Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In vitro pharmacological profiles of E3040, 6-hydroxy-5, 7-dimethyl-2-(methylamino)-4-(3-pyridylmethyl) benzothiazole were investigated. Against the 5-lipoxygenase activity of rat basophilic leukemia cells, E3040 and zileuton (a 5-lipoxygenase inhibitor) had an IC(50) of 0.23 and 0.93 microM, respectively. Against the thromboxane A(2) synthetase activity of human platelets, E3040 had an IC(50) of 0.01 microM, which was comparable to that of OKY-1581 (sodium (E)-3-[4-(3-pyridylmethyl) phenyl]-2-methylacrylate, a thromboxane A(2) synthetase inhibitor). Against cyclooxygenase activity of sheep seminal vesicles, E3040 showed no inhibition (IC(50), >300 microM). Sulfasalazine and 5-aminosalicylic acid, therapeutic drugs for inflammatory bowel disease, inhibited 5-lipoxygenase activity with an IC(50) of 293 and 970 microM, respectively. Sulfasalazine inhibited thromboxane A(2) synthetase activity with an IC(50) of 20 microM. In rat peritoneal leukocytes, E3040 inhibited leukotriene B(4) and thromboxane B(2) production with an IC(50) of 0.17 and 0.24 microM, respectively. E3040 inhibited leukotriene B(4) production in human neutrophils and thromboxane B(2) production in human platelets (IC(50) of 0.21 and 0.09 microM, respectively). These results indicated that E3040 potently inhibited 5-lipoxygenase and thromboxane A(2) synthetase and blocked leukotriene B(4) and thromboxane B(2) production in rat peritoneal and human blood cells.
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PMID:In vitro effects of E3040, a dual inhibitor of 5-lipoxygenase and thromboxane A(2) synthetase, on eicosanoid production. 1143 Sep 33

We investigated whether and how could various modulators of arachidonic acid metabolism affect apoptosis induced by tumour necrosis factor-alpha (TNF-alpha) in human myeloid leukaemia HL-60 cells. These included arachinonyltrifluoromethyl ketone (AACOCF3; cytosolic phospholipase A2 inhibitor), indomethacin (cyclooxygenase inhibitor), MK-886 (3-[1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl]-2,2-dimethyl propanoic acid; 5-lipoxygenase-activating protein inhibitor), nordihydroguaiaretic acid (general lipoxygenase inhibitor), and arachidonic acid itself. Incubation of HL-60 cells with nordihydroguaiaretic acid resulted in apoptosis and it was characterised by mitochondria membrane depolarisation, release of cytochrome c from mitochondria into cytosol and activation of caspase-3. Indomethacin and nordihydroguaiaretic acid synergistically potentiated TNF-alpha-induced apoptosis, while arachidonic acid, AACOCF3 and MK-886 did not modulate its effects. Furthermore, indomethacin potentiated apoptosis in cells treated with a differentiating agent, all-trans retinoic acid, which induces resistance to TNF-alpha. However, the observed effects were probably not associated either with the cyclooxygenase- or lipoxygenase-dependent activities of indomethacin and nordihydroguaiaretic acid, respectively. Since indomethacin may reportedly activate peroxisome proliferator-activated receptors (PPARs), the effects of specific ligands of PPARs on apoptosis were studied as well. It was found that selective PPARs ligands had no effects on TNF-alpha-induced apoptosis. The findings suggest that arachidonic acid metabolism does not play a key role in regulation of apoptosis induced by TNF-alpha in the present model. Nevertheless, our data raise the possibility that indomethacin could potentially be used to improve the treatment of human myeloid leukaemia.
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PMID:Inhibitors of arachidonic acid metabolism potentiate tumour necrosis factor-alpha-induced apoptosis in HL-60 cells. 1147 Feb 54

Gingerols, the active components of ginger (the rhizome of Zingiber officinale, Roscoe), represent a potential new class of platelet activation inhibitors. In this study, we examined the ability of a series of synthetic gingerols and related phenylalkanol analogues (G1-G7) to inhibit human platelet activation, compared to aspirin, by measuring their effects on arachidonic acid (AA)-induced platelet serotonin release and aggregation in vitro. The IC(50) for inhibition of AA-induced (at EC(50)=0.75 mM) serotonin release by aspirin was 23.4+/-3.6 microM. Gingerols and related analogues (G1-G7) inhibited the AA-induced platelet release reaction in a similar dose range as aspirin, with IC(50) values between 45.3 and 82.6 microM. G1-G7 were also effective inhibitors of AA-induced human platelet aggregation. Maximum inhibitory (IC(max)) values of 10.5+/-3.9 and 10.4+/-3.2 microM for G3 and G4, respectively, were approximately 2-fold greater than aspirin (IC(max)=6.0+/-1.0 microM). The remaining gingerols and related analogues maximally inhibited AA-induced platelet aggregation at approximately 20-25 microM. The mechanism underlying inhibition of the AA-induced platelet release reaction and aggregation by G1-G7 may be via an effect on cyclooxygenase (COX) activity in platelets because representative gingerols and related analogues (G3-G6) potently inhibited COX activity in rat basophilic leukemia (RBL-2H3) cells. These results provide a basis for the design of more potent synthetic gingerol analogues, with similar potencies to aspirin, as platelet activation inhibitors with potential value in cardiovascular disease.
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PMID:Gingerols and related analogues inhibit arachidonic acid-induced human platelet serotonin release and aggregation. 1155 71

