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)

The in vitro cytotoxicity of 6 amino-5 formylmethylamino-1,3 dimethyluracil (ADMU) a major metabolite of caffeine in rats was studied by cell counts or [3H]thymidine incorporation in the murine Lewis lung carcinoma (3LL) and L929 fibroblast cells and in the human E cell line derived from an ovarian carcinoma. Unlike 5-fluorouracil (5FU) which was markedly cytotoxic, ADMU concentrations up to 60 micrograms/ml were devoid appreciable cytocidal action. Similarly, 1-10 micrograms 5FU markedly inhibited the blastogenic response of rat lymphocytes to PHA, whereas lymphoproliferation was not affected at ADMU concentrations up to 100 micrograms/ml. In vivo administration of ADMU (40 mg/kg, twice a day on day 1 to 3) to L1210 leukaemia-bearing mice caused a transient short-lasting reduction of tumour cell numbers only on day 6 after leukaemia inoculation.U
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PMID:In vitro and in vivo cytotoxicity of 6 amino-5-formyl-methylamino-1,3-dimethyl uracil, a uracilic metabolite of caffeine. 708 Jan 2

The action of two structurally related DNA intercalating agents has been studied and compared, namely 4'-(9-acridinylamino) methanesulphon-m-anisidide (amsacrine, mAMSA) and 1,4-bis(butylamino)benzo[g]phthalazine (ABP) on the cell cycle and differentiation of U-937 human promonocytic leukemia cells. mAMSA (0.1 microM) and ABP (4 microM) reduced the proliferation activity to a similar extent and caused little cell mortality. At these subcytotoxic concentrations mAMSA induced the cells to accumulate at the G2 phase of the cycle, while cycle inhibition provoked by ABP was not phase specific. In addition, mAMSA caused an increase in the cell mass while ABP provoked cell shrinkage. This was consistent with the fact that ABP considerably inhibited protein synthesis, while mAMSA did not significantly affect this activity. SDS/K+DNA precipitation assays indicated that mAMSA, but not ABP, stimulated protein-DNA covalent complex formation. Finally, it was found that mAMSA, but not ABP, elicited the expression of differentiation markers, namely nitroblue tetrazolium reduction, activation of vimentin and leukocyte integrin (CD11b/CD18 and CD11c/CD18) expression, and downregulation of c-myc expression. The DNA intercalators doxorubicin and mitoxantrone, which like mAMSA induced the cells to accumulate at the G2 phase and increased the cell mass, induced the expression of differentiation markers. In contrast, the intercalators aclarubicin and caffeine and the non-intercalator novobiocin, which produced minor alterations on cell-cycle distribution and caused cell shrinkage, did not significantly elicit differentiation. These results support the conclusion that differentiation of myeloid leukemia cells by cytostatic drugs depends on the perturbations of the cell cycle, leading to disproportionate increases in cell mass.
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PMID:The action of the DNA intercalating agents 4'-(9-acridinylamino) methanesulphon-m-anisidide and 1,4-bis(butylamino) benzo[g]phthalazine in U-937 human promonocytic cells: relationship between cell cycle and differentiation. 751 13

