Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0027651 (tumor)
685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The biological activity, including metabolism and modulation of ornithine decarboxylase activity and DNA synthesis, of arachidonic acid (AA) and eicosapentaenoic acid (EPA) were compared in epidermal cells from SENCAR mice. Radiolabelled AA and EPA were found to be similarly incorporated into and released from membrane phospholipids of unstimulated cultures. However, when cells were stimulated with the tumor promoter 12-0-tetradecanoylphorbol-13-acetate (TPA), the release of AA was significantly higher than the release of EPA. The extent of metabolism of AA and EPA to prostaglandins was determined in both freeze-thawed cell preparations and in viable cultured cells. In the freeze-thawed preparations, use of AA as a substrate resulted in significantly more PGF than when EPA was used as the substrate. However, more PGE3 was formed than PGE2. PGD levels were the same for either fatty acid precursor. Prostaglandin production was also determined in viable cultured cells since other influences such as phospholipase A2 activity can modify prostaglandin production. Control cultures prelabelled with either AA or EPA produced similar amounts of the respective PGF, PGE, and PGD. However, TPA-stimulated cultures produced significantly higher amounts of each prostaglandin in cultures prelabelled with AA compared to cells prelabelled with EPA. HETE or HEPE production was the same both for cultured cells prelabelled with AA or EPA and for homogenates from uncultured cells incubated directly with the radiolabelled fatty acids. TPA-induced ornithine decarboxylase (ODC) was significantly higher in AA-treated cultures compared to EPA-treated cultures. AA supports DNA synthesis to a greater extent than EPA, either alone or in the presence of TPA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Eicosapentaenoic and arachidonic acid: comparison of metabolism and activity in murine epidermal cells. 254 33

Madin-Darby canine kidney cells (MDCK) are known to release free arachidonic acid and arachidonic acid metabolites (AA) in response to tumor-promoting phorbol esters, such as tetradecanoyl phorbol-13-acetate, and to agonists active at alpha 1-adrenergic and bradykinin B2 receptors. These experiments were conducted to define the role of Ca2+/phospholipid-dependent protein kinase (protein kinase C) activation in the stimulation of AA release, in the clonal isolate cell line MDCK-D1, by use of three inhibitors of protein kinase C, sphingosine, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7), and staurosporine. We found that alpha 1-adrenergic- and bradykinin-stimulated [3H]AA release can be distinguished by differential dependence on protein kinase C; epinephrine-stimulated release was more dependent on protein kinase C activation than was bradykinin-stimulated release. The inhibition of bradykinin-stimulated AA release by sphingosine (20.2 +/- 6.1%) was substantially less than the inhibition observed for tetradecanoyl phorbol-13-acetate- (67.2 +/- 5.5%) and epinephrine-stimulated release (50.2 +/- 9.2%). These findings were confirmed by results using H-7 and staurosporine. The relative independence of bradykinin-stimulated AA release of protein kinase C was also demonstrated by the inability of phorbol ester-induced down-regulation of protein kinase C to eliminate bradykinin-stimulated AA release. The inhibition of alpha 1-adrenergic receptor-mediated AA release by sphingosine, H-7, and staurosporine was not due to a change in receptor number or affinity. Analysis of the products comprising [3H]AA release indicated that treatment with sphingosine did not change the composition of the released AA (34-48% prostaglandin E2, 17-27% free arachidonic acid, and 25-51% unidentified metabolites). These results indicate that two different types of hormone receptors in the same cell type can promote AA release by mechanisms that differ in their dependence on protein kinase C. The protein kinase C-dependent mechanism may represent protein kinase C-mediated activation of phospholipase A2.
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PMID:Defining the role of protein kinase C in epinephrine- and bradykinin-stimulated arachidonic acid metabolism in Madin-Darby canine kidney cells. 254 87

