundant in CWR22Rv1, a model for prostate cancer transition from androgen-dependent to the hormone-refractory state, but was marginally expressed in JCA-1 cells as representing more advanced stage prostate cancer. These results provide evidence for the existence of distinctive RTPs in mammalian cells and that RAC is a facile approach to identify and purify RTPs.
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PMID:Identification and purification of resveratrol targeting proteins using immobilized resveratrol affinity chromatography. 1538 Oct 63

We developed a high-throughput HTRF (homogeneous time-resolved fluorescence) assay for Akt kinase activity and screened approx. 270000 compounds for their ability to inhibit the three isoforms of Akt. Two Akt inhibitors were identified that exhibited isoenzyme specificity. The first compound (Akt-I-1) inhibited only Akt1 (IC50 4.6 microM) while the second compound (Akt-I-1,2) inhibited both Akt1 and Akt2 with IC50 values of 2.7 and 21 microM respectively. Neither compound inhibited Akt3 nor mutants lacking the PH (pleckstrin homology) domain at concentrations up to 250 microM. These compounds were reversible inhibitors, and exhibited a linear mixed-type inhibition against ATP and peptide substrate. In addition to inhibiting kinase activity of individual Akt isoforms, both inhibitors blocked the phosphorylation and activation of the corresponding Akt isoforms by PDK1 (phosphoinositide-dependent kinase 1). A model is proposed in which these inhibitors bind to a site formed only in the presence of the PH domain. Binding of the inhibitor is postulated to promote the formation of an inactive conformation. In support of this model, antibodies to the Akt PH domain or hinge region blocked the inhibition of Akt by Akt-I-1 and Akt-I-1,2. These inhibitors were found to be cell-active and to block phosphorylation of Akt at Thr308 and Ser473, reduce the levels of active Akt in cells, block the phosphorylation of known Akt substrates and promote TRAIL (tumour-necrosis-factor-related apoptosis-inducing ligand)-induced apoptosis in LNCap prostate cancer cells.
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PMID:Identification and characterization of pleckstrin-homology-domain-dependent and isoenzyme-specific Akt inhibitors. 1545 5

Peptide deformylase activity was thought to be limited to ribosomal protein synthesis in prokaryotes, where new peptides are initiated with an N-formylated methionine. We describe here a new human peptide deformylase (Homo sapiens PDF, or HsPDF) that is localized to the mitochondria. HsPDF is capable of removing formyl groups from N-terminal methionines of newly synthesized mitochondrial proteins, an activity previously not thought to be necessary in mammalian cells. We show that actinonin, a peptidomimetic antibiotic that inhibits HsPDF, also inhibits the proliferation of 16 human cancer cell lines. We designed and synthesized 33 chemical analogs of actinonin; all of the molecules with potent activity against HsPDF also inhibited tumor cell growth, and vice versa, confirming target specificity. Small interfering RNA inhibition of HsPDF protein expression was also antiproliferative. Actinonin treatment of cells led to a tumor-specific mitochondrial membrane depolarization and ATP depletion in a time- and dose-dependent manner; removal of actinonin led to a recovery of the membrane potential consistent with indirect effects on the electron transport chain. In animal models, oral or parenteral actinonin was well tolerated and inhibited human prostate cancer and lung cancer growth. We conclude that HsPDF is a new human mitochondrial enzyme that may provide a novel selective target for anticancer therapy by use of actinonin-based antibiotics.
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PMID:Human mitochondrial peptide deformylase, a new anticancer target of actinonin-based antibiotics. 1548 58

The potential anti-angiogenic activities of water-soluble condensed tannins isolated from black beans were evaluated using HEL 299 normal human fibroblast lung cells, Caco-2 colon, MCF-7 and Hs578T breast, and DU 145 human prostatic cancer cells. Condensed tannins at 0.24-24 microM did not affect the growth of normal cells, but dose-dependently induced cancer cell death by apoptosis as shown by a concentration-dependent decrease in ATP and cell gross morphology. After 24h exposure to Caco-2, MCF-7, Hs578T, and DU 145 cancer cells, water-soluble black bean condensed tannins at 24 microM suppressed fetal bovine serum stimulated cell migration, the secretion of matrix metalloproteinase-2 (MMP-2 or gelatinase A), matrix metalloproteinase-9 (MMP-9 or gelatinase B), and vascular endothelial growth factor VEGF(165) receptor expression by the cancer cells in the conditioned media. The potential health enhancing properties of condensed tannins from black beans as inhibitors of angiogenesis is discussed.
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PMID:Inhibition of Caco-2 colon, MCF-7 and Hs578T breast, and DU 145 prostatic cancer cell proliferation by water-soluble black bean condensed tannins. 1567 Aug 92

