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

To date no hematopoietic progenitors of dendritic Langerhans' cells (DLC), which represent an highly efficient class of antigen presenting cells, have been identified or the cytokines they elaborate have been defined. Here we describe an acute leukemia patient whose blasts (90-96% in peripheral blood and bone marrow) had a phenotype consistent with putative progenitors of DLC. The patient was treated with ara-C and VP-16 but did not achieve remission. The blasts had lobulated nuclei, no cytoplasmic vacuolation or Auer rods and were weakly positive for acid phosphatase and non-specific esterase and negative for PAS, granzyme A, dipeptidyl aminopeptidase IV, ATPase/ADPase and lysozyme production. The blasts were positive for CD1a, CD4, CD16, CD35, HLADR, HLADQ, CD11b, CD11c, CD14, CD33, CD34, CD11a, CD71, CD19, CD25, IL-2R beta and negative for CD2, CD7, CD8, CD10, CD22, CD56, CD57, surface or cytoplasmic CD3, TCR delta and TCR beta, HTLV-1p19 and P-glycoprotein. On liquid culture with or without 5 x 10(-9) M 12-O-tetradecanoylphorbol-13-acetate (TPA) for 3 days, the blasts formed aggregates of proliferating and elongating cells on the wall of the flasks with a decline in CD34, numerous dendritic processes appeared on the cells and there was strong positivity for ATPase/ADPase, but no other changes in phenotype. No macrophages were observed, indicating derivation from separate DLCs. Cytogenetic analysis showed chromosomal abnormalities and electron microscopy showed Birbeck granules. Southern blotting of DNA showed rearrangement of one allele for both JH and TCR beta but no HTLV-1 related sequences. Culture supernatants from blasts cultured with or without TPA showed the production of large amounts of IL-8, IL-6, TNF-alpha, MIP-1 alpha, IL-10 and interferon gamma and modest amounts of IL-1 alpha, GM-CSF and stem cell factor. The presence not only of CD1a, HLADR, HLADQ and many other characteristics including Birbeck granules, but also differentiation along the lines of DLC with appearance of dendritic processes on the cells and expression of ATPase/ADPase activity, indicate that the leukemic blasts in our patient represented a leukemic counterpart of normal progenitors of DLC and the leukemia a new entity which could possibly be classified as AML-M8. Lastly, many pro-inflammatory cytokines produced by DLC could contribute to inflammation and IL-10 to immunosuppression.
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PMID:Phenotype, genotype and cytokine production in acute leukemia involving progenitors of dendritic Langerhans' cells. 791 55

1. We have investigated the effect of 2',5'-di (tert-butyl)-1,4-benzohydroquinone (BHQ) and thapsigargin, inhibitors of the intracellular Ca(2+)-ATPase, on ionic currents in rat basophilic leukaemia (RBL-2H3) cells under whole cell voltage clamp. 2. The whole cell current was inwardly rectifying and reversed at -35 +/- 6 mV (n = 16). The conductance of the inward current increased as the concentration of extracellular K+ was raised from 2.7 to 5.4, 10.8 and 21.6 mM. BaCl2 (100 microM) reduced the current to a small linear component and shifted the reversal potential to -4 +/- 3 mV (n = 6). A concentration of 50 microM BaCl2 produced 45 +/- 10% (n = 4) blockade of the inward current. 3. BHQ and thapsigargin were examined for their effects on the inwardly rectifying current. A maximal blockade of inward current was obtained within 6 min after perfusion with 10 microM BHQ. The small current remaining after blockade with BHQ had a linear voltage-dependence and reversed direction at -6 +/- 9 mV (n = 6). Thapsigargin (up to 3 microM) was without effect on the inward rectifier. 4. In contrast to the blockade of the inward rectifier produced by BaCl2 which was predominantly on the steady state current, particularly at the very hyperpolarized holding potentials (-120 mV), blockade by BHQ was equally strong on the instantaneous as well as the steady state current. 5. Blockade of the inward rectifier by BHQ may cause depolarization of the cell which will affect Ca2+ influx during investigations with BHQ. Thapsigargin does not block the inward rectifier and will not inhibit Ca2+ influx in this way.
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PMID:Blockade of the inward rectifier potassium current by the Ca(2+)-ATPase inhibitor 2',5'-di(tert-butyl)-1,4-benzohydroquinone (BHQ). 795 72

