Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Activation of alpha1-adrenoceptor stimulation regulates eicosanoid metabolism and growth in vascular smooth muscle cells (VSMCs). The purpose of this study was to investigate the functional implications of lipoxygenase pathway in alpha1-adrenoceptor-stimulated VSMCs growth through mutually exclusive biological functions, that is cell proliferation and cell death. 2. Phenylephrine (10 microM), a specific alpha1-adrenoceptor agonist, enhanced [3H]-thymidine incorporation by 300% above basal. Nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor, caused 36 and 50% decrease in phenylephrine (10 microM)-stimulated [3H]-thymidine incorporation at concentrations of 1 microM and 10 microM respectively. 3. Inversely, treatment of phenylephrine (10 microM)-stimulated VSMCs with NDGA induced DNA fragmentation in a dose-dependent fashion. The level of induction of DNA fragmentation by NDGA was 225, 319 and 406% above the phenylephrine (10 microM)-level at concentrations of 0.1 microM, 1 microM and 10 microM, respectively. This induction of DNA fragmentation was partially prevented by exogenous 15-hydroxyeicosatetraenoic acid (15-HETE). The inhibition of apoptosis was 53 and 63% at concentrations of 5 microM and 10 microM of 15HETE, respectively, as compared with phenylephrine (10 microM) in the presence of NDGA (10 microM). 4. Furthermore, we performed the time-course analysis of Bcl-2 protein expression in phenylephrine (10 microM)-stimulated VSMCs. The expression of Bcl-2 protein disappeared after a 2 h incubation in the presence of NDGA (10 microM), but remained stable after a 2 h incubation period in the absence of NDGA (10 microM). 5, These results suggest that the lipoxygenase pathway is involved in cell proliferation by preventing apoptosis through the level of Bcl-2 protein expression.
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PMID:The regulation of mitogenesis and apoptosis in response to the persistent stimulation of alpha1-adrenoceptors: a possible role of 15-lipoxygenase. 942 4

MK 886, an arachidonic acid-related analog which inhibits the enzyme, 5-lipoxygenase by an indirect mechanism involving the 5-lipoxygenase activating protein, rapidly increased U937 cytosol Ca(2+), much of which localized around the cell nuclei. Five-lipoxygenase activity was not directly involved since the direct redox-dependent 5-LPOx inhibitor, SC-41661A did not increase Ca(2+). U937 cells subsequently undergo classic type 1 programmed cell death. At least initially the ionized calcium originates from internal stores. Coincident with the rise in U937 ionized calcium, MK 886 rapidly increased reactive oxygen species and reduced mitochondrial membrane potential, as judged by several fluorescent probes. The Ca(2+) response of myeloid leukemia-derived HL-60 cells to MK 886 was similar and both cell lines express Bcl-2 protein. Bcl-2-negative Panc-1 and PC-3 cells did not respond to MK 886 with a Ca(2+) signal but did develop oxidative stress and a decline in mitochondrial membrane potential; these events are thought to contribute to the inhibition of cell proliferation and induction of a type 2 PCD. In addition to its marked inhibition of Bcl-2 mRNA synthesis, an interesting hypothesis is that MK 886, serving as a low molecular weight ligand, either by direct or indirect inhibition of U937 Bcl-2 protein function, possibly related to an ion channel activity, alters the distribution of intracellular, possibly nuclear Ca(2+), thereby promoting the development of type 1 programmed cell death.
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PMID:Increased cytosol Ca(2+) and type 1 programmed cell death in Bcl-2-positive U937 but not in Bcl-2-negative PC-3 and Panc-1 cells induced by the 5-lipoxygenase inhibitor MK 886. 1205 16