Antigenic stimulation of rat basophilic leukemia cells releases Ca2+ from internal stores and increases membrane permeability to Ca2+. The delta isomer of hexachlorocyclohexane (delta-HCH) is structurally similar to myo-inositol-1,4,5-trisphosphate (IP3) and is a potent releaser of stored Ca2+ from permeabilized cells. This release of Ca2+ is not mediated by a competitive interaction with the IP3 receptor on the Ca2+ release channel on the endoplasmic reticulum. In intact cells, delta-HCH and, to a lesser extent, lindane (gamma-hexachlorocyclohexane) transiently increase the intracellular Ca2+ concentration. The return to basal concentrations is mediated by the plasma membrane Ca2+ pumps and not by resequestration of Ca2+ into intracellular stores. Treatment of cells with delta-HCH (25-100 microM), but not lindane, leads to a progressive inhibition of the antigen- and thapsigargin-stimulated Ca2+ signal. Caffeine, a modulator of the ryanodine receptor Ca2+ channel, attenuates the rise in intracellular Ca2+ induced by delta-HCH, suggesting that ryanodine receptor-like Ca2+ channels may be present in RBL cells. At 25 microM delta-HCH, a concentration that does not inhibit the antigen-stimulated Ca2+ signal, the release of [3H]serotonin from antigen-stimulated cells is enhanced as is secretion of [3H]serotonin from cells pretreated with 25-100 microM lindane. The depletion of Ca2+ from intracellular stores by delta-HCH should evoke Ca2+ entry into the cells by a capacitative mechanism; however; divalent cation permeability across the plasma membrane (Mn2+ influx) is not increased but rather is decreased by delta-HCH. An understanding of the mechanism of action of delta-HCH in releasing stored Ca2+ and blocking Ca2+ influx across the plasma membrane may provide insights into the regulation of capacitative Ca2+ entry in nonexcitable cells.
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PMID:The delta isomer of hexachlorocyclohexane induces rapid release of the myo-inositol-1,4,5-trisphosphate-sensitive Ca2+ store and blocks capacitative Ca2+ entry in rat basophilic leukemia cells. 756 33

Pulse treatments of U-937 human promonocytic leukemia cells with the DNA topoisomerase-II inhibitors 4'-(9-acridynilamino)methanesulfon-m-anisidide (amsacrine, mAMSA) or etoposide (VP-16) caused growth inhibition, G2-arrest, increase in cell size and expression of differentiation markers. All these effects were greatly reduced by the presence of 5-10 mM caffeine. In addition, caffeine partially prevented the increase in the number of topoisomerase-DNA cleavable complexes caused by the topoisomerase inhibitors, as determined by SDS/CIK precipitation assays; it caused chromatin condensation, as determined by flow cytometry assays, and interacted with mAMSA in solution, as suggested by spectrophotometric assays. Pulse treatment with caffeine greatly inhibited RNA synthesis but not DNA or protein synthesis, as indicated by labelled precursor incorporation assays. The transcription inhibitor 5,6-dichloro-I-beta-D-ribofuranosylbenzymidazole reduced the mAMSA- and VP-16-produced growth inhibition in a similar manner. It is concluded that RNA synthesis inhibition is one of the possible mechanisms by which caffeine protects cells from the action of topoisomerase-II inhibitors.
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PMID:Caffeine attenuates the action of amsacrine and etoposide in U-937 cells by mechanisms which involve inhibition of RNA synthesis. 820 82

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

Caffeine is known to potentiate the cytotoxic effects of DNA damaging agents and increases the sensitivity of p53-deficient cells to X-irradiation (X-IR). We have analyzed the cell cycle and cell death control after X-IR in the absence or presence of caffeine in hematological cell lines with various configurations of the p53 gene; EBV-immortalized lymphoblastoid cells with heterozygous p53 mutation (wt/mt), human leukemia cell lines HL60 and KOPM28 with no and mutant p53 expression, respectively. These cell lines display an impaired G0/G1 checkpoint and G2 delay following X-IR, and resistance to apoptosis, which are in accordance with findings previously reported. When irradiated in combination with caffeine, all these cell lines overrode the G2 delay and accumulated at G0/G1. The cell cycle modifications in these cell lines correlated with the increase in radiation-induced p34Cdc2 kinase activity by caffeine. These cell cycle control modifications by caffeine, however, were not associated with enhancement of radiation-induced apoptosis or reduction of clonogenic growth activity in these cell lines. These results suggest that the cytocidal effect of caffeine may need to be verified independently of its cell cycle regulatory activities at least in some cases with p53 mutation.
Leukemia 1999 Jan
PMID:DNA damage-associated cell cycle and cell death control is differentially modulated by caffeine in clones with p53 mutations. 1004 63

