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

In an attempt to characterize the mechanisms that are operative at the early stages of the induction of apoptosis by bufalin, a component of the traditional Chinese medicine chan'su, we examined the effects of bufalin on plasma membrane potential, as determined by monitoring the uptake by cells of rhodamine 123. Bufalin induced apoptosis in human monocytic leukemia THP-1 cells, in human lymphoblastic leukemia MOLT-3 cells, and in human colon adenocarcinoma COLO320DM cells but not in normal human leukocytes, for example, polymorphonuclear cells and lymphocytes, and not in murine leukemia P388D1 and M1 cells. Treatment for 3 h with bufalin at 10(-6) M caused a decrease in the plasma membrane potential in several lines of human tumor cells but not in murine leukemia cells. No changes in mitochondrial membrane potential, as monitored with the fluorescent dye JC-1, and no release of cytochrome c were observed within at least 6 h after the start of treatment with bufalin. Moreover, overexpression of bcl-2 in human leukemia HL60 cells that had been transfected with cDNA for bcl-2 prevented bufalin-induced apoptosis but had no significant effect on the change in plasma membrane potential induced by bufalin. Since bufalin specifically inhibits the Na+,K(+)-ATPase of human but not murine tumor cells, and since this inhibition leads to a change in intracellular concentration of Na+ ions, our findings suggest that bufalin induces apoptosis in human tumor cells selectively via inhibition of the Na+,K(+)-ATPase, which acts upstream of the bcl-2 protein.
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PMID:Induction of apoptosis by bufalin in human tumor cells is associated with a change of intracellular concentration of Na+ ions. 1042 18

Treatment of human leukemia THP-1 cells with bufalin, a specific inhibitor of Na(+)-K(+)-ATPase, sequentially induces c-fos and inflammatory cytokines interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) gene expressions before the appearance of mature phenotypes of monocytic cells. In this study we examined the signal transduction leading to bufalin-induced gene expressions. Bufalin selectively activated extracellular signal-regulated kinase (ERK), compared with other mitogen-activated protein (MAP) kinase family members. Pretreatment of THP-1 cells with PD-98059, an inhibitor of the ERK-kinase cascade, abolished bufalin-induced c-fos and IL-1 beta gene expressions, indicating that the ERK-kinase cascade mediates the induction of inflammatory cytokines by bufalin. Inhibition of the Na(+)/Ca(2+) exchanger by KB-R7943 and of protein kinase C (PKC) by Ro-31-8220 suppressed ERK activation and gene expressions of c-fos and IL-1 beta. These findings suggest that Na(+)-K(+)-ATPase inhibition by bufalin induces calcium influx and thereby activates PKC and ERK. In cells treated with an inhibitor of p38 MAP kinases, SB-203580, bufalin-mediated ERK activation became persistent and the induction of IL-1 beta and TNF-alpha expressions was significantly augmented. These results suggest that cross talk in bufalin-mediated ERK activation is negatively regulated by endogenous p38 MAP kinase activations.
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PMID:ERK signaling mediates the induction of inflammatory cytokines by bufalin in human monocytic cells. 1071 38

OC144-093 is a novel substituted diarylimidazole (Mr 495) generated using the OntoBLOCK system, a solid-phase combinatorial chemistry technology, in combination with high-throughput cell-based screening. OC144-093 reversed multidrug resistance (MDR) to doxorubicin, paclitaxel, and vinblastine in human lymphoma, breast, ovarian, uterine, and colorectal carcinoma cell lines expressing P-glycoprotein (P-gp) with an average EC50 of 0.032 microM. Inhibition of MDR by OC144-093 was reversible, but the effect persisted for at least 12 h after removal of compound from the culture medium. OC144-093 had no effect on the response to cytotoxic agents by cells in vitro lacking P-gp expression or expressing a multidrug resistance-associated protein (MRP-1). OC144-093 was not cytotoxic by itself against 15 normal, nontransformed, or tumor cell lines, regardless of P-gp status, with an average cytostatic IC50 of >60 microM. OC144-093 blocked the binding of [3H]azidopine to P-gp and inhibited P-gp ATPase activity. The compound was >50% p.o. bioavailable in rodents and dogs and did not alter the plasma pharmacokinetics of i.v.-administered paclitaxel. OC144-093 increased the life span of doxorubicin-treated mice engrafted with MDR P388 leukemia cells by >100% and significantly enhanced the in vivo antitumor activity of paclitaxel in MDR human breast and colon carcinoma xenograft models, without a significant increase in doxorubicin or paclitaxel toxicity. The results demonstrate that OC144-093 is an orally active, potent, and nontoxic inhibitor of P-gp-mediated multidrug resistance that exhibits all of the desired properties for treatment of P-gp-mediated MDR, as well as for prevention of MDR prior to selection and/or induction of refractory disease.
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PMID:Discovery and characterization of OC144-093, a novel inhibitor of P-glycoprotein-mediated multidrug resistance. 1085 Apr 44

