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)

Nordihydroguaiaretic acid (NDGA), quercetin, eicosatetraynoic acid (ETYA), phenidone, and esculetin, agents known to inhibit cellular lipoxygenase (LO) activity, also inhibit human natural killer cell-mediated cytotoxicity (NK-CMC) of K562 tumor target cells (TC) in a dose-dependent fashion. Kinetic analysis demonstrated that LO inhibitors blocked an early event in the activation of the lytic mechanism but did not impair conjugate formation. LO inhibitors also did not affect subsequent chromium release, indicating that their site of inhibition was the NK cell and not the TC. The lipoxygenase products 5-hydroperoxyeicosatetraenoic acid (5-HPETE) and leukotriene-B4 significantly enhanced NK activity, with 5-HPETE being the more effective. Other LO products tested included 15-HPETE and the hydroxy derivatives 15-hydroxyeicosatetraenoic acid (15-HETE) and 5-HETE. These LO metabolites were either without effect on NK-CMC or inhibitory, depending upon the concentration. Additionally, we examined the ability of 5-HPETE to circumvent the effects of LO inhibitors and found that, in the presence of NDGA, ETYA or quercetin, 5-HPETE significantly (p less than 0.001) restored lytic activity. Inhibitors of LTB4 and LTC4 synthesis, diethylcarbamazine and U-60,257 respectively, produced no inhibition of NK activity. In fact, U-60,257 significantly (p less than 0.05) enhanced NK-CMC. Previous studies in our laboratory, with a new technique which allows for the separation of NK cells from K562 cells, have shown that K562-treated effector cells are greater than 90% inactivated when retested against fresh K562 in the standard chromium release assay. Lipids were extracted from K562-treated, Percoll-purified LGL and evaluated by thin-layer chromatography (TLC) and high-performance liquid chromatography (HPLC). No significant increases were seen in the arachidonic acid-derived LO products evaluated. Thus, our studies indicate that lipoxygenation may be required in the activation of NK-CMC, possibly as a means to generate oxygen radicals which have been previously implicated in NK-CMC.
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PMID:Role of lipoxygenation in human natural killer cell activation. 308 33

Phospholipase A2 inhibitors and lipoxygenase inhibitors markedly suppressed mouse skin ODC (ornithine decarboxylase) induction and promotion of papilloma by TPA. The inhibitory potency was related to the inhibition of epidermal 12-lipoxygenase. Lipoxygenase inhibitors, such as AA 861 and tetrahydrochalcone were lacking in the inhibitory action on protein kinase C. Moreover, palmitoylcarnitin, a protein kinase C inhibitor, inhibited TPA-induced differention of HL 60 cells and TPA-induced epidermal ODC induction and tumor promotion in mouse skin. Intraperitoneal injection of TPA also induced ODC in liver, kidney and spleen, but not in the skin of mice. In isolated mouse epidermal cells, TPA and diacylglycerol induced ODC. The induction of ODC was inhibited by phospholipase A2 inhibitors, lipoxygenase inhibitors, anticalmodulines, Ca++ entry blockers and Ca++ antagonists. These results indicate that intracellular Ca++ is involved in TPA induction of ODC.
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PMID:[Factors controlling tumor promotion induced by TPA]. 308 83

Phorbol ester binding was examined in two lines of murine fibrosarcoma cells. The two cell lines were isolated from the same parent tumor but respond differentially to stimulation with phorbol esters. In one of the lines, these agents stimulate a rapid attachment and spreading response and induce directional migration. The other cell line does not migrate in response to stimulation with phorbol esters and the attachment and spreading response is slow. The cell line which responds actively to phorbol ester stimulation is highly malignant when injected into syngeneic animals while the other line is of low tumorigenicity and is virtually non-metastatic. In spite of these differences, both lines were found in the present study to bind [3H]4 beta-phorbol-12 beta, 13 alpha-dibutyrate in a receptor-mediated fashion. The characteristics of binding were virtually identical between the two cell lines. In additional studies, arachidonic acid metabolism was examined in the same two lines. In the highly responsive line, PMA stimulated a rapid release of [3H]arachidonic acid and its conversion into cyclooxygenase and lipoxygenase products. In the less-responsive line, PMA stimulated a slower release of [3H]arachidonic acid from prelabeled cells. The quantity of arachidonic acid metabolites produced was also much less. These studies suggest that the disparity between the two cell lines in their response to phorbol ester stimulation is not the result of differences in the initial interaction between the cells and ligand but may result from alterations in their signal transductance mechanism. This may be the result of inherent differences in capacity for arachidonic acid metabolism.
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PMID:Phorbol ester binding and phorbol ester-induced arachidonic acid metabolism in a highly responsive murine fibrosarcoma cell line and in a less-responsive variant. 308 51