Several studies have suggested that high dietary fat intake, particularly essential fatty acids, is associated with pancreatic cancer development and growth. Our previous studies have demonstrated that blockade of either the 5-lipoxygenase (LOX) or 12-LOX pathway of arachidonic acid metabolism inhibited pancreatic cancer cell proliferation and induced apoptosis. This study investigated the underlying mechanisms for LOX inhibitor-induced apoptosis and the potential of LOX inhibitors as antipancreatic cancer agents using the athymic mice xenograft model. Apoptosis of pancreatic cancer cells induced by LOX inhibitors (including the nonselective LOX inhibitor nordihydroguaiaretic acid, the 5-LOX inhibitor Rev-5901, and the 12-LOX inhibitor baicalein) was confirmed by growth inhibition, annexin V binding, and terminal deoxynucleotidyl transferase-mediated nick end labeling assay in MiaPaCa-2 and AsPC-1 human pancreatic cancer cells. Expression of the antiapoptotic proteins Bcl-2 and Mcl-1 was significantly decreased after LOX inhibitor treatment while that of the proapoptotic protein bax was increased. LOX inhibitors also markedly induced the release of cytochrome c from mitochondria into the cytosol. Caspase-9, caspase-7, and caspase-3 but not caspase-8 were activated after treatment, concomitant with cleavage of the capase-3 substrate poly(ADP-ribose) polymerase. In vivo studies in the athymic mice xenograft model also confirmed the growth inhibitory effect and induction of apoptosis by these LOX inhibitors in pancreatic cancer. In conclusion, LOX inhibitors block pancreatic cancer cell proliferation and induce apoptosis through the mitochondrial pathway both in vivo and in vitro. LOX inhibitors are likely to be valuable for the treatment of human pancreatic cancer.
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PMID:Lipoxygenase inhibitors attenuate growth of human pancreatic cancer xenografts and induce apoptosis through the mitochondrial pathway. 1248 14

A series of epidemiological, experimental and preliminary clinical trials strongly suggest that mesalazine or 5-aminosalicyclic acid (5-ASA) may have antineoplastic and potentially prophylactic chemopreventive properties. It is assumed that mesalazine may have similar genetic and molecular targets as nonsteroidal anti-inflammatory drugs (NSAIDs), which is further supported by its close similarity with aspirin, differing only in its structure by the presence of an amino group at position 5 of the benzene ring. The putative chemopreventive actions include the inhibition of inflammatory cascades and/or reactions involved in cell growth and proliferation, such as cyclo-oxygenase (COX-1 and COX-2), which regulate cell proliferation through the formation of prostaglandins; lipoxygenase; nuclear factor kappaB (NFkappaB), responsible for the subsequent expression of pro-inflammatory molecules; MAP kinases and Bcl-2, as well as the activation of apoptotic processes, such as the stimulation of intestinal sphingomyelinase. The peroxisome-proliferator-activated receptor delta (PPARdelta), which also regulates gene transcription, is thought to play a role in both inflammatory and non-inflammatory driven carcinogenesis. This may be another significant target. It is hypothesized that 5-ASAs may prevent the enhancing effect of prostaglandins on PPARdelta binding to DNA by its COX inhibitory properties, decreasing proliferation of colorectal mucosal cells in non-inflammatory bowel disease patients with sporadic polyps of the large bowel.
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PMID:Review article: mechanisms of action of mesalazine in preventing colorectal carcinoma in inflammatory bowel disease. 1295 Apr 15

Many natural components of plant extracts are studied for their beneficial effects for health and particularly on carcinogenesis chemoprevention. In the present study, we investigated the effects of diosgenin on erythroleukemia HEL cells. Our results demonstrated that diosgenin induced G2/M arrest of cell cycle progression through p21 up-regulation in a p53-independent pathway and strong induction of apoptosis in HEL cells. Apoptosis induction was accompanied by an increase in Bax/Bcl-2 ratio, PARP cleavage and DNA fragmentation. Moreover, we showed for the first time that diosgenin provoked a collapse of mitochondrial membrane potential with an increase in intracellular calcium levels. It is well known that [Ca2+]i increase is one of the major activators of cytosolic PLA2. In our study, we demonstrated that diosgenin treatment induced cPLA2 activation through translocation to the cellular membrane. Moreover, arachidonic acid metabolism activation led to cyclooxygenase-2 (COX-2) but not lipoxygenase overexpression. Surprisingly, we observed a COX-2 up-regulation associated with apoptosis induction by diosgenin. These findings suggest that diosgenin has a potential chemopreventive effect; future studies should evaluate the mechanism of COX-2 activation during diosgenin-induced apoptosis in cancer cell lines.
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PMID:Diosgenin induces cell cycle arrest and apoptosis in HEL cells with increase in intracellular calcium level, activation of cPLA2 and COX-2 overexpression. 1528 56