Secretion of interleukin 8 (IL-8) and its regulation was investigated in myelomonocytic leukaemia cell lines. Quantification by ELISA revealed a constitutive production in the cell lines HL-60, ML-2, MONO-MAC-6 and MUTZ-3 ranging between 1500 and ca. 5000 pg/ml IL-8 per million cells. No measurable IL-8 was detected in the culture medium of MONO-MAC-1 and THP-1. Stimulation with lipopolysaccharide (LPS) or tetradecanoyl phorbol acetate (TPA) significantly increased the IL-8 level secreted by all cell lines; the best producers were TPA-treated MONO-MAC-6 and MUTZ-3 cultures, generating more than 50 000 pg/ml IL-8. Also the calcium ionophore A-23187, IL-13, macrophage colony-stimulating factor (M-CSF), thapsigargin, an inhibitor of the Ca(2+)-ATPase, and tumour necrosis factor-alpha (TNF-alpha) strongly enhanced the IL-8 production in MONO-MAC-6 cells. The glucocorticoid dexamethasone and the protein kinase inhibitor staurosporine distinctively inhibited the IL-8 production of MONO-MAC-6 cells. Thus, our results demonstrate a strong constitutive IL-8 secretion in human myelomonocytic leukaemia cell lines; the variety of different modulators affecting IL-8 production leads to the suggestion of a multiple regulation of IL-8 expression and secretion.
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PMID:Multiple regulation of constitutive and induced interleukin 8 secretion in human myelomonocytic cell lines. 1093 Mar 3

Whole-cell patch-clamp experiments were performed to examine the mechanism underlying the inability of intracellular Ins(1,4,5)P(3) to activate the Ca(2+) release-activated Ca(2+) current (I(CRAC)) in rat basophilic leukaemia (RBL)-1 cells under conditions of weak cytoplasmic Ca(2+) buffering. Dialysis with Ins(1,4,5)P(3) in weak Ca(2+) buffer did not activate any macroscopic I(CRAC) even after precautions had been taken to minimize the extent of Ca(2+) entry during the experiment. Following intracellular dialysis with Ins(1,4,5)P(3) for >150 s in weak buffer, external application of the sarcoplasmic/endoplasmic-reticulum Ca(2+)-ATPase (SERCA) pump blocker thapsigargin activated I(CRAC), and the current developed much more quickly than when thapsigargin was applied in the absence of Ins(1,4,5)P(3). This indicates that the Ins(1,4,5)P(3) receptors had not inactivated much over this timecourse. When external Ca(2+) was replaced by Ba(2+), Ins(1,4,5)P(3) still failed to generate any detectable I(CRAC) even though Ba(2+) permeates CRAC channels and is not taken up into the intracellular Ca(2+) stores. In strong Ca(2+) buffer, I(CRAC) could be activated by muscarinic-receptor stimulation, provided protein kinase C (PKC) was blocked. In weak buffer, however, as with Ins(1,4,5)P(3), stimulation of these receptors with carbachol did not activate I(CRAC) even after inhibition of PKC. The inability of Ins(1,4,5)P(3) to activate macroscopic I(CRAC) in weak Ca(2+) buffer was not altered by inhibition of Ca(2+)-dependent phosphorylation/dephosphorylation reactions. Our results suggest that the inability of Ins(1,4,5)P(3) to activate I(CRAC) under conditions of weak intracellular Ca(2+) buffering is not due to strong inactivation of the Ins(1,4,5)P(3) receptors. Instead, a futile Ca(2+) cycle across the stores seems to be occurring and SERCA pumps resequester sufficient Ca(2+) to ensure that the threshold for activation of macroscopic I(CRAC) has not been exceeded.
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PMID:Sarcoplasmic/endoplasmic-reticulum-Ca2+-ATPase-mediated Ca2+ reuptake, and not Ins(1,4,5)P3 receptor inactivation, prevents the activation of macroscopic Ca2+ release-activated Ca2+ current in the presence of physiological Ca2+ buffer in rat basophilic leukaemia-1 cells. 1117 Oct 53