Prostaglandin (PG) H synthase and eicosanoid products of arachidonic acid metabolism have been implicated in several steps in the carcinogenic process. This study assessed these parameters using primary cultures of human urothelial cells. To determine the possible presence of permeability barriers to agonist stimulation, incubations were performed with adherent cells in the presence or absence of thioglycolate pretreatment or with cell suspensions. No evidence for permeability barriers was observed. With adherent cells in the absence of thioglycolate, radioimmunoassayable PGE2 was stimulated by epinephrine less than 12-O-tetradecanoylphorbol-13-acetate = thrombin less than bradykinin = A23187 much less than arachidonic acid. Tumor promoters but not non-tumor promoters stimulated PGE2 synthesis. 1-Oleoyl-2-acetylglycerol which like 12-O-tetradecanoylphorbol-13-acetate activates protein kinase C also increased PGE2 synthesis. Cells prelabeled with [14C]arachidonic acid were exposed to agonists and the profile of eicosanoids synthesized was assessed by high performance liquid chromatography. With bradykinin, the pattern of eicosanoids synthesized was 6-keto-PGE1 alpha (12% of total 14C label), thromboxane B2 (0.4%), PGF2 alpha (1.7%), PGE2 (18%), PGD2 (1%), leukotrienes (0.4 to 1%), 12-hydroxy-5,8,10-heptadecatrienoic acid (3%), 15-hydroxy-5,8,11,13-eicosatetraenoic acid (4%), 12-hydroxy-5,8,10,14-eicosatetraenoic acid (0%) and 5-hydroxy-5,8,12,14-eicosatetraenoic acid (2%). Thus, human urothelial cells contain both prostaglandin H synthase and lipoxygenase pathways with the former being more prominent. These pathways may participate in urinary bladder carcinogenesis.
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PMID:Eicosanoid synthesis by cultured human urothelial cells: potential role in bladder cancer. 309 68

A single exposure to a low concentration (10(-10) mol/L) of several tumor promoters, namely 12-O-tetradecanoylphorbol-13-acetate (TPA), phenobarbital (PB), nafenopin, saccharin, teleocidin, benzoyl peroxide, butylated hydroxytoluene (BHT), dichlorodiphenyltrichloroethane (DDT), lindane, clofibrate, and melittin significantly stimulated DNA synthesis of neonatal rat hepatocytes in 4-day-old primary cultures. These cultures were kept in low-calcium (0.01 mmol/L) HiWoBa2000 synthetic medium, thereby evoking a neoplastic phenotype in otherwise normal (i.e., non-initiated) cells. The simultaneous addition of a single dose of alpha-tocopherol (10(-4) mol/L) or selenous acid (10(-5) mol/L), just as that of exogenous superoxide dismutase (SOD) (4), together with each of the above agents fully suppressed the stimulation of hepatocytic DNA synthesis by the xenobiotics. Hence, these findings strengthen the view that superoxide anions (or some other oxidizing compounds) act as the common mediators of the mitogenic effects of various tumor promoters in hepatocytes. Inhibition kinetics studies, in which TPA in a single dose (10(-10) mol/L) was used as the paradigmatic compound together with several kinds of inhibitors of its activity showed that the early mitogenic effects of TPA, i.e., the commitment of quiescent (G0) hepatocytes and the reentry into active cycling of hepatocytes spontaneously poised at the G1/S boundary, required oxidizing compounds, arachidonate metabolism derivatives, and plasmalemmal calcium-binding sites and transmembrane calcium fluxes. Instead, a later TPAs effect, the flow into DNA synthesis of hepatocytes previously committed to cycle, was shown to be controlled by retinoid-modulable activities, by some product(s) of the lipoxygenase pathway, and again by plasmalemmal calcium-binding sites and transmembrane calcium fluxes. Such results reveal that in the neonatal rat hepatocyte the ability to answer to a single mitogenic stimulus and the metabolic pathways by which this answer is enacted depend upon the mitotic cycle setting of the hepatocytes at the moment of the experimental treatment.
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PMID:Studies on the mechanisms by which tumor promoters stimulate the growth of primary neonatal rat hepatocytes. 309 99