Micromolar concentrations of the five-lipoxygenase inhibitor, MK 886 induce a "type 1" (apoptotic, extrinsic, death domain, receptor-dependent, caspase-positive) form of programmed cell death in Bcl-2-positive U937 human monoblastoid and HL-60 myeloid leukemia cells. A "type 2" (intrinsic, mitochondria-dependent, autophagic, in some examples caspase-negative (Panc-1)) form is induced in Panc-1 pancreatic and PC3 prostate cell lines. The latter two lines from epithelial-derived solid human cancers are Bcl-2-negative. Micromolar MK 886 induces an acute rise in Ca2+ in washed, Ca2+-poor U937 and HL60 cells in Ca2+ and Mg2+-free Hank's buffer. In U937 cells, much of the increase, or more properly redistribution, is nuclear in location (HL-60 not tested). No MK-886-induced acute Ca2+ increase developed in Panc-1 or PC3 cells. Bcl-2-positive HeLa cervical cancer cells exhibited an acute MK 886-induced increase in Ca2+. In the U937, PC3 and Panc-1 cells examined, MK-886 rapidly increased oxidative stress and decreased mitochondrial membrane potential, indicating that neither event is directly determinative for the altered distribution of Ca2+ or the form of PCD observed. Inhibition of increased U937 Ca2+ by the anti-oxidant, N-acetyl-L-cysteine, the effects of inhibitors of mitochondrial function including antimycin A, atractyloside, cyclosporin A, the L/N channel blocker loperamide, the intracellular chelator BAPTA and 2 agents, HA-14 and 3-methyl-antimycin A3 that impair Bcl-2 function further define these events. These differences in the Ca2+ response and possibly also the form of PCD that results may depend upon the presence of Bcl-2 or a related protein participating in a juxta-nuclear / nuclear Ca2+ ion channel. The role of mitochondria, the mechanism by which increased oxidative stress initiates the rapid release of Ca2+ from intracellular, possibly juxta-nuclear / nuclear sites or its redistribution to U937 Ca2+ nuclei, and whether this "signal" or possibly even ROS themselves mandate the type of PCD observed, presumably by differential modulation of transcription, remain to be determined. Lastly, these results demonstrate that, as might be expected, "soil" (cell type) trumps "seed" (inciting agent)".
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PMID:Reactive oxygen species and redox-induced programmed cell death due to MK 886: cells ("soil") "trump" agent ("seed"). 1579 62

Gamma-linolenic acid (GLA) induced apoptosis of tumor cells without harming normal cells. Both cyclo-oxygenase (COX) and lipoxygenase (LO) inhibitors did not inhibit the selective tumoricidal action of GLA in some, but not all, tumor cells suggesting that GLA by itself is active. In contrast, anti-oxidants such as vitamin E blocked the tumoricidal action of GLA. GLA-treated tumor but not normal cells produced a 2-3-fold increase in free radicals and lipid peroxides. GLA decreased the anti-oxidant content of tumor cells, expression of oncogenes ras, and Bcl-2, enhanced the activity of p53, protected normal cells and tissues from the toxic actions of radiation and anti-cancer drugs, enhanced the cytotoxic action of anti-cancer drugs and reversed tumor cell drug resistance. In the animal glioma model, GLA induced tumor regression and preserved the surrounding normal brain tissue. In three open-label clinical studies, intra-tumoral injection of GLA induced significant reduction of glioma without any significant side effects. The low neurotoxicity of GLA to normal brain neurons and selective activity against tumor cells suggests that it could be an effective anti-glioma molecule.
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PMID:Gamma-linolenic acid therapy of human glioma-a review of in vitro, in vivo, and clinical studies. 1759 36