The role of arachidonic acid (AA) metabolism in the stimulation of oxygen radical production by murine peritoneal macrophages treated with tumor promoters was assessed. In vivo administration of the phospholipase A2 inhibitor dibromacetophenone, the anti-inflammatory steroid fluocinolone acetonide or the lipoxygenase inhibitor nordihydroguiaretic acid just prior to i.p. injection of phorbol-12-myristate-13-acetate (PMA, 100 ng) into unmanipulated CD-1 female mice resulted in a dose-dependent decrease in the number of peritoneal exudate cells (PEC) producing superoxide anion radical (O2) as assessed by the reduction of nitroblue tetrazolium, i.e. the formation of formazan-positive PEC. The cycloxygenase inhibitor indomethacin had no effect on the number of formazan-positive PEC caused by PMA treatment. The ability of PMA, phorbol-12,13-dibutyrate mezerein, phorbol-12,13-diacetate and 4-O-Me-PMA to stimulate the production of oxygen radicals by murine peritoneal macrophages correlated with their ability to stimulate the release of [3H]AA equivalents from the macrophages. The calcium ionophore A23187 which stimulated significant [3H]AA equivalent release did not stimulate superoxide anion radical production by the macrophages. PMA administered i.p. to SENCAR mice increased the number of formazan-positive PEC 4-to 5-fold compared with similarly treated C57BL/6 mice. PMA also stimulated the release of twice the amount of [3H]AA equivalents from peritoneal macrophages from SENCAR mice compared with that released by macrophages from C57BL/6 mice. The addition of low concentrations of AA (1-10 microM) in vitro to casein-elicited murine peritoneal macrophages treated with low concentrations of PMA (1 ng/ml) resulted in a 2-fold potentiation of the amount of superoxide anion radical produced compared with PMA treatment alone as assessed by the reduction of cytochrome c. These results demonstrate that AA and/or a lipoxygenase product can potentiate the production of oxygen radicals by murine peritoneal macrophages treated with tumor promoters.
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PMID:Arachidonic acid potentiates superoxide anion radical production by murine peritoneal macrophages stimulated with tumor promoters. 255 22

Tumor necrosis factor (TNF) is cytotoxic for several transformed cell lines in vitro. In the presence of LiCl, the murine fibrosarcoma cell lines L929 and WEHI 164 clone 13 became greater than 10 times more sensitive to TNF-mediated cytotoxicity. The human tumor cell lines BT20 and HeLa D98/AH2 were also responsive to the cytotoxicity-enhancing effect of LiCl. Other monovalent or divalent cations did not affect TNF-mediated cytotoxicity. The potentiating effect of LiCl on TNF cytotoxicity was largely independent of transcription, and LiCl could be added to the cells as early as 2 hr before or as late as 4 hr after TNF without loss of effectiveness. The mechanism by which LiCl increases the cytotoxic response seems to differ from the sensitizing effect of actinomycin D or interferon gamma, since the latter treatments overcame TNF resistance of several cell lines, whereas LiCl did not. Evidence is presented that LiCl acts, either directly or indirectly, via the TNF-activated phospholipase A2 pathway. In nude mice, a combination of TNF and LiCl led to hemorrhagic necrosis and growth inhibition of L929 tumors, whereas little effect was observed when TNF was administered alone. HeLa D98/AH2 tumors also were sensitive to the potentiating effect of LiCl in vivo. We conclude that LiCl enhances the effectiveness of TNF in vitro and in vivo, results that may have therapeutic implications.
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PMID:Lithium chloride potentiates tumor necrosis factor-mediated cytotoxicity in vitro and in vivo. 255 14

The effects of inhibitors of arachidonic acid metabolism and antioxidants on the rat liver tumor promotion activity of phenobarbital (PB) were assessed using the enzyme-altered focus as the end-point lesion. Fischer 344 male rats were initiated with N-nitrosodiethylamine (200 mg/kg) and then divided into five groups placed on basal diet, diet containing 0.05% PB, diet containing 0.05% PB plus 0.75%, 1% or 1.5% levels of various inhibitors of arachidonic acid metabolism or antioxidants, or diet containing 1% or 1.5% inhibitors or antioxidants alone for 10 weeks, and then killed. p-Bromophenacyl bromide, an inhibitor of phospholipase A2, significantly inhibited the promotion activity of PB at dose levels of 0.75% and 1.5%, reaching plateau at 0.75%. Both quercetin, an inhibitor of lipoxygenase, and morin, a dual inhibitor of lipoxygenase-cyclooxygenase, significantly reduced the promotion activity of PB at the 1.5% but not 0.75% dose levels. Moreover, acetylsalicylic acid, an inhibitor of cyclooxygenase dose-dependently inhibited the promotion activity of PB. Among the antioxidants investigated, vitamin E did not affect, but n-propyl gallate and ethoxyquin exerted a dose-dependent inhibition of PB promotion. These results are strongly suggestive of an involvement of phospholipase A2, lipoxygenase and cyclooxygenase arachidonic acid metabolic pathways in the mechanisms underlying PB enhancement of hepatocarcinogenesis.
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PMID:Possible involvement of arachidonic acid metabolism in phenobarbital promotion of hepatocarcinogenesis. 257 27