Human leukemia (HL)-60 cells were differentiated by several agents, and prostaglandins (PGs) and thromboxane (TX) synthesizing activity increased in response to the differentiation of the cells. We examined the expression of messenger RNA (mRNA) for TX-synthesizing enzymes, cyclooxygenase (COX)-1, COX-2 and TXA(2) synthase, in dimethyl sulfoxide (DMSO)-differentiated HL-60 cells by reverse transcriptase polymerase chain reaction (RT-PCR), and A23187-stimulated TXB(2) production, a stable metabolite of TXA(2), by radioimmunoassay (RIA). A23187-stimulated TXB(2) production, and mRNA abundance for COX-2, were not detected in non-treated HL-60 cells. TXA(2) synthase mRNA were barely detected in non-treated HL-60 cells. DMSO-induced HL-60 cells gained induction of TXB(2) synthesis and mRNA for COX-2 and TXA(2) synthase during granulocytic differentiation. COX-1 mRNA was constitutively expressed. A23187-stimulated TXB(2) production in DMSO-treated cells was inhibited by NS-398, a specific COX-2 inhibitor. These results demonstrated that TXB(2) production in granulocytic HL-60 cells was regulated at both the enzyme level of COX-2 and TXA(2) synthase.
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PMID:Induction of thromboxane A2 synthesizing enzymes in DMSO-induced granulocytic differentiation of HL-60 cells. 1246 61

Arachidonic acid (AA)-induced cytotoxicity was evaluated in leukocytes: the human leukemia cell lines HL-60, Jurkat and Raji and in rat lymphocytes. Such cytotoxicity was dose- and time-dependent. At concentrations below 5 microM, AA was not toxic; at 10-400 microM, AA induced apoptosis and at concentrations beyond 400 microM, necrosis. The minimum exposure time to trigger cell death was of around 1 h, but the effect was increased by longer exposure times until 6-24 h. Apoptosis was morphologically characterized by a decrease in cell and nuclear volume, chromatin condensation and DNA fragmentation and the presence of lipid bodies, without changes in organelle integrity. Biochemically, AA-induced apoptosis was associated with internucleosomal fragmentation and caspase activation, evaluated by PARP cleavage and the use of a caspase inhibitor. Necrosis was characterized by increased cell volume, presence of loose chromatin, appearance of vacuoles, loss of membrane integrity and of the definition of organelles. The apoptotic effect of AA was studied as to oxidative-reductive imbalance and the participation of eicosanoids. Apoptotic AA treatment was accompanied by an increase in the quantity of thiobarbituric acid reactive substances (TBARS), low-level chemiluminescence and in the glutathione disulfide/reduced glutathione ratio, indicating oxidative stress. The addition of tocopherol, ascorbate, prostaglandin E2 and lipoxygenase inhibitors delayed cell death, whereas the inhibition of cyclooxygenase promoted AA-induced cell death. Cell treatment with AA was accompanied by increased cellular production of LTB4. AA, therefore, is cytotoxic at physiological and supraphysiological concentrations, causing apoptosis and necrosis. Cell treatment with apoptotic concentrations of AA involves oxidative stress and changes in eicosanoid biosynthesis.
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PMID:Arachidonic acid cytotoxicity in leukocytes: implications of oxidative stress and eicosanoid synthesis. 1248 94

The change in cellular reducing potential, most likely reflecting an oxidative burst, was investigated in arachidonic acid- (AA) stimulated leukocytes. The cells studied included the human leukemia cell lines HL-60 (undifferentiated and differentiated into macrophage-like and polymorphonuclear-like cells), Jurkat and Raji, and thymocytes and macrophages from rat primary cultures. The oxidative burst was assessed by nitroblue tetrazolium reduction. AA increased the oxidative burst until an optimum AA concentration was reached and the burst decreased thereafter. In the leukemia cell lines, optimum concentration ranged from 200 to 400 microM (up to 16-fold), whereas in rat cells it varied from 10 to 20 microM. Initial rates of superoxide generation were high, decreasing steadily and ceasing about 2 h post-treatment. The continuous presence of AA was not needed to stimulate superoxide generation. It seems that the NADPH oxidase system participates in AA-stimulated superoxide production in these cells since the oxidative burst was stimulated by NADPH and inhibited by N-ethylmaleimide, diphenyleneiodonium and superoxide dismutase. Some of the effects of AA on the oxidative burst may be due to its detergent action. There apparently was no contribution of other superoxide-generating systems such as xanthine-xanthine oxidase, cytochromes p-450 and mitochondrial electron transport chain, as assessed by the use of inhibitors. Eicosanoids and nitric oxide also do not seem to interfere with the AA-stimulated oxidative burst since there was no systematic effect of cyclooxygenase, lipoxygenase or nitric oxide synthase inhibitors, but lipid peroxides may play a role, as indicated by the inhibition of nitroblue tetrazolium reduction promoted by tocopherol.
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PMID:Arachidonic acid triggers an oxidative burst in leukocytes. 1457 10

