UMLS:C0023418 - FACTA Search

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Query: UMLS:C0023418 (leukemia)
93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tepoxalin [5-(4-chlorophenyl)-N-hydroxy-(4-methoxyphenyl)-N-methyl-1H- pyrazole-3-propanamide] is a potent inhibitor of sheep seminal vesicle cyclooxygenase (CO) (IC50 = 4.6 microM), rat basophilic leukemia cell (RBL-1) lysate CO (IC50 = 2.85 microM) and CO from intact RBL-1 cells (IC50 = 4.2 microM). The compound inhibits the production of thromboxane B2 (TxB2) in Ca++ ionophore A-23187-stimulated human peripheral blood leukocytes (HPBL; IC50 = 0.01 microM) and human whole blood (IC50 = 0.08 microM) and is a potent inhibitor of epinephrine-induced human platelet aggregation (IC50 = 0.045 microM). Tepoxalin inhibits lipoxygenase (LO) in RBL-1 lysates (IC50 = 0.15 microM) and intact RBL-1 cells (IC50 = 1.7 microM) and inhibits the generation of leukotriene B4 (LTB4) in calcium ionophore A-23187-stimulated HPBL (IC50 = 0.07 microM) and human whole blood (IC50 = 1.57 microM). Human platelet 12-LO (IC50 = 3.0 microM) is inhibited, but 15-LO is only weakly so (IC50 = 157 microM). In vivo, tepoxalin, administered orally, demonstrated potent anti-inflammatory activity in the established adjuvant arthritic rat (ED50 = 3.5 mg/kg) and potent analgesic activity in the acetic acid abdominal construction assay in mice (ED50 = 0.45 mg/kg). In an ex vivo whole blood eicosanoid production assay, tepoxalin produces a dose-related inhibition of prostaglandin (PG) and LT production in dogs (PGF2 alpha - ED50 = 0.015 mg/kg; LTB4 - ED50 = 2.37 mg/kg) and adjuvant arthritic rats following oral administration. In adjuvant arthritic rats, tepoxalin is devoid of ulcerogenic activity within its anti-inflammatory therapeutic range (1-33 mg/kg p.o.) and does not exhibit ulcerogenic activity in normal rats at doses lower than 100 mg/kg (UD50 = 173 mg/kg p.o.). Tepoxalin represents a new class of anti-inflammatory drugs which may exhibit less gastrointestinal toxicity and may be efficacious in immunoinflammatory disease states where excessive PG and LT production has been implicated and may offer a significant alternative to nonsteroidal and corticosteroidal anti-inflammatory therapy.
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PMID:Tepoxalin: a dual cyclooxygenase/5-lipoxygenase inhibitor of arachidonic acid metabolism with potent anti-inflammatory activity and a favorable gastrointestinal profile. 799 52

Interleukin-4 inhibits several monocyte functions like A23187-induced expression of cytokines and c-fos and c-jun proto-oncogene mRNA expression. In an attempt to elucidate the mechanism by which this inhibitive effect is mediated, we compared the effect of IL-4 on A23187-induced c-fos and c-jun mRNA expression in conjunction with inhibitors that selectively inhibit the cyclooxygenase dependent (indomethacin) and lipoxygenase dependent (NDGA) pathway of arachidonic acid (AA) metabolism. NDGA inhibited A23187-induced c-fos mRNA expression by a similar magnitude as IL-4, whereas the effect of indomethacin was only minor. A23187-induced c-jun mRNA expression was not affected by indomethacin and only slightly inhibited by NDGA. These results indicate that in human monocytes c-fos mRNA expression is at least partly controlled by the lipoxygenase directed pathway of AA metabolism, whereas the cyclooxygenase dependent pathway is not involved in the regulation of proto-oncogene expression. This was supported by the finding that leukotriene B4 (LTB4) and 5'-hydroperoxyeicosatetraenoic acid (5'-HPTETE), which are two lipoxygenase metabolites, strongly induced c-fos mRNA, whereas c-jun mRNA expression was slightly affected. However, the inhibitive effect of IL-4 could not be ascribed to a reduced production of LTB4 suggesting that the mode of IL-4 action lies behind the conversion of AA to 5'-HPETE and LTB4.
Leukemia 1994 Jul
PMID:Interleukin-4-mediated inhibition of C-Fos mRNA expression: role of the lipoxygenase directed pathway. 803 10