PAF is a phospholipid formed from the action of phospholipase A2 upon cellular membranes in response to immunologic or hypoxic stimuli. PAF does not exist in its active form as a storage product within cells, but is synthesized rapidly after phospholipase A2 activation. A potent lipid released by multiple cell types in mammalian systems, the emerging perspective is that PAF is a major endogenous mediator influencing the pathogenesis and outcome of ischemia and conditions of circulatory shock. These effects appear to be especially relevant to the syndrome of MSOF during critical illness. All of the major criteria for validation of a shock factor have been fulfilled for PAF. First, PAF has been measured in biological fluid of animals during shock states, although this is not an easy task since PAF is formed in minute amounts and is rapidly metabolized. Nevertheless, combinations of high pressure liquid chromatography (HPLC) and bioassay methods employing washed rabbit platelets have been successfully utilized in this regard. Second, synthetic PAF has been injected into cell suspensions, isolated tissues, and live animals, where it produces most of the effects attributed to endogenous PAF released by immunologic or hypoxic stimuli. These studies have shown that PAF exerts a variety of pathophysiologic actions, including (1) cardiodepression (that is, a negative inotropic effect), (2) reductions in systemic blood pressure, (3) leakage of fluid from the microvasculature, (4) bronchoconstriction, and (5) platelet aggregation. All of these actions of PAF can initiate or exacerbate shock and ischemic injury in multiple organ systems. Third, specific PAF receptor antagonists have been found to markedly attenuate the severity of endotoxic, anaphylactic, hemorrhagic, and traumatic shock, as well as acute myocardial ischemia. In all these conditions, a variety of PAF receptor antagonists (including PAF analogues and structurally dissimilar substances) have improved survival and have retarded pathophysiologic processes believed to be important in causing tissue injury. These processes include lysosomal membrane damage and proteolysis. Moreover PAF receptor antagonists attenuate the release of secondary toxic factors in shock, such as myocardial depressant factor. Thus, administration of specific PAF receptor antagonists early in the course of circulatory shock and organ ischemia may prove to be useful therapeutic agents in a variety of life-threatening disorders. In addition to having direct actions, PAF appears to function as a pivotal agent in a chain of mediators producing tissue injury. Recent evidence suggests that tumor necrosis factors (i.e., cachectin) stim
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PMID:Induction of tissue injury and altered cardiovascular performance by platelet-activating factor: relevance to multiple systems organ failure. 265 Aug 21

Exposure of isolated SENCAR mouse epidermal cells to the tumor promoter 12-0-tetradecanoylphorbol-13-acetate (TPA) in vitro resulted in the production of oxidant species detected as chemiluminescence. This oxidant response can be inhibited by superoxide dismutase and copper complexes but not catalase or scavengers of hydroxyl radical or singlet oxygen, suggesting that the oxidant is superoxide anion. Inhibitors of various parts of the arachidonate cascade affect the TPA-induced oxidant response in a manner that corresponds to their effects on in vivo tumor promotion experiments. Agents that inhibit lipoxygenase activity, i.e. nordihydroguaiaretic acid, benoxaprofen, but not agents that are cyclooxygenase inhibitors, i.e. indomethacin, are effective in suppressing the oxidant response to TPA. Phospholipase C but not phospholipase A2 or D produced an oxidant response kinetically similar to that elicited by TPA. The inhibitors of TPA-induced oxidants inhibited the phospholipase C response to the same extent, suggesting that TPA and phospholipase C may produce an oxidant species through a common mechanism, via phospholipid turnover-protein kinase C activation. The relevance of oxidant production to the tumor promotion process is suggested by the ability of exogenous xanthine/xanthine oxidase, a superoxide anion-generating system, to induce ornithine decarboxylase, a characteristic of TPA-treated cells. In addition, oxidant production is significantly lower in cells from the TPA-promotion resistant C57BL/6J mouse. These studies provide further support for a role for reactive oxygens in the tumor promotion process.
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PMID:Reactive oxygen in the tumor promotion stage of skin carcinogenesis. 284 22