Although sensitivity to intracellular ATP is considered to be one of the hallmarks of swelling activated Cl- current (I(Cl,swell)) involved in regulatory volume decrease (RVD) following hypotonic stress, the type and manner of such sensitivity seems to vary in different cell types. Here by using whole-cell patch-clamp recording we investigated ATP sensitivity of I(Cl,swell) in LNCaP human prostate cancer cell line. Suppression of endogenous ATP production with metabolic inhibitors (oligomycin, iodoacetate and rotenone) during cell dialysis with ATP- and Mg2+-free pipette solution did not prevent I(Cl,swell) in response to hypotonic exposure. However, supplementing this solution with 5 mM Na-ATP led to the development of I(Cl,swell) with nearly 305 higher density and less pronounced voltage-dependent inactivation (manifested mainly by the increase of non-inactivated current component) at positive potentials. On the contrary, inclusion of 1 mM Mg2+ in the patch pipette resulted in even smaller I(Cl,swell) (30% lower density compared to Mg2+-free conditions), which inactivated completely on prolonged depolarization. The presence of 5 mM Mg-ATP in the pipette did not affect I(Cl,swell) density. Neither intervention significantly altered the rate of I(Cl,swell) development in response to hypotonicity. We conclude that intracellular ATP, a positive modulator of I(Cl,swell)-carrying volume-regulated anion channel (VRAC) in LNCaP cells most likely acts via binding rather than hydrolysis and/or phosphorylation reactions, whereas intracellular Mg2+ is VRAC inhibitor.
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PMID:[Adenosine triphosphate-dependence of volume sensitive chloride current in LNCaP cell line of human prostate cancer]. 1580 Dec

Lysosomes, lysosomal enzymes and oxidant processes are known to be involved in cancer processes. The prostasomes contain proteins and enzymes that would constitute pathways for the hydrolysis of proteins and peptides. However, integrated biochemical and cell biology studies are necessary to understand how lysosomal enzymes and prostasomal enzymes combined with oxidant processes could initiate cancer. Most prostate cancer is likely to be initiated in the prostate duct system. The lysosomal enzymes acid phosphatase and glucosidase and prostasomal proteins and enzymes are found in human semen and therefore have come through prostate ducts. The hypothesis presented here is that the lysosomal enzymes and prostasomes are exocytosed from prostate cells into the duct system of the prostate where their hydrolytic enzymes and oxidative processes, for example, the iron from the iron-sulfur clusters of the prostasomal dehydrogenases, damage proteins and other components of cells leading to the initiation of cancer. Risk factors for prostate cancer are known to initiate activity of lysosomal enzymes and could initiate activity of prostasomal enzymes. These risk factors include: ionizing radiation, oxidative stress, environmental toxicants and dietary components including those with high fat content. Other dietary components in fruits and vegetables protect against prostate cancer and can be hypothesized as decreasing cellular output of lysosomal or protasomal enzymes or inhibiting lysosomal and prostasomal enzymes in the duct system. Measurements of multiple lysosomal and prostasomal enzyme activities and their biochemical pathways are vital to the understanding of protectors to inhibit lysosomal or prostasomal enzyme activities that might be leading to prostate cancer. Inhibitors of lysosomal and prostasomal enzymes can be investigated in cellular and biochemical systems, and these inhibitors could be used to control these enzyme activities in vivo. In situ enzyme analyses including substrates producing fluorescent products are applicable. Screening assays could be developed to detect in vivo lysosomal and prostasomal enzyme activities in semen. Lysosomal enzyme activities may be precursors to the onset of other kinds of cancer with other similar non-invasive screening techniques possible. Present knowledge encompasses mobilization of sperm when prostasomes bind to sperm in semen. A further hypothesis of this study projects that prostasomal dehydrogenases and their NADH products initiate the formation of ATP in the sperm mitochondria which activates flagellar movement. This overall hypothesis suggests protection against prostate cancer by inhibitors of lipid peroxidation including the dietary antioxidants selenium, vitamin E and lycopene and also cysteine glutathione.
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PMID:Lysosomal and prostasomal hydrolytic enzymes and redox processes and initiation of prostate cancer. 1582 10


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