In the absence of serum, growth of ML-1 human myeloblastic leukemia cells is induced by the insulin-like growth factor-1 (IGF1) together with transferrin (Tf), whereas monocytic differentiation is initiated by the transforming growth factor-beta (TGF-beta) in combination with Tf. Initiation of growth was followed by the rapid release of arachidonic acid (AA), hydroxyeicosatetraenoic acids (HETEs) and phospholipids into the culture medium. In contrast, induction of differentiation occurred without the release of these lipids beyond the level present in control. Inhibitors of enzymes involved in the formation of AA and of HETEs, including phospholipase A2 and lipoxygenases, caused interference with growth but not with differentiation, and an inhibitor of the cyclooxygenase path affected neither growth nor differentiation. These results indicate that the initiation of ML-1 cell growth but not of cell differentiation is dependent upon the increased formation of AA and its derivatives formed primarily via the lipoxygenase path.
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PMID:Differential effect of growth- and differentiation-inducing factors on the release of eicosanoids and phospholipids from ML-1 human myeloblastic leukemia cells. 811 43

A variety of assay systems have been utilized to evaluate the inhibition of the key enzyme in leukotriene (LT) biosynthesis, 5-lipoxygenase (5-LO). We have developed an assay utilizing a cytosolic preparation of 5-LO from rat basophilic leukemia (RBL-1) cells. Enzyme activity was monitored by continuous measurement of oxygen consumption. High performance liquid chromatography (HPLC) analysis of products showed exclusive generation of 5-LO products. The assay proved useful for the evaluation of a variety of chemical classes of lipoxygenase inhibitors and clearly differentiated those compounds which extended the lag phase (e.g. A-64077) as opposed to the propagation phase of the enzyme activity (e.g. SK & F 105561). The data generated were in reasonable agreement with results from the assay of isolated human monocyte 5-LO and, with the exception of compounds which appear to have a significant effect on 5-LO translocation (e.g. MK-886 and Wy-49 232), inhibition of LT production by intact monocytes. This assay system proved to be a convenient and informative method to analyze inhibition of 5-LO activity.
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PMID:Use of a continuous assay of oxygen consumption to evaluate the pharmacology of 5-lipoxygenase inhibitors. 814 Jan 20

Ligands including phytohaemagglutinin (PHA) and anti-CD3 monoclonal antibodies trigger the generation of inositol lipid-derived second messengers following their binding to cell-surface structures of human T lymphoid cells. Previous evidence has suggested that the generation of leukotrienes may play an intermediary role in coupling the ligation of T lymphoid cell-surface structures to the inositol lipid signalling system in these cells (A.R. Mire-Sluis et al. (1989) FEBS Lett. 258, 84-88). Here we have studied the actions of two novel selective leukotriene biosynthesis inhibitors, MK 886 and BW A4C and of two general lipid soluble antioxidants, butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA) on this pathway. Neither MK 886 nor BW A4C abrogated stimulation of inositol lipid breakdown following PHA or anti CD3 treatment of T lymphocytes. By contrast, this pathway was inhibited by BHT and BHA. These observations, together with our failure to demonstrate the generation of lipoxygenase products following PHA stimulation of T lymphocytes, suggests that an antioxidant-sensitive step other than the generation of leukotrienes plays a critical role in coupling cell-surface receptors to the inositol lipid signalling system in these cells. By contrast none of these inhibitors abrogated ligand-stimulated inositol lipid signalling in Jurkat T acute lymphoblastic leukaemia cells. These results suggest a heterogeneity in the organization of the signal transduction machinery in lymphoid cells at different stages of differentiation.
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PMID:Antioxidants impair the coupling of cell-surface ligand receptors to the inositol lipid signalling pathway in human T lymphocytes but not in Jurkat T lymphoblastic leukemia cells. Evidence that leukotrienes are not involved in the coupling mechanism. 839 39

The proliferation of malignant hemopoietic cell lines is inhibited by antagonists of 5-lipoxygenase, suggesting that the endogenous generation of leukotrienes via the action of this enzyme may play some role in the proliferation of these cells (Snyder D. S., Castro R. & Desforges J. F. (1989), Expl Hemat. 17, 6). Here we have confirmed that the lipoxygenase inhibitors piriprost, nordihydroguiaretic acid and BW755C decreased DNA synthesis and proliferation of leukemic cell lines. However, the concentrations of these drugs required for half-maximal inhibition of proliferation were significantly greater than their IC50 values for 5-lipoxygenase inhibition. We therefore studied the actions of two novel, potent lipoxygenase inhibitors, BWA4C and MK886, on proliferation (as measured by estimating the number of viable, trypan blue-excluding cells) and DNA synthesis (measured by the incorporation of radiolabeled thymidine) in the leukemia cell lines HL60, K562 and Jurkat. Neither parameter was affected by concentrations of these drugs which were shown in parallel studies to substantially inhibit leukotriene generation in whole blood. The data show that endogenous leukotriene generation does not play a significant role in the regulation of proliferation of these leukemic cell lines and suggest that conclusions about leukotriene involvement in the control of cellular metabolic pathways based on the use of lipoxygenase inhibitors should be re-assessed.
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PMID:Evidence that endogenous generation of leukotrienes does not regulate proliferation of malignant hemopoietic cell lines. 845 Jun 72