Cells of the TP53-deficient human leukemia cell line HL60 continue to progress throughout the cell cycle and arrest in the G2/M phase during protracted exposure to exponentially decreasing low-dose-rate radiation. We have hypothesized that G2/M-phase arrest contributes to the extent of radiation-induced cell death by apoptosis as well as to overall cell killing. To test this hypothesis, we used caffeine and nocodazole to alter the duration of G2/M-phase arrest of HL60 cells exposed to exponentially decreasing low-dose-rate irradiation and measured the activity of G2/M-phase checkpoint proteins, redistribution of cells in the phases of the cell cycle, cell death by apoptosis, and overall survival after irradiation. The results from these experiments demonstrate that concomitant exposure of HL60 cells to caffeine (2 mM) during irradiation inhibited radiation-induced tyrosine 15 phosphorylation of the G2/M-phase transition checkpoint protein CDC2/p34 kinase and reduced G2/M-phase arrest by 40-46% compared to cells irradiated without caffeine. Radiation-induced apoptosis also decreased by 36-50% in cells treated with caffeine and radiation compared to cells treated with radiation alone. Radiation survival was significantly increased by exposure to caffeine. In contrast, prolongation of G2/M-phase arrest by pre-incubation with nocodazole enhanced radiation-induced apoptosis and overall radiation-induced cell killing. To further study the role of cell death by apoptosis in the response to exponentially decreasing low-dose-rate irradiation, HL60 cells were transfected with the BCL2 proto-oncogene. The extent of G2/M-phase arrest was similar for parental, neomycin-transfected control and BCL2-transfected cells during and after exponentially decreasing low-dose-rate irradiation. However, there were significant differences (P < 0.01) in the extent of radiation-induced apoptosis of parental and neomycin- and BCL2-transfected cells after irradiation, with significantly less radiation-induced apoptosis and higher overall survival in BCL2-transfected cells than similarly irradiated control cells. These data demonstrate that radiation-induced G2/M-phase arrest and subsequent induction of apoptosis play an important role in the response of HL60 cells to low-dose-rate irradiation and suggest that it may be possible to increase radiation-induced apoptosis by altering the extent of G2/M-phase arrest. These findings are clinically relevant and suggest a novel therapeutic strategy for increasing the efficacy of brachytherapy and radioimmunotherapy.
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PMID:G2/M-phase arrest and death by apoptosis of HL60 cells irradiated with exponentially decreasing low-dose-rate gamma radiation. 1036 Jul 85

Considering of novel biochemical modulation by some foods and beverages, we have performed screening for green tea components that have enhancing effects on doxorubicin (DOX) induced antitumor activity. Components, such as caffeine, theanine, (-)-epigallocatechin gallate (EGCG) and flavonoids have inhibitory effects on the DOX efflux from Ehrlich ascites carcinoma cells. Thus, it is suggested that EGCG and flavonoids may enhance DOX induced antitumor activity and increase the DOX concentrations in tumors through the inhibition of DOX efflux. It is expected that these components in green tea exhibit low toxicity and that there are few side effects of drinking green tea in combination with an antitumor agent. We think that the intake of a favorite beverage favors a positive mental attitude of a patient and increases the efficacy of the chemotherapeutic index, and that this efficacy is useful for improving the quality of life on cancer chemotherapy. In DOX resistant P388 leukemia cell bearing mice theanine increased the DOX induced efficacy through an increase in the DOX concentrations in the tumors. Theanine attacked the same transport process for DOX in both types of cells, elevated the DOX concentration and increased the DOX induced antitumor activity.
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PMID:Efficacies of tea components on doxorubicin induced antitumor activity and reversal of multidrug resistance. 1071 80