Viruses have developed strategies to counteract the apoptotic response of the infected host cells. Modulation of apoptosis is also thought to be a major component of viral persistence and progression to leukemia induced by retroviruses like human T-lymphotropic virus type 1 (HTLV-1) and bovine leukemia virus (BLV). Here, we analyzed the mechanism of ex vivo apoptosis occurring after isolation of peripheral blood mononuclear cells from BLV-infected sheep. We show that spontaneous apoptosis of ovine B lymphocytes requires at least in part a caspase 8-dependent pathway regardless of viral infection. Cell death is independent of cytotoxic response and does not involve the tumor necrosis factor alpha/NF-kappaB/nitric oxide synthase/cyclooxygenase pathway. In contrast, pharmaceutical depletion of reduced glutathione (namely, gamma-glutamyl-l-cysteinyl-glycine [GSH]) by using ethacrynic acid or 1-pyrrolidinecarbodithioic acid specifically reverts inhibition of spontaneous apoptosis conferred indirectly by protective BLV-conditioned media; inversely, exogenously provided membrane-permeable GSH-monoethyl ester restores cell viability in B lymphocytes of BLV-infected sheep. Most importantly, intracellular GSH levels correlate with virus-associated protection against apoptosis but not with general inhibition of cell death induced by polyclonal activators, such as phorbol esters and ionomycin. Finally, inhibition of apoptosis does not correlate with the activities of GSH peroxidase and GSH reductase. In summary, our data fit into a model in which modulation of the glutathione system is a key event involved in indirect inhibition of apoptosis associated with BLV. These observations could have decisive effects during therapeutic treatment of delta-retroviral pathogenesis.
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PMID:Involvement of glutathione as a mechanism of indirect protection against spontaneous ex vivo apoptosis associated with bovine leukemia virus. 1516 11

We studied the effect of specific inhibitors of 5- and 12-lipoxygenases as well as the product of cyclooxygenase activity, prostaglandin E2, on proliferation and death of P388 leukemia cells. Inhibition of 5- and 12-lipoxygenases in the cells inhibits proliferation and induces apoptosis. The concentrations of baicalein, an inhibitor of 12-lipoxygenase, and AA861, an inhibitor of 5-lipoxygenase, causing a 50% death rate (LC50) proved to be the same, 50 microM. Excessive prostaglandin also inhibited proliferation of the cells and induced apoptosis. The LC50 for prostaglandin E2 was 4 microM. The obtained data suggest that apoptosis in P388 cells after lipoxygenase inhibition can be induced by both deficiency of lipoxygenase products and excess of prostaglandins in the cell.
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PMID:[Apoptosis in P388 leukemia cells induced by specific inhibitors of 5- and 12-lipoxygenase and the product of cyclooxygenase, prostaglandin E2]. 1535 52

Previous studies have demonstrated that N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), a well-known DNA alkylating agent, induces G2/M arrest and apoptotic cell death in several human cancer cell lines. In the present study, we investigated the effects of MNNG on the growth of a U937 human leukemia cell model. The effects of this compound were also tested on cyclooxygenase (COX) activity. Treatment of U937 cells with MNNG resulted in the inhibition of viability and the induction of apoptosis in a concentration-dependent manner, which was associated with a dose-dependent upregulation in pro-apoptotic Bax protein, downregulation of anti-apoptotic Bcl-2 and Bcl-xL proteins, and proteolytic activation of caspase-3 protease. Furthermore, MNNG decreased the levels of COX-2 mRNA and protein expression without significant changes in the levels of COX-1, which was correlated with inactivation of the reporter construct of a COX-2 promoter and decrease in prostaglandin E2 synthesis. Taken together, these findings provide important new insights into the possible molecular mechanisms of the anti-cancer activity of MNNG.
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PMID:Induction of apoptosis and inhibition of cyclooxygenase-2 expression by N-methyl-N'-nitro-N-nitrosoguanidine in human leukemia cells. 1584 16

Cancer is predicted to become the leading cause of death--surpassing heart disease--by the end of this decade. Colorectal cancer is a major health concern, with more than 1,000,000 new cases and 500,000 deaths expected worldwide per year. There is much evidence to suggest a link between the consumption of non-steroidal anti-inflammatory drugs (NSAIDs) and the prevention of colorectal cancer (CRC). The consumption of NSAIDs is not problem free, and the number of deaths due to NSAIDs equals the number of deaths from AIDS or leukemia. Therefore, although chemoprevention of CRC is possible, drugs that have more acceptable side effect profiles than the currently available NSAIDs are required. Since up to 50% of polyps and 85% of colonic tumors in humans overexpress cyclooxygenase (COX-2), COX-2 inhibitors are an ideal drug candidate for CRC prevention or treatment.
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PMID:Cyclooxygenase-2 inhibition prevents colorectal cancer: from the bench to the bed side. 1621 Aug 75


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