Newborn rat keratinocytes, the NBR cell line, synthesized the cyclooxygenase metabolic products, prostaglandins E2 and F2 alpha, and the lipoxygenase metabolic product, hydroxyeicosatetraenoic acid. This metabolism was stimulated by incubation of the cells with the Ca++ ionophore, A23187; melittin; bradykinin; recombinant human f-met epidermal growth factor; the tumor promoter, 12-O-tetradecanoylphorbol-13-acetate; and the synthetic analog of diacylglycerol, 1-oleoyl-2-acetyl glycerol. Production of the cyclooxygenase products was inhibited by the synthetic glucocorticoid, dexamethasone. The stimulation appeared to be modulated by deesterification of arachidonic acid from the cellular lipids, presumably by phospholipase A2. Increased intracellular levels of Ca++ and phosphorylating activities that result from polyphosphoinositol turnover as well as phosphorylating activities independent of phosphatidylinositol turnover appear to be regulating phospholipase A2 hydrolysis of phospholipids.
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PMID:Modulation of arachidonic acid metabolism in a cultured newborn rat keratinocyte cell line. 310 Jun 52

TPA (12-O-tetradecanoylphorbol-13-acetate) is an effective tumor promoter that affects a variety of ion transport processes. To examine the relationship between effects on transport and growth and differentiation, we have been studying the actions of TPA on frog skin, a particularly well-characterized epithelium. We have reported that high concentrations of TPA stimulate base-line short-circuit current (ISC) and inhibit the subsequent natriferic action of vasopressin. The current study of 89 preparations extends those findings. The Km of the stimulatory effect of TPA is approximately 3 nM; this high affinity indicates that the transport phenomenon does not simply reflect a nonspecific interaction of phorbol ester with the plasma membranes. TPA acts largely or entirely at the mucosal surface of both split and whole skins; thus the sidedness of the effect does not arise from adsorption onto the underlying connective tissue when TPA is applied to the serosal surface of whole skin. Amiloride, an inhibitor of apical Na+ entry, abolishes ISC across frog skins pretreated with TPA. The phorbol ester also increases ISC across split skins, preparations which do not produce net Cl-transport. Indomethacin (1 microM) blocks PGE1 release, but does not alter the response to TPA at a fivefold lower concentration than previously used. NDGA (nordihydroguaretic acid, 10 microM), an inhibitor of the lipoxygenase pathway, partially inhibited the responses of ISC to 8 nM TPA. The present results indicate that frog skin is highly responsive to TPA at concentrations known to activate protein kinase C in broken-cell preparations.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of TPA on short-circuit current across frog skin. 310 64