Multidrug resistance mediated by the multidrug resistance-associated protein MRP1 is associated with decreased drug accumulation, which is in turn dependent on cellular glutathione. We have reported that verapamil, an inhibitor of drug transport, caused a decrease in cellular glutathione in CCRF-CEM/E1000 MRP1-overexpressing leukaemia cells (Biochem Pharmacol 55;1283--9, 1998). We now demonstrate that other inhibitors of MRP1-mediated drug transport (e.g. MK571, indomethacin, genistein, and nifedipine) deplete cellular glutathione in these leukaemia cells (>30% decrease; P < 0.01) while having no effect on the parental CCRF-CEM cells. However, treatment with etoposide or vincristine (at similar molar concentrations) caused a 20% decrease in glutathione. Verapamil-stimulated glutathione transport correlated with MRP1 expression in a series of drug-resistant cells, and glutathione was quantitatively recovered in the extracellular media. Further, verapamil-stimulated glutathione transport was rapid (50% decrease in 10 min), dose-dependent, and inhibited by vanadate, an inhibitor of ATPase activity, but not by sulphobromophthalein (BSP) or methionine, inhibitors of hepatic glutathione transporters. Incubation of CCRF-CEM/E1000 cells in 25 mM glutathione not only showed that verapamil-mediated efflux occurred against the concentration gradient, but also demonstrated the MRP1-mediated uptake of glutathione (P < 0.01 compared to the parental CCRF-CEM cells), which was not inhibited by vanadate. These results demonstrate that while MRP1 transports glutathione in the presence of inhibitors of drug transport, there is no convincing evidence for co-transport of glutathione with drug. They further demonstrate that MRP1 mediates the facilitated transport of glutathione into the MRP1-overexpressing CEM/E1000 cells, suggesting that MRP1 may play a major role in cellular glutathione homeostasis.
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PMID:Verapamil-stimulated glutathione transport by the multidrug resistance-associated protein (MRP1) in leukaemia cells. 1144 50

Under physiological conditions of weak intracellular Ca(2+) buffering (0.1 mM EGTA), the second messenger Ins(1,4,5)P(3) often fails to activate any detectable store-operated Ca(2+) current. However, it has been reported that the fungal metabolite adenophostin A [which has a severalfold higher affinity than Ins(1,4,5)P(3) for Ins(1,4,5)P(3) receptors] consistently activates the current under similar conditions. Here, whole-cell patch clamp experiments have been performed to examine how adenophostin A can activate the store-operated Ca(2+) current (I(CRAC)) in RBL-1 (rat basophilic leukaemia) cells. In a strong intracellular Ca(2+) buffer, saturating concentrations of adenophostin A activated I(CRAC) maximally and the current amplitude and kinetics were indistinguishable from those obtained with high concentrations of Ins(1,4,5)P(3). In a weak Ca(2+) buffer, adenophostin A consistently activated I(CRAC), but the current was submaximal. High concentrations of Ins(1,4,5)P(3) or the non-metabolizable analogue Ins(2,4,5)P(3) were largely ineffective under these conditions. The size of I(CRAC) to adenophostin A in weak Ca(2+) buffer could be significantly increased by either inhibiting sarcoplasmic/endoplasmic-reticulum Ca(2+)-ATPase ('SERCA') pumps with thapsi-gargin or enhancing mitochondrial Ca(2+) uptake, although blocking the mitochondrial Ca(2+) uniporter with Ruthenium Red did not suppress the activation of the current. Changing the levels of free ATP in the recording pipette did not enhance the size of I(CRAC) evoked by adenophostin A. We also examined two structurally distinct analogues of adenophostin A (manno-adenophostin and ribophostin), for which the affinities for the Ins(1,4,5)P(3) receptor are similar to that of Ins(1,4,5)P(3) in equilibrium binding experiments. Although these analogues were able to activate I(CRAC) to its maximal extent in strong buffer, ribophostin, but not manno-adenophostin, consistently activated the current in weak buffer. We conclude that adenophostin A and ribophostin are able to activate I(CRAC) in weak buffer through a mechanism that is quite distinct from that employed by Ins(1,4,5)P(3) and manno-adenophostin and is not related to equilibrium affinities.
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PMID:Adenophostin A and ribophostin, but not inositol 1,4,5-trisphosphate or manno-adenophostin, activate the Ca2+ release-activated Ca2+ current, I(CRAC), in weak intracellular Ca2+ buffer. 1174 38

