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)

We examined the effects of tetrandrine (TET) on Ca2+ mobilization in various types of cells using inositol trisphosphate-generating drugs and compared it with those using the microsomal Ca(2+)-ATPase inhibitor thapsigargin (TG) which is a tool for analyzing Ca2+ store-regulated Ca2+ entry (capacitative Ca2+ entry). In rat pheochromocytoma PC12 cells, 100 microM TET abolished high K+ (30 mM)-induced sustained increase in [Ca2+]i and partially inhibited bradykinin (1 microM)-induced or TG (100 nM)-induced Ca2+ entry. In NIH/3T3 fibroblasts, 100 microM TET abolished Ca2+ entry induced by bombesin (1 microM) or TG (100 nM). In rat glioma C6 cells, the addition of 100 microM TET reduced the sustained elevation of [Ca2+]i induced by endothelin 1 (10 nM) or TG (100 nM) declining to the resting level. In rat parotid acinar cells, 100 microM TET abolished a sustained increase in [Ca2+]i induced by carbachol (100 microM) or TG (100 nM). In human leukemia T-cell line Jurkat, 100 microM TET did not inhibit Ca2+ entry evoked by the anti-CD3 antibody OKT3 (10 micrograms/ml) or TG (100 nM). The present results suggest that the action of TET on Ca2+ entry is dependent on cell types.
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PMID:Calcium antagonistic actions of tetrandrine depend on cell types. 858 49

A Na+,K(+)-ATPase inhibitor, bufalin, has been shown previously to induce leukemia cell differentiation. The presence of a circulating Na+,K(+)-ATPase inhibitor has been proposed in mammals. The aim of this study was to explore an endogenous bufalin-like factor that induces leukemia cell differentiation. We found a fraction, designated as fraction A, obtained from human plasma extract that inhibits the growth of several human-derived leukemia cell lines. The effect of the fraction was retained after protease digestion or heat treatment. Murine leukemia cells and ouabain-resistant cells, which are insensitive to bufalin, appeared to be refractory to fraction A in terms of growth inhibition. Fraction A also induced functional and morphological maturation in THP-1 cells. Fraction A was recognized by anti-bufalin anti-serum and inhibited 3H-bufalin binding to K562 cells. These findings suggest that fraction A shows a similar behavior to that of bufalin on leukemia cells by inhibiting Na+,K(+)-ATPase. We propose that an endogenous Na+,K(+)-ATPase inhibitor in human plasma may play a role in cell differentiation.
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PMID:A cardiotonic steroid bufalin-like factor in human plasma induces leukemia cell differentiation. 863 64

We undertake a quantitative investigation of changes in intracellular free Ca2+ concentration ([Ca2+]i) in antigen-stimulated rat basophilic leukemia (RBL-2H3) cells, which include contributions of both Ca2+ store release and Ca2+ influx from the medium. Following Keizer and De Young (J. Keizer and G. De Young. Biophys. J. 61: 649-660, 1992), we develop a highly constrained mathematical model for [Ca2+]i oscillations in RBL-2H3 cells, which includes activation of the inositol trisphosphate receptor (IP3R) by inositol 1,4,5-trisphospate, indirect Ca2+ activation of the IP3R via Ca2+ -dependent activity of phospholipase C-gamma, slow inhibition of the IP3R by cytosolic Ca2+, refilling of Ca2+ stores by a Ca2+ -ATPase (SERCA)-type pump, and a simple representation of the dependence of plasma membrane (PM) fluxes on experimental conditions. Using this full (open cell) model, we simulate [Ca2+]i responses for protocols in which antigen concentration and external Ca2+ are manipulated and compare out calculations with experimental data. In protocol A, cells are stimulated in the presence of external Ca2+, in protocols B and C, cells are stimulated in the absence of external Ca2+, with external Ca2+ later reapplied in protocol C. We are able to reproduce quantitatively the important features of all three protocols, including the dose response of protocol B, the [Ca2+]i response to thapsigargin, and lag time results, and we provide qualitative explanations for the responses derived from our calculations. We also develop a simplified (closed cell) version of the model in which PM fluxes are neglected and total free Ca2+ concentration ([Ca2+]T) is a slowly varying parameter. This permits us to explain in a simple graphical fashion how PM fluxes may influence [Ca2+]i responses in RBH-2H3 cells through modulation of [Ca2+]T.
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PMID:Effect of Ca2+ influx on intracellular free Ca2+ responses in antigen-stimulated RBL-2H3 cells. 863 49