When irradiated with broad-band visible light in the presence of merocyanine 540 (MC540), murine leukemia L1210 cells grown under selenium-deficient conditions (Se(-) cells) accumulated lipid hydroperoxides and lost viability more rapidly than selenium-satisfied (Se(+) cells). These findings suggest that cytoprotection against photoperoxidation and photokilling is mediated at least in part by selenoperoxidase (SePX) action. Similar protection against photoinactivation of an intrinsic membrane enzyme, the Na+,K(+)-ATPase, has been observed. Thus, irradiation of MC540-sensitized Se(-) cells resulted in an immediate and progressive inactivation of ouabain-sensitive Na+,K(+)-ATPase; by contrast, activity loss in Se(+) cells was preceded by a prominent lag. Enzyme photo-inactivation in Se(-) cells was inhibited by ebselen, an SePX mimetic, confirming that SePX(s) is (are) involved in natural protection. Desferrioxamine treatment (iron sequestration/inactivation) resulted in higher hydroperoxide levels and slower Na+,K(+)-ATPase inactivation during MC540/light exposure, whereas ferric-8-hydroxyquinoline treatment (iron supplementation) had the opposite effect. Thus, iron appears to play an important role in both of these processes. In contrast, photoinactivation of another intrinsic enzyme in L1210 cells, acetylcholinesterase (AChE), was unaffected by selenium or iron manipulation. On the basis of these findings, we propose that lipid peroxidation plays an important role in the photoinactivation of Na+,K(+)-ATPase, but not AChE. This is consistent with the fact that Na+,K(+)-ATPase's active site lies within the membrane bilayer, whereas AChE's active site lies outside the bilayer.
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PMID:Cytoprotection against merocyanine 540-sensitized photoinactivation of the Na+,K(+)-adenosine triphosphatase in leukemia cells: glutathione and selenoperoxidase involvement. 801 11

Human leukemia K562 cell differentiation induction by naturally occurring bufadienolides purified from the Chinese drug Senso and synthetic bufalin derivatives was examined by a nitro blue tetrazolium reduction assay. Bufalin showed the strongest activity among all the bufadienolides tested in this study. The degree of the induction of nitro blue diformazan positive cells by the bufadienolides correlated well with their inhibitory activities against Na+,K(+)-ATPase prepared from K562 cells in vitro. N+,K(+)-ATPases from a variant K562 clone (ouabain resistant, OuaR) and murine leukemia cell line M1-T22, which were insensitive to the bufadienolides in terms of growth inhibition and cell differentiation, appeared to be refractory to bufalin in vitro. A binding study of 3H-bufalin and 3H-ouabain revealed that saturated levels of both ligands associated with K562 cells were virtually similar; however, affinity of 3H-bufalin was considerably higher than 3H-ouabain. The saturated level of 3H-bufalin observed in the OuaR cells was approximately half of that observed in K562 cells without a change in its affinity. Association of 3H-bufalin with K562 cells was completely blocked by pretreatment of the cells with cold ouabain at concentrations saturating the binding sites. These results suggest that bufalin acts on the cells by binding to sites on the cell membrane which also bind ouabain. It is thus proposed that N+,K(+)-ATPase inhibition is closely related to the initiation process in the induction of K562 cell differentiation induced by bufalin.
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PMID:Involvement of Na+,K(+)-ATPase inhibition in K562 cell differentiation induced by bufalin. 802 Dec 91

The alkyl-lysophospholipids are a new family of anticancer drugs which target the cell membrane as their site of action. Enzymes involved in signal transduction (protein kinase C and phosphatidylinositol phospholipase C), phospholipid biosynthesis (lysophosphatidyl acyltransferase and CTP:cholinephosphate cytidylyltransferase) and maintenance of membrane integrity (Na,K ATPase sodium pump) are inhibited. A unique feature of the alkyl-lysophospholipids is their selective cytotoxicity to neoplastic cells. This suggests that the compound would be an excellent agent for purging residual leukemic cells from marrows of patients in remission prior to autologous bone marrow transplantation. Preclinical studies in a murine leukemia model and in an in vitro human system demonstrated successful elimination of leukemic cells from a mixture of normal and leukemic marrows. Twenty-nine poor risk patients with acute leukemia underwent autologous bone marrow transplantation and were reinfused with marrow treated in vitro with edelfosine. Nine of these patients remain in remission free of leukemia from 368 to 1369 days. These encouraging results warrant further investigation.
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PMID:Bone marrow purging in acute leukemia with alkyl-lysophospholipids: a new family of anticancer drugs. 802 24