Lipoxygenases induce malignant tumor progression and lipoxygenase inhibitors have been considered as promising anti-tumor agents. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is one of the most promising candidates for new cancer therapeutics. Combined treatment with nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor, and TRAIL markedly induced apoptosis in Jurkat T-cell leukemia cells at suboptimal concentrations for each agent. The combined treatment efficiently activated caspase-3, -8 and -10, and Bid. The underling mechanism by which NDGA enhanced TRAIL-induced apoptosis was examined. NDGA did not change the expression levels of anti-apoptotic factors, Bcl-x(L), Bcl-2, cIAP-1, XIAP and survivin. The expression of death receptor-related genes was investigated and it was found that NDGA specifically up-regulated the expression of death receptor 5 (DR5) at mRNA and protein levels. Down-regulation of DR5 by small interfering RNA prevented the sensitizing effect of NDGA on TRAIL-induced apoptosis. Furthermore, NDGA sensitized prostate cancer and colorectal cancer cells to TRAIL-induced apoptosis. In contrast, NDGA neither enhanced TRAIL-induced apoptosis nor up-regulated DR5 expression in normal peripheral blood mononuclear cells. Another lipoxygenase inhibitor, AA861, also up-regulated DR5 and sensitized Jurkat and DU145 cells to TRAIL. These results indicate that lipoxygenase inhibitors augment the apoptotic efficiency of TRAIL through DR5 up-regulation in malignant tumor cells, and raise the possibility that the combination of lipoxygenase inhibitor and TRAIL is a promising strategy for malignant tumor treatment.
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PMID:Lipoxygenase inhibitors induce death receptor 5/TRAIL-R2 expression and sensitize malignant tumor cells to TRAIL-induced apoptosis. 1764 80

The aim of this study was to elucidate the mechanisms of action for potential targets of therapeutic intervention related to the arachidonic acid cascade in muscular dystrophy. Primary cultures from a Duchenne patient were used to study the expression of dystrophin-1, utrophin, desmin, neonatal myosin heavy chain (MHCn) and Bcl-2 during inhibition of phospholipase A2 (PLA2), cyclooxygenase (COX) and lipoxygenase (LOX). Hypo-osmotic treatment was applied in order to trigger Ca2+ influx and PLA2 activity. Inhibition of PLA2 and LOX with prednisolone and nordihydroguaiaretic acid (NDGA) caused a semi-quantitative increase of utrophin and Bcl-2-, and a dose-dependent, quantitative increase of desmin expression, an effect that was augmented by hypo-osmotic treatment. Our results indicate that LOX inhibitors, similarly to corticosteroids, can be beneficial in the treatment of muscular dystrophies.
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PMID:Effects of inhibitors of the arachidonic acid cascade on primary muscle culture from a Duchenne muscular dystrophy patient. 1799 95

Monocytes isolated and cultured according to standard procedures from the blood of 22 healthy donors display an activation process, monitored as adhesion and increased exposure of CD11. Starting from very early time points, monocytes undergo a deep redox modulation, i.e., they increase reactive oxygen species (ROS) formation and decrease glutathione content; at the same time, the anti-apoptotic protein Bcl-2 is substantially up-regulated. The cause-effect relationship between these parameters was investigated. On the one side, pharmacological glutathione depletion with BSO further increases ROS formation and Bcl-2 levels. On the other side, scavenging of ROS by Trolox prevents Bcl-2 up-regulation. Two lipoxygenase (LOX) inhibitors (CAPE or AA861) prevent ROS increase and, accordingly, also prevent Bcl-2 up-regulation. All this evidence supports the redox-sensitivity of Bcl-2 regulation. Trolox, CAPE and AA861, i.e., all treatments that abolish ROS increase and prevent Bcl-2 up-regulation, increase the rate of cell loss, whereas BSO, increasing Bcl-2, reduces cell loss and induces chemo-resistance. Thus, explanted healthy monocytes seem to undergo an oxidation-dependent maturation implying increased survival via Bcl-2 up-regulation, perhaps mimicking physiological activation.
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PMID:Oxidation-dependent maturation and survival of explanted blood monocytes via Bcl-2 up-regulation. 1876 35


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