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)

A basis set of polyamine analogues was designed and synthesized. These compounds were used to initiate a systematic investigation of the role of chain length, terminal nitrogen alkyl group size, and symmetry of the methylene backbone in the antineoplastic properties of polyamine analogues. New synthetic methods predicated on our earlier polyamine fragment synthesis are described for accessing the tetraamines of interest. An unsymmetrically substituted diamine reagent, N-(tert-butoxycarbonyl)-N,N'-bis(mesitylenesulfonyl)-1,4-diaminobu tane, was developed for entry into unsymmetrical tetraamines. All of the tetraamines synthesized were first evaluated in a murine leukemia L1210 cell IC50 assay at 48 and 96 h. In an attempt to correlate this behavior with some aspect of polyamine metabolism, each compound was tested for its ability to compete with spermidine for the polyamine uptake apparatus, its impact on the polyamine biosynthetic enzymes ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (AdoMetDC), and its effect on the polyamine-catabolizing enzyme spermidine/spermine N1-acetyltransferase (SSAT) and on polyamine pools. While there was no obvious correlation between the 48 and 96 h IC50's and the impact of the analogues on polyamine metabolism, there were other structure-activity relationships. Correlations were observed to exist between chain length and IC50's and between terminal alkyl substituents and impact on Ki, ODC, and AdoMetDC. Also, preliminary studies suggest a relationship may exist between the 48 and 96 h IC50 activities and the analogue's chronic toxicity in vivo. Finally, when the overall length of the polyamine backbone was held constant, the symmetry of the methylene chains of the polyamine fragments was shown to be unimportant to the compound's activity.
 ...
PMID:Antiproliferative properties of polyamine analogues: a structure-activity study. 793 75

To determine whether non-metabolizable derivatives of spermidine and spermine exert anticancer effects, L1210 leukemic mice were treated with 5,8-dimethylspermidine and 5,8-dimethylspermine. Both derivatives cured 5% of the leukemic mice. The increase in median survival time, however, was slight. In combination with alpha-difluoromethylornithine (DFMO), an ornithine decarboxylase inhibitor, only 5,8-dimethylspermine had a favorable effect. Treatment with DFMO is known to increase the uptake of extracellular polyamines and presumably their derivatives, by depleting the intracellular putrescine and spermidine content. However, treatment of L1210 leukemia cells in vitro with DFMO did not affect the uptake of the methyl-substituted polyamines added to the growth medium. 5,8-Dimethylspermidine and 5,8-dimethylspermine repressed the ornithine decarboxylase activity when added to cultures of L1210 leukemia cells. S-Adenosylmethionine decarboxylase activity was only repressed by 5,8-dimethylspermine. This finding may explain the potentiation by this derivative and not by 5,8-dimethylspermidine, of the antileukemic effect of DFMO.
 ...
PMID:Antileukemic effects of non-metabolizable derivatives of spermidine and spermine. 848 91

Polyamines play major roles in ionic and osmotic regulation, but their exact involvement in specific ion transport processes is poorly defined. Treatment of L1210 mouse leukaemia cells with either 5 mM alpha-difluoromethylornithine (DFMO), a suicide substrate of ornithine decarboxylase, or 25 microM N1,N12-bis(ethyl)spermine (BE-3-4-3), a dysfunctional polyamine analogue, caused a stable decreased in intracellular pH (pHi) by 0.1-0.4 unit from steady-state control values between 7.4 and 7.6, as measured either by partition of a weak acid or with a fluorescent pH-sensitive probe. This effect was not related to cell growth status or differences in metabolic acid generation, and was observed in either the presence or absence of HCO3-. Exogenous spermidine (10-25 microM) or putrescine (25-50 microM) fully reversed DFMO- or BE-3-4-3-induced acidification within 2 and 8 h respectively. Recovery of pHi in L1210 cells after a nigericin- or NH4(+)-mediated acid load in HCO3(-)-free buffers was mediated by Na+/H+ antiporter activity, in addition to a minor Na(+)-independent and amiloride-insensitive pathway. Decreased steady-state pHi was maintained in polyamine-depleted L1210 cells after recovery from acid stress. Moreover, the pHi-dependence of the rate of Na(+)-dependent H+ extrusion after an acid stress was altered by DFMO and BE-3-4-3, resulting in a set-point which was lower by 0.25-0.30 pH unit in polyamine-depleted cells. On the other hand, neither the rate nor the magnitude of Na+/H(+)-exchanger-mediated alkalinization induced by hypertonic shock was decreased by polyamine depletion. Thus polyamine depletion induces a persistent defect in pHi homeostasis which is due, at least in part, to a stable decrease in the pHi set-point of the Na+/H+ exchanger.
 ...
PMID:Stable intracellular acidification upon polyamine depletion induced by alpha-difluoromethylornithine or N1,N12-bis(ethyl)spermine in L1210 leukaemia cells. 855 15