We show here that murine leukemia virus-based retrovirus vector transgene expression is rapidly silenced in human tumor cell lines lacking expression of Brm, a catalytic subunit of the SWI/SNF chromatin remodeling complex, even though these vectors can successfully enter, integrate, and initiate transcription. We detected this gene silencing as a reduction in the ratio of cells expressing the exogenous gene rather than a reduction in the average expression levels, indicating that down-regulation occurs in an all-or-none manner. Retroviral gene expression was protected from silencing and maintained in Brm-deficient host cells by exogenous expression of Brm but not BRG1, an alternative ATPase subunit in the SWI/SNF complex. Introduction of exogenous Brm to these cells suppressed recruitment of protein complexes containing YY1 and histone deacetylase (HDAC) 1 and 2 to the 5'-long terminal repeat region of the integrated provirus, leading to the enhancement of acetylation of specific lysine residues in histone H4 located in this region. Consistent with these observations, treatment of Brm-deficient cells with HDAC inhibitors but not DNA methylation inhibitors suppressed retroviral gene silencing. These results suggest that the Brm-containing SWI/SNF complex subfamily (trithorax-G) and a complex including YY1 and HDACs (Polycomb-G) counteract each other to maintain transcription of exogenously introduced genes.
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PMID:Maintenance of integrated proviral gene expression requires Brm, a catalytic subunit of SWI/SNF complex. 1185 Apr 27

The ability of the protein kinase C down-regulator bryostatin 1 to potentiate 1-beta-D-arabinofuranosylcytosine (ara-C)-induced apoptosis was examined in human leukemia cells (U937) over-expressing the antiapoptotic protein Bcl-x(L). Coadministration of bryostatin 1 with ara-C resulted in enhanced cytosolic release of cytochrome c and Smac/DIABLO, procaspase-3 and -9 activation, loss of mitochondrial membrane potential (Deltapsi(m)), poly(ADP-ribosyl)phosphorylase degradation, apoptosis, and loss of clonogenic survival in U937/Bcl-x(L) cells, although effects were not as marked as in empty-vector control cells. Whereas the broad caspase inhibitor ZVAD-fluoromethyl ketone blocked ara-C/bryostatin 1-mediated caspase activation, loss of Deltapsi(m, )and apoptosis in U937 cells, it failed to diminish cytochrome c release. In contrast, ectopic expression of Bcl-x(L) blocked cytochrome c redistribution as well as all other events involved in ara-C/bryostatin 1-mediated apoptosis. The ability of ectopic expression of cytokine response modifier A to attenuate, albeit partially, bryostatin 1-mediated potentiation of ara-C-related apoptosis suggested a contributory role for activation of the extrinsic pathway in this phenomenon. Finally, the F(0)F(1) ATPase inhibitor oligomycin effectively blocked cytochrome c release as well as loss of Deltapsi(m) and apoptosis in U937/Bcl-x(L) cells. Together, these findings support the concept that bryostatin 1 potentiates ara-C lethality in human leukemia cells ectopically expressing Bcl-x(L) by diminishing the capacity of this antiapoptotic protein to antagonize cytochrome c release. In addition, they raise the possibility that activation of caspase cascades operating independently of Bcl-x(L)-associated mitochondrial actions may also contribute to enhanced lethality.
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PMID:Bryostatin 1 increases 1-beta-D-arabinofuranosylcytosine-induced cytochrome c release and apoptosis in human leukemia cells ectopically expressing Bcl-x(L). 1196 Oct 58

To detect low levels of histamine, we developed a histamine microsensor using recombinant histamine oxidase. Histamine oxidase with a histidine tag was readily purified using a histidine affinity column. The enzyme showed higher catalytic activity on histamine than diamines (e.g., putrescine and cadaverine) or N(tau)-methylhistamine. The sensor had three carbon film electrodes modified with osmium-polyvinylpyridine-based gel containing horseradish peroxidase, histamine oxidase, and Ag. When a standard solution of histamine was aspirated at a flow rate of 2 microl/min, the detected current was proportional to the histamine concentration and the lower detection limit was 11.3 nM. When rat basophilic leukemia cells (1 x 10(6)) were stimulated by various concentrations of antigen (2, 20, and 200 ng/ml), the histamine concentrations were 0.32, 2.7, and 1.3 microM, respectively, and 20 ng/ml of antigen was found to be the optimal concentration for the antigen-antibody reaction. In contrast, when thapsigargin, an inhibitor of Ca-ATPase in the endoplasmic reticulum, was added (50, 100, and 500 nM), the detected current increased with thapsigargin concentrations and the measured histamine concentrations were 28 nM, 1.3 microM, and 2.7 microM, respectively. These results indicate that the microsensor is useful for the analysis of histamine release from mast cells.
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PMID:Real-time monitoring of histamine released from rat basophilic leukemia (RBL-2H3) cells with a histamine microsensor using recombinant histamine oxidase. 1200 1


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