Interactions between the checkpoint abrogator UCN-01 and several pharmacological inhibitors of the mitogen-activated protein kinase (MAPK) kinase (MEK)/MAPK pathway have been examined in a variety of human leukemia cell lines. Exposure of U937 monocytic leukemia cells to a marginally toxic concentration of UCN-01 (e.g., 150 nM) for 18 h resulted in phosphorylation/activation of p42/44 MAPK. Coadministration of the MEK inhibitor PD184352 (10 microM) blocked UCN-01-induced MAPK activation and was accompanied by marked mitochondrial damage (e.g., cytochrome c release and loss of DeltaPsi(m)), caspase activation, DNA fragmentation, and apoptosis. Similar interactions were noted in the case of other MEK inhibitors (e.g., PD98059; U0126) as well as in multiple other leukemia cell types (e.g., HL-60, Jurkat, CCRF-CEM, and Raji). Coadministration of PD184352 and UCN-01 resulted in reduced binding of the cdc25C phosphatase to 14-3-3 proteins, enhanced dephosphorylation/activation of p34(cdc2), and diminished phosphorylation of cyclic AMP-responsive element binding protein. The ability of UCN-01, when combined with PD184352, to antagonize cdc25C/14-3-3 protein binding, promote dephosphorylation of p34(cdc2), and potentiate apoptosis was mimicked by the ataxia telangectasia mutation inhibitor caffeine. In contrast, cotreatment of cells with UCN-01 and PD184352 did not substantially increase c-Jun-NH(2)-terminal kinase activation nor did it alter expression of Bcl-2, Bcl-x(L), Bax, or X-inhibitor of apoptosis. However, coexposure of U937 cells to UCN-01 and PD184352 induced a marked increase in p38 MAPK activation. Moreover, SB203580, which inhibits multiple kinases including p38 MAPK, partially antagonized cell death. Lastly, although UCN-01 +/- PD184352 did not induce p21(CIP1), stable expression of a p21(CIP1) antisense construct significantly increased susceptibility to this drug combination. Together, these findings indicate that exposure of leukemic cells to UCN-01 leads to activation of the MAPK cascade and that interruption of this process by MEK inhibition triggers perturbations in several signaling and cell cycle regulatory pathways that culminate in mitochondrial injury, caspase activation, and apoptosis. They also raise the possibility that disrupting multiple signaling pathways, e.g., by combining UCN-01 with MEK inhibitors, may represent a novel antileukemic strategy.
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PMID:Pharmacological inhibitors of the mitogen-activated protein kinase (MAPK) kinase/MAPK cascade interact synergistically with UCN-01 to induce mitochondrial dysfunction and apoptosis in human leukemia cells. 1143 48

Nitracrine (Ledakrin) is an antitumor drug which is activated by cellular enzymes and binds covalently to DNA. Previous studies have shown that covalent binding and crosslinking of DNA is associated with the cytotoxic and antitumor activities of this compound. In this study, cell cycle perturbations, effects on DNA synthesis and the cell death process initiated by Nitracrine were studied in murine leukemia L1210 cells. We show that exposure of L1210 cells to Nitracrine at the IC(99) concentration delayed progression through the S phase and transiently arrested cells in G(2)/M as found by flow cytometry. Higher drug concentration (2 x IC(99)) inhibited cell cycle progression in the S phase and induced rapid cell death. Both studied concentrations of the drug produced different effects on DNA synthesis as determined by bromodeoxyuridine incorporation, with a delay in the S phase progression at EC(99) concentration and irreversible arrest in early S phase at the higher dose (2 x IC(99)). At both concentrations of Nitracrine cell death occurred preferentially in the S phase as revealed by the TUNEL assay. When cells treated with the drug for 4 hours were post-incubated in the presence of 1 mM caffeine this led to rapid cell death and suppression of the G(2) arrest. This was associated with a about 10-fold increase in the cytotoxicity of Nitracrine. Similar effects were observed for another DNA crosslinking agent, cis-platinum, and to a lesser extent, for DNA topoisomerase I inhibitor, camptothecin. Together, our studies show that suppression of G(2) arrest induced by Nitracrine greatly enhances its cytotoxicity toward L1210 cells.
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PMID:Modulation of G(2) arrest enhances cell death induced by the antitumor 1-nitroacridine derivative, Nitracrine. 1210 94


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