The variation of the selenium status of leukocytes was used as a tool to investigate the influence of selenium-containing glutathione peroxidases on the formation of 5-lipoxygenase metabolites in vitro and ex vivo. Selenium-deficient rat basophilic leukemia cells had < 1% of control glutathione peroxidase activity and 35% of control phospholipid hydroperoxide-glutathione peroxidase activity. Upon stimulation, these cells released an 8-fold amount of lipoxygenase metabolites compared to controls. No (5S)-hydroperoxyeicosatetraenoic acid was detectable in whole cells; however, it was found in homogenates of selenium-deficient cells. Addition of 0.25 microgram/ml selenium to selenium-deficient cells restored control phospholipid hydroperoxide-glutathione peroxidase activity within 8 h, whereas glutathione peroxidase activity needed 7 days. 12 h after resupplementation, selenium-deficient cells had 3% glutathione peroxidase and 100% phospholipid hydroperoxide-glutathione peroxidase activity compared to controls. Resupplemented cells released control amounts of 5-lipoxygenase metabolites, indicating that restoration of phospholipid hydroperoxide-glutathione peroxidase activity is associated with a selenium-adequate leukotriene metabolism. Leukocytes that were isolated from selenium-deficient rats released a 7-fold amount of total lipoxygenase metabolites compared to cells from control animals. By injecting normally fed rats with 500 micrograms/kg selenium as Na2SeO3, leukocyte phospholipid hydroperoxide-glutathione peroxidase activity was raised 8-fold within 114 h compared to controls. Leukocytes from these animals produced significantly less lipoxygenase metabolites than controls. These findings indicate that phospholipid hydroperoxide-glutathione peroxidase activity is primarily responsible for the reduction of 5-hydroperoxyeicosate-traenoic acid and therefore governs the actual activity of leukocyte 5-lipoxygenase via regulating the tone of endogenous hydroperoxides.
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PMID:Selenoenzymes regulate the activity of leukocyte 5-lipoxygenase via the peroxide tone. 845 1

The biochemical signaling mechanisms involved in transducing the effects of interferon-gamma (IFN-gamma) on human leukemia-derived HL-60 cell differentiation are not completely understood. Recent studies established the existence of a sphingomyelin (SM) cycle that operates in response to the action of IFN-gamma on HL-60 cells, but the mechanisms by which IFN-gamma induces the SM hydrolysis remain unexplored. In this study, biochemical events mediating IFN-gamma effects on SM turnover and their specificity and role in HL-60 differentiation were investigated. The activation of the SM cycle by IFN-gamma occurred rapidly, with a decrease of approximately 20% in the SM level observed after 60 minutes with a concomitant increase in ceramide level. Treatment of HL-60 cells with IFN-gamma did not influence the 1,2-diacylglycerol concentration, intracellular Ca2+ concentration, or phospholipase D activity. IFN-gamma stimulated a rapid release of arachidonic acid (AA) from HL-60 cells; the effect was abolished by the pretreatment of cells with pertussis toxin, suggesting a role for a pertussis-toxin-sensitive G protein in IFN-gamma-mediated activation of phospholipase A2 (PLA2). At 4 to 120 hours after the stimulation of the cells with IFN-gamma, a significant increase in the particulate and soluble PLA2 activity was observed, corresponding to an increase in the level of immunoreactive cPLA2 in both cytosol and membrane fractions. The treatment of cells with tyrosine kinase inhibitor herbimycin A completely abolished the effect of IFN-gamma on PLA2 activity in membrane and cytosolic fractions, but had no effect on IFN-gamma-mediated early AA release suggesting dual mechanism of PLA2 activation. Melittin, potent activator of PLA2, and AA mimicked the effect of IFN-gamma on SM hydrolysis. Pretreatment of HL-60 cells with the PLA2 inhibitor, bromophenacyl bromide (BPB), or pertussis toxin abolished the effect of IFN-gamma on SM hydrolysis; exogenous addition of AA overcame the effects of BPB and pertussis toxin. Long-term exposure (5 days) of HL-60 cells to IFN-gamma caused an increase in nitroblue tetrazolium (NBT)-reducing and nonspecific esterase (NSE) activity and induced expression of Fc gamma RI (CD64) without significant effects on cell number, adherence, or phagocytic activity. The treatment of cells with AA or melittin induced NBT, NSE, and CD64 expression to the level similar to that observed with IFN-gamma, and no further increase was observed with the combination of IFN-gamma and AA or IFN-gamma and melittin. Treatment of HL-60 cells with indomethacin, an inhibitor of cyclo-oxygenase, and nordihydroguaiaretic acid (NDGA), an inhibitor of lipoxygenase, had no effects on IFN-gamma-mediated induction of CD64 expression. These studies indicate a key role for the phospholipase A2/AA pathway, as an early biochemical signal elicited by the occupation of IFN-gamma-receptor, in mediating IFN-gamma induction of the SM cycle and phenotypic changes associated with differentiation of HL-60 along monocytic lineage.
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PMID:Arachidonic acid mediates interferon-gamma-induced sphingomyelin hydrolysis and monocytic marker expression in HL-60 cell line. 897 80