NMRI and SENCAR, two stocks of mice commonly used in multistage skin carcinogenesis studies, were compared with respect to the effects of inhibitors of arachidonic acid metabolism for the following 12-O-tetra-decanoylphorbol-13-acetate (TPA)-elicited events: tumor promotion, DNA synthesis in vivo and in vitro, ornithine decarboxylase induction, and prostaglandin (PG) E2 synthesis. Previous work had shown that the cyclooxygenase inhibitor indomethacin enhanced TPA promotion in SENCAR mice. We report here that over the same dose range (50 to 200 micrograms) indomethacin caused a dose-dependent inhibition of promotion in NMRI mice. Significant reversal of this inhibition was achieved with concomitant application of 10 micrograms PGF2 alpha but not PGE2. DNA synthesis studies showed that low doses of indomethacin and flurbiprofen increased TPA-stimulated DNA synthesis in primary cultures from SENCAR mice; indomethacin suppressed this response in NMRI cultures. In vivo DNA synthesis studies showed the same pattern: indomethacin enhanced TPA-stimulated DNA synthesis in SENCAR mice but inhibited in NMRI mice. Other classes of inhibitors of arachidonate metabolism (i.e., the cyclooxygenase-lipoxygenase inhibitors 5,8,11,14-eicosatetraynoic acid and phenidone and the phospholipase A2 inhibitor dibromoacetophenone) had inhibitory activity in vitro and in vivo in both stocks of mice. Indomethacin was found to inhibit TPA-induced ornithine decarboxylase activity to the same extent in both mice. Indomethacin was also very effective in inhibiting TPA-induced PGE2 synthesis in both stocks of mice. 5,8,11,14-Eicosatetraynoic acid and phenidone were likewise suppressive in both stocks of mice. It is concluded that the NMRI and SENCAR mice respond similarly to TPA with respect to promotion, DNA synthesis, ornithine decarboxylase induction, and PG synthesis. The difference appears to be in the degree of involvement of the lipoxygenase pathway.
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PMID:Events associated with mouse skin tumor promotion with respect to arachidonic acid metabolism: a comparison between SENCAR and NMRI mice. 310 6

The effects of thapsigargin, which is a histamine secretagogue and has recently been found to be a non-(12-O-tetradecanoylphorbol-13-acetate) (TPA)-type tumor promoter in two-stage carcinogenesis using mouse skin, on arachidonic acid metabolism in rat peritoneal macrophages were examined. The release of radioactivity from 3H arachidonic acid-labeled macrophages was increased at doses more than 10 ng/ml. Prostaglandin E2 production was also increased dose-dependently without inducing prominent changes in cell morphology. The potency to stimulate prostaglandin E2 production by thapsigargin was stronger than that by TPA at a dose of 10 ng/ml when measured 6 h after the incubation. HPLC analysis revealed that thapsigargin stimulated the production of lipoxygenase products such as leukotriene B4 and 12-hydroxyeicosatetraenoic acid as well as cyclooxygenase products such as prostaglandin E2 and 6-keto prostaglandin F 1 alpha. Thapsigargin, an analogue of thapsigargin, also stimulated prostaglandin E2 production. The mechanism of the action of thapsigargin was discussed. It was confirmed that the tumor promoters are associated with the activity to stimulate arachidonic acid metabolism irrespective of their type, TPA-type or non-TPA-type.
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PMID:Stimulation of arachidonic acid metabolism in rat peritoneal macrophages by thapsigargin, a non-(12-O-tetradecanoylphorbol-13-acetate) (TPA)-type tumor promoter. 311 Jan 74

Phospholipase C (PLC), an enzyme involved in the hydrolysis of membrane phospholipid- phosphatidylinositol-bisphosphate to inositol triphosphate and diacylglycerol, and Phorbol 12, myristate 13, acetate (PMA), a tumor promoting agent, could significantly stimulate testosterone (T) secretion from Leydig cells. Arachidonic acid (AA) stimulated T secretion by about 2 fold. The steroidogenic effect of PLC and AA was biphasic. At low concentrations both PLC and AA (100 mU and 12.5 microM, respectively) augmented hCG induced T secretion, while at higher concentrations (PLC: 500 mU and AA: 200 microM) they inhibited steroid production. AA also had a biphasic effect on hCG induced cyclic AMP secretion. 5, 8, 11, 14 Eicosatetraynoic acid (ETYA), a general inhibitor of AA metabolism, and Nordihydroguaiaretic acid (NDGA), an inhibitor of the lipoxygenase pathway of AA metabolism, inhibited hCG induced T secretion while indomethacin, an inhibitor of cyclo-oxygenase pathway, had no effect on hCG induced T secretion. We conclude from these data that AA plays a role in the regulation of hCG induced steroidogenic responses in rat Leydig cells and that the metabolite(s) of AA that are involved are not cyclooxygenase products.
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PMID:Arachidonic acid is involved in the regulation of hCG induced steroidogenesis in rat Leydig cells. 311 May 30


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