The N and C terminals and tyrosine-phosphorylating site of the middle-sized tumor antigen of polyoma virus were chemically synthesized. The sequences of these peptides were Met-Asp-Arg-Val-Leu-Ser-Arg-Ala-Asp-Lys (N-MT), Met-Leu-Phe-Ile-Leu-Ile-Lys-Arg-Ser-Arg-His-Phe (C-MT), and Glu-Glu-Glu-Glu-Tyr-Met-Pro-Met-Glu (MT-Tyr), respectively. Among these peptides, the C-MT peptide inhibited phospholipase A2 (EC 3.1.1.4), phospholipase C (EC 3.1.4.3), and phospholipase D (EC 3.1.4.4). In addition, phosphatidylinositol-specific phospholipase C (EC 3.1.4.10) was also inhibited by this peptide. To study the mechanism of the inhibition, kinetic analysis was performed using phospholipase A2 from porcine pancreas. The degree of inhibition of phospholipase was dose dependent, and maximal inhibition was observed at pH 8.8. This peptide inhibited phospholipase A2 in a competitive manner for low-affinity sites of Ca2+, and in a noncompetitive manner for phospholipid substrates. When a fatty acid in the 2 position of the glycerol moiety of phosphatidylcholine was replaced by palmitic acid (C16:0), oleic acid (C18:1), linoleic acid (C18:2), eicosatrienoic acid (C20:3), or arachidonic acid (C20:4), the degree of inhibition of phosphatidylcholine hydrolysis by the C-MT peptide decreased. Inhibition of phospholipase A2 by the C-MT peptide was reversed by low concentrations of sodium deoxycholate but not by Triton X-100 or Nonidet P40, nonionic detergents. These detergents and the modification of acyl groups altered the micellar state of phospholipids. These results, taken together, suggest that the binding of the C-MT peptide near the low-affinity Ca2+ binding sites modifies the interaction of phospholipid substrates with the active center of phospholipase A2.
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PMID:Inhibition of phospholipases by Met-Leu-Phe-Ile-Leu-Ile-Lys-Arg-Ser-Arg-His-Phe, C terminus of middle-sized tumor antigen. 285 79

Biologically active 125I-cytotoxin from Pseudomonas aeruginosa binds to plasma membranes from Ehrlich ascites tumor cells in a saturable manner. The Scatchard plot indicated a single binding site with a capacity of 260 pmoles/mg of membrane protein and a KD of 2 X 10(-8) M. Specific binding was dependent on temperature, pH and ionic strength. Thus constant levels of bound 125I-cytotoxin were attained either within 30 min at 30 degrees C or within 3 h at 4 degrees C. Binding was 30-fold higher at 4 degrees C vs 30 degrees C and 2-6-fold higher at pH 5.3 vs pH 8.3. Binding was not effected by 50 mM sugar or sialic acid. 300 mM sucrose, however, instead of phosphate buffer, reduced binding by 50%. Pretreatment of plasma membranes with trypsin or papain led to a significant decrease in 125I-cytotoxin binding. A pretreatment with phospholipase C or D had no effect, whereas phospholipase A2 induced a decrease by 34%. The collected data suggest that the binding site for 125I-cytotoxin within the plasma membrane from Ehrlich ascites tumor cells is a membrane protein. Correlation of 125I-cytotoxin binding and membrane action of the unlabelled cytotoxin can be observed through (a) increased lowering of the cellular K+ and Na+ gradient by decrease of medium pH, (b) decreased toxicity after substitution of ions by sugar, and (c) increased breakdown of cellular cationic gradient after temperature shift from 4 degrees C to 37 degrees C.
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PMID:Interaction of Pseudomonas aeruginosa cytotoxin with plasma membranes from Ehrlich ascites tumor cells. 300 83

The effect of the synthetic diacylglycerol, sn-1,2-dioctanoylglycerol (diC8), on the expression of the surface transferrin receptor reveals that exogenous diC8 can act as an intracellular activator of protein kinase C and stimulate both down-regulation and increased receptor phosphorylation in a manner similar to that induced by the active tumor promotor, 4 beta-phorbol 12,13-dibutyrate. Unlike the spontaneously irreversible effect noted when 4 beta-phorbol 12, 13-dibutyrate is added, this same effect mediated by diC8 is brief, lasting only minutes, and is spontaneously reversible. The rate of reversibility is dependent on the concentration of diC8 added, and it is associated with rapid formation of a newly detected intracellular phospholipid that corresponds to sn-1,2-dioctanoyl phosphatidic acid. These data, in conjunction with findings that demonstrate that exogenous diacylglycerols (including diC8) when added to cells do not stimulate cellular phospholipase A2 or C, argue that protein kinase C is activated only briefly in this system since exogenous diC8 is subject to rapid intracellular metabolism to phosphatidic acid.
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PMID:Intracellular activation of protein kinase C and regulation of the surface transferrin receptor by diacylglycerol is a spontaneously reversible process that is associated with rapid formation of phosphatidic acid. 300 42


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