Topical application of curcumin inhibits chemically induced carcinogenesis on mouse skin, and oral administration of curcumin inhibits chemically induced oral, forestomach, duodenal, and colon carcinogenesis. Curcumin and other inhibitors of cyclooxygenase and lipoxygenase are thought to inhibit carcinogenesis by preventing the formation of arachidonic acid metabolites. In contrast to our expectation of a tumorigenic effect of arachidonic acid, we found that treatment of 7,12-dimethylbenz[a]anthracene-initiated mouse skin with very high doses of arachidonic acid twice daily, 5 days a week for 26 weeks, failed to result in tumors. We considered the possibility that some of the cancer chemopreventive effects of curcumin may be related to an effect of this compound on cellular differentiation, and we investigated the effect of curcumin on differentiation in the human promyelocytic HL-60 leukemia cell model system. Although curcumin alone had little or no effect on cellular differentiation, when it was combined with all-trans retinoic acid or 1alpha,25-dihydroxyvitamin D3 a synergistic effect was observed. It is possible that many dietary chemicals in fruits, vegetables, and other edible plants can prevent cancer by synergizing with endogenously produced stimulators of differentiation such as all-trans retinoic acid, 1alpha,25-dihydroxyvitamin D3, and butyrate. More research is needed to test this hypothesis. Administration of green or black tea inhibits carcinogenesis in several animal models, and tumor growth is also inhibited. Several examples were presented of chemopreventive agents that inhibit carcinogenesis in one animal model but enhance carcinogenesis in a different animal model. Greater efforts should be made to understand mechanisms of cancer chemoprevention and to determine whether a potential chemopreventive agent is useful in many experimental settings or whether it is useful in only a limited number of experimental settings.
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PMID:Some perspectives on dietary inhibition of carcinogenesis: studies with curcumin and tea. 934 92

Hydroxyeicosatetraenoic acids (HETEs) and hydroxyoctadecadienoic acids (HODEs) are major bioactive lipids formed via the lipoxygenase oxygenation of arachidonic and linoleic acid, respectively. These metabolites appear to be involved in various cellular actions including cell proliferation, migration and regulation of enzyme activities such as phospholipases and kinases. In view of the diversity of biological effects of these hydroxy fatty acids, it seems likely that multiple mechanisms are involved. Previous reports showed that 15(S)-HETE inhibited the 5-lipoxygenase in rat basophilic leukemia (RBL-1) cell homogenates and established the presence of specific cellular HETE binding sites in these and other cells. The present study used 15(S)-HETE biotin hydrazide and 15(S)-HETE biotin pentyl amide as probes to identify membrane target proteins present in RBL-1 cells that specifically interact with HETEs and HODEs. Two membrane-associated proteins, with apparent molecular weights of 43 and 58 kDa, were identified that specifically interact with these probes and competition experiments indicated that 13(S)-HODE and 15(S)-HETE were the most effective competitors for the hydrazide probe, followed in decreasing effectiveness by 5(S)-HETE, arachidonic acid, 15(R)-HETE, stearic acid and 12(S)-HHT, a cyclooxygenase product. The two proteins were isolated and microsequencing analysis established their identities as actin and the alpha-subunit of mitochondrial ATP synthase, respectively. In vitro binding studies confirmed that purified actin is a potential 15-HETE binding protein. Subcellular cytosolic fractions exhibited fewer protein-probe complexes than membrane fractions. The association of HETEs and HODEs with these cytoskeletal and mitochondrial proteins, respectively, represents a new development in the potential actions of these hydroxy fatty acids.
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PMID:Novel membrane target proteins for lipoxygenase-derived mono(S)hydroxy fatty acids. 1036 81

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