The human T-cell leukemia/lymphotropic virus type I (HTLV-I) induces T-cell leukemia and transforms human T cells in vitro. A recently identified protein with a molecular weight of 12,000 (12K) (p12I), encoded by single- and double-spliced mRNAs transcribed from the 3' end of the HTLV-I genome, has been shown to localize in the perinuclear compartment and in the cellular endomembranes. The p12I protein exhibits significant amino acid sequence similarity to the E5 oncoprotein of bovine papillomavirus type 1 (BPV-1). Both proteins are very hydrophobic, contain a glutamine residue in the middle of a potential transmembrane region(s), and are localized in similar cellular compartments. Because of these observations, we investigated whether the p12I resemblance to E5 correlated with a similarity in their biological behavior. We expressed the p12I protein to evaluate its ability to functionally cooperate with the BPV-1 E5 oncoprotein and to bind to a cellular target of the E5 protein, the 16K component of the vacuolar H+ ATPase. Cotransfection of the mouse C127 cell line with the p12I and E5 cDNAs showed that although p12I alone could not induce focus formation, it strongly potentiated the transforming activity of E5. In addition, the p12I protein bound to the 16K protein as efficiently as the E5 protein. These findings might provide new insight for potential mechanisms of HTLV-I transformation and suggest that p12I and E5 represent an example of convergent evolution between RNA and DNA viruses.
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PMID:The human T-cell leukemia/lymphotropic virus type I p12I protein cooperates with the E5 oncoprotein of bovine papillomavirus in cell transformation and binds the 16-kilodalton subunit of the vacuolar H+ ATPase. 823 Apr 93

The study was conducted on human leukemia (K 562) cells to characterize the mechanisms implicated in the regulation of the polyamine spermidine (Spd) transport process. The antagonists of calmodulin, trifluoperazine (TFP), W-7 (N-[6-aminohexyl]-5-chloro-1-naphthelenesulfonamide), or mellitin inhibited significantly polyamine Spd uptake in these cells. The translocation of calmodulin towards plasma membrane and a concomitant decrease in its contents in cytosol were directly correlated with the time course increases similar to that of Spd uptake, indicating that calmodulin is recruited towards plasma membrane during the Spd transport process. Diminution of free intracellular calcium, (Ca2+)i, by preincubating the cells in BAPTA (bis[2-amino-5-methylphenoxyl]-ethane-N,N,N',N',-tetraacetate) buffer inhibited Spd transport significantly. Addition of lanthanum (LAN), a molecule known to inhibit Ca2+ efflux via Ca(2+)-ATPase, curtailed Spd uptake by these cells. LAN inhibited Vmax, but not the Km, of Spd uptake, indicating that the former does not directly interact with the polyamine transporter; rather it regulates the transport process, probably via its action on Ca(2+)-ATPase. Calmodulin-stimulated uptake of 45Ca2+ by inside-out vesicles of K 562 cells, a measure of Ca(2+)-ATPase activity. Furthermore, addition of LAN inhibited both basal and calmodulin-stimulated activity of Ca(2+)-ATPase. Thapsigargin (THAP), a molecule known to elevate (Ca2+)i due to its action on the endoplasmic reticulum, increased Spd transport whereas addition of LAN inhibited THAP-stimulated Spd transport activity. THAP increased free (Ca2+)i in these cells, and a pre-addition of LAN to these cells curtailed the THAP-stimulated increases of (Ca2+)i concentrations. Addition of Spd brought about elevations in (Ca2+)i contents. Caffeine also increased (Ca2+)i in these cells; however, it failed to stimulate significantly the Spd uptake process, indicating that (Ca2+)i which is involved in the regulation of polyamine transport pathways does not belong to the calcium-induced calcium-release (CICR) pool. Replacement of Ca2+ from the incubation medium (i.e., 0% Ca2+) resulted in higher uptake activity as compared to that in 100% Ca2+ medium, demonstrating that in 100% Ca2+ medium the calcium efflux process is quickly compensated by calcium refilling/influx from the extracellular medium, while in 0% Ca2+ medium there is perpetual efflux of (Ca2+)i which contributes to higher Spd uptake process. The results of this study suggest that an increase in free (Ca2+)i and its release from the cells via Ca(2+)-ATPase, and concomitant activation of calmodulin, which controls Ca(2+)-pump activity, are involved in the regulation of the Spd uptake process in human leukemia cells.
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PMID:Polyamine transport regulation by calcium and calmodulin: role of Ca(2+)-ATPase. 825 60

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


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