Under resting conditions, steady-state [Ca] in agonist-sensitive Ca stores reflects a balance between active uptake (usually mediated by a thapsigargin-sensitive Ca-ATPase of the SERCA family) and passive efflux of Ca. Even though this pump-leak cycle appears to be a common property of Ca-storing organelles, little is known about the nature of the leak pathway. Ca homeostasis in thapsigargin-sensitive internal Ca stores of single permeabilized BHK-21 fibroblasts was examined using digital image processing of compartmentalized mag-fura-2 (a low-affinity Ca indicator). It is shown here that the leak of Ca from internal stores is regulated specifically by the cytosolic ATP concentration. The rate of leak was 3.6 times slower in 0.375 mM[ATP] than in 4 mM [ATP] (Na or Mg salt). These effects were observed in the presence of 0 Ca/EGTA, thapsigargin, heparin, and ruthenium red, and therefore appear to be independent of the Ca-ATPase, the InsP(3) receptor and the ryanodine receptor. The ATP-stimulated leak was seen in a variety of cell types, including rat basophilic leukemia cells and mouse pancreatic acinar cells. Other nucleotides (ADP, GTP, CTP, and UTP) and nonhydrolyzable ATP analogs (AMP-PNP and ATPgammaS) did not reproduce the action of ATP. Changes in cellular metabolism and ensuing alterations in [ATP] will be expected to influence the filling state of internal Ca stores through effects on the passive leak pathway, potentially leading to modulation of Ca signaling and organellar function.
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PMID:ATP regulates calcium leak from agonist-sensitive internal calcium stores. 864 63

1. The Ca(2+)-antagonism of tetrandrine (TET) on the Ca2+ mobilization in various types of cells were reviewed. Inositol trisphosphate (IP3)-generating drugs were used as Ca(2+)-mobilizing agonists and the effects were compared with those produced by using the microsomal Ca(2+)-ATPase inhibitor thapsigargin (TG), which is a tool for analysing Ca2+ store-regulated Ca2+ entry (capacitative Ca2+ entry). 2. In rat phaeochromocytoma PC12 cells, 100 mumol/L TET abolished high K+ (30 mmol/L)-induced sustained increases in cytoplasmic Ca2+ concentrations ([Ca2+]i) and partially inhibited bradykinin (1 mumol/L)- or TG (100 nmol/L)-induced Ca2+ entry. 3. In NIH/3T3 fibroblasts and rat parotid acinar cells, 100 mumol/L TET abolished Ca2+ entry induced by bombesin (1 mumol/L) and carbachol (100 mumol/L), respectively, or TG (100 nmol/L). However, in the human leukaemia T cell line Jurkat, 100 mumol/L TET did not inhibit Ca2+ entry evoked by either the anti-CD3 antibody OKT3 (10 mg/L) or TG (100 nmol/L). 4. In rat glioma C6 cells, the effects of TET on Ca2+ mobilization were further examined. At a high concentration, TET (300 mumol/L) alone did not affect [Ca2+]i in C6 cells. Tetrandrine inhibited the peak and sustained increases in [Ca2+]i induced by bombesin and TG in a dose-dependent manner. Although TET or TG did not produce increases in IP3, TET did inhibit increases in IP3 produced by bombesin. 5. Our results suggest that the action of TET on Ca2+ entry is dependent on cell types and that TET inhibits both Ca2+ entry from the extracellular medium and Ca2+ release from intracellular stores in rat glioma C6 cells.
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PMID:Tetrandrine as a calcium antagonist. 888 3

The purpose of this study was to elucidate the mechanism of 201Thallium-chloride (201Tl) uptake in tumor cells and its possible relationship to potassium channels. The subcellular biodistribution of 201Tl in tumor cells was examined in colon cancer (LS180) bearing nude mice using sequential centrifugation. The involvement of potassium channels in 201Tl uptake in tumor cells was examined by uptake inhibition with potassium channel blockers (ouabain, bumetanide, and glibenclamide) in cultured leukemia cells (K562). Greater than 90% of 201Tl was found in the soluble cytoplasmic fraction. 201Tl uptake was inhibited by ouabain and bumetanide but not by glibenclamide. These data demonstrate that 201Tl uptake in tumor cells is mediated by the Na(+)-K+ ATPase and the Na(+)-K(+)-2Cl- cotransporter with 201Tl acting as a potassium analogue.
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PMID:Mechanism of 201thallium-chloride uptake in tumor cells and its relationship to potassium channels. 947 Oct 98

The influence of cooling on the intracellular concentration of Ca2+ ([Ca2+]i) was tested in cell lines expressing chemical receptors. First, when ATP was externally added to rat basophilic leukemia (RBL-2H3) cells, cooling from 37 degrees C to 27 degrees C induced a transient rapid increase in [Ca2+]i. In the absence of extracellular Ca2+, the [Ca2+]i response was induced whereas an inhibitor of microsomal Ca2+ ATPase, thapsigargin, largely abolished the [Ca2+]i response, suggesting that the internal Ca2+ store liberate the Ca2+. A purinergic receptor antagonist, suramin, completely inhibited the [Ca2+]i response to the cooling. Secondly, when serotonin (5-HT) was added to rat glioma C6BU-1 cells, the cooling induced a transient increase in [Ca2+]. This [Ca2+]i response was induced in the absence of external Ca2+, suggesting that the internal Ca2+ stores liberate the Ca2+. These results raise the possibility that some G protein-coupled receptors are sensitive to cooling in the presence of agonist for the receptor.
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PMID:Cooling sensitive [Ca2+]i response associated with signaling of G protein-coupled receptors. 970 96

The antiallergic drugs astemizole and norastemizole inhibit exocytosis in mast cells, which might be relevant for their therapeutic action. From previous studies, it appeared that the drugs inhibited 45Ca2+ influx. Here, we present a more detailed study on the effects of astemizole and norastemizole on Ca2+ fluxes. Fura-2-loaded rat basophilic leukemia (RBL-2H3) cells were activated through the high-affinity receptor for IgE (FcepsilonRI) with antigen or by the endoplasmatic reticulum ATPase inhibitor thapsigargin, bypassing direct FcepsilonRI-related events. It appeared that astemizole (>15 microM), in contrast to norastemizole, showed a dual effect on intracellular calcium concentration ([Ca2+]i): a rise in intracellular calcium concentration was induced, which originated in the release of intracellular Ca2+ stores, whereas Ca2+ influx via store-operated Ca2+ (SOC) channels was inhibited. Ca2+ influx was further characterized using Ba2+ influx, whereas processes in the absence of Ca2+ influx were studied using Ni2+ or EGTA. It was concluded that the drugs most likely affect the store-operated Ca2+ channels in RBL cells directly. The two effects of astemizole on Ca2+ fluxes had opposing influences on exocytosis, thereby accounting for the biphasic effect of increasing astemizole concentration on mediator release in RBL cells.
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PMID:Dual effect of the anti-allergic astemizole on Ca2+ fluxes in rat basophilic leukemia (RBL-2H3) cells: release of Ca2+ from intracellular stores and inhibition of Ca2+ release-activated Ca2+ influx. 971 81

Multidrug resistance (MDR), caused by overexpression of either P-glycoprotein or the multidrug resistance-associated protein (MRP), is characterized by a decreased cellular drug accumulation due to an enhanced drug efflux. Many studies on cells overexpressing MRP and/or Pgp, have shown a concentration of the drug inside cytoplasmic acidic vesicles followed by an exocytotic process. In this study, we examined the effects of 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole or NBD (a H+-ATPase pump inhibitor), buthionine sulphoximine or BSO (an inhibitor of glutathione (GSH) biosynthesis) and verapamil or VPL (a calcium channel blocker) on the subcellular distribution of daunorubicin or DNR in K562 cells overexpressing MRP (K-H30) and Pgp (K-H300) and A549 cells overexpressing spontaneously MRP. Nucleo-cytoplasmic distribution of DNR was carried out using scanning confocal microspectrofluorometry. This technique allows determination of nuclear accumulation of anthracyclines. Our results show that nuclear accumulation of DNR in K-H30 and A549 cells was increased by NBD, BSO and VPL while in K-H300 cells, only VPL was able to increase nuclear accumulation of DNR. Similarly, NBD, BSO and VPL could reverse DNR resistance in K-H30 cells whereas, in K-H300 cells, only VPL increased the sensitivity of these cells. These data suggest a requirement for GSH in MRP-mediated resistance and suggest that even if vesicular sequestration can happen in cells overexpressing MRP and Pgp proteins, probably only the MRP protein is able to extrude the drug through intracellular vesicles and efflux. Finally, NBD and BSO might be a useful agents in facilitating discrimination between Pgp and MRP phenotypes and prognosis in patients.
Leukemia 1998 Oct
PMID:Characterization of H+-ATPase-dependent activity of multidrug resistance-associated protein in homoharringtonine-resistant human leukemic K562 cells. 976 97

The previously uncharacterized CDC24 homology domain of BCR, which is missing in the P185 BCR-ABL oncogene of Philadelphia chromosome (Ph1)-positive acute lymphocytic leukemia but is retained in P210 BCR-ABL of chronic myelogeneous leukemia, was found to bind to the xeroderma pigmentosum group B protein (XPB). The binding appeared to be required for XPB to be tyrosine-phosphorylated by BCR-ABL. The interaction not only reduced both the ATPase and the helicase activities of XPB purified in the baculovirus system but also impaired XPB-mediated cross-complementation of the repair deficiency in rodent UV-sensitive mutants of group 3. The persistent dysfunction of XPB may in part underlie genomic instability in blastic crisis.
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PMID:The BCR-ABL oncoprotein potentially interacts with the xeroderma pigmentosum group B protein. 987 96


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