Polyamines have been shown to participate in the rectification of cloned inwardly rectifying potassium channels, a class of potassium channel proteins that conducts inward current more readily than outward current. Here, basophil leukemia cells were used to determine the effects of polyamines on a native, inwardly rectifying potassium current. Rat basophil leukemia cells were cultured in the presence of two different polyamine biosynthesis inhibitors, and both the electrophysiological properties and the polyamine levels were monitored. Treatment with alpha-difluoromethylornithine, a specific ornithine decarboxylase inhibitor, resulted in no significant change of electrophysiological properties. In contrast, treatment with 5'-[(Z)-4-amino-2-butenyl]- methyl-amino-5'-deoxyadenosine (MDL73811), an inhibitor of S-adenosylmethionine decarboxylase, resulted in increased outward currents through inwardly rectifying potassium channels while intracellular putrescine was markedly increased and spermidine and spermine levels were decreased. Fluctuations of intracellular polyamine concentrations as imposed by MDL73811 were directly translated in an altered cell excitability. Based on these results we conclude that the rectification properties of native inwardly rectifying potassium channels are largely controlled by intracellular spermine.
 ...
PMID:Regulation by spermine of native inward rectifier K+ channels in RBL-1 cells. 862 98

In difluoromethylornithine-resistant L1210 cells stimulated to grow from quiescence, haloperidol caused an early and dose-dependent inhibition of the induction of ornithine decarboxylase (ODC) activity, with an IC50 of 3.5 microM. This effect was accompanied by a reduction in the ODC mRNA level and inhibition of cell growth. Other sigma ligands of different chemical classes inhibited the induction of ODC activity, whereas sulpiride, a dopamine antagonist devoid of sigma-binding affinity, was ineffective. These results indicate that the inhibition of ODC expression may be an early event involved in the antiproliferative response of leukemia cells to haloperidol.
 ...
PMID:Inhibition of the expression of ornithine decarboxylase by haloperidol in difluoromethylornithine-resistant leukemia cells. 893 49

Mammalian S-adenosylmethionine decarboxylase (AdoMetDC) catalyses a regulatory important step in the biosynthesis of polyamines and is a potential target for therapeutic agents against various parasitic diseases and proliferative disorders. In the present study we examined the effects of a newly synthesized AdoMetDC inhibitor. 4-amidinoindan-1-one 2'-amidinohydrazone (CGP 48664), on polyamine metabolism in the mouse leukaemia cell line L1210. Treatment of the cells with 2 microM CGP 48664 led to a depletion of cellular spermidine and spermine. The putrescine content, in contrast, was markedly increased. Cells seeded in the presence of the inhibitor showed a significant decrease in growth rate, which was fully reversed by the addition of 2 microM spermidine or 1 microM spermine. The syntheses of ornithine decarboxylase and AdoMetDC were greatly increased in cells treated with CGP 48664. These increases were not correlated with similar changes in the mRNA levels, indicating the involvement of a translational mechanism. CGP 48664 was demonstrated to be a very poor competitor of spermidine uptake in the L1210 cells. L1210 cells deficient in polyamine transport were as sensitive to the antiproliferative effect of the inhibitor as were the parental cells, indicating that CGP 48664 did not enter the cells by the polyamine transport system. In addition to inhibiting AdoMetDC, CGP 48664 stabilized the enzyme against degradation. In the present study we also demonstrated that aminoguanidine (AMG), which is frequently used in cellular systems to inhibit any action of serum polyamine oxidase, apparently inhibits AdoMetDC by an irreversible mechanism that markedly stabilizes the enzyme against proteolytic degradation. CGP 48664 and the parental compound methylglyoxal bis(guanylhydrazone), which is also a potent inhibitor of AdoMetDC, contain one or two AMG-like moieties; the importance of these residues in the inhibition of AdoMetDC is discussed.
 ...
PMID:CGP 48664, a potent and specific S-adenosylmethionine decarboxylase inhibitor: effects on regulation and stability of the enzyme. 907 76

Ceramide has emerged as a novel lipid mediator in cell growth and apoptosis. In difluoromethylornithine-resistant L1210 cells stimulated to growth from quiescence, the cell-permeant analogues of ceramide N-acetylsphingosine (C2-ceramide) and N-hexanoylsphingosine (C6-ceramide) inhibited the induction of ornithine decarboxylase (ODC) activity with IC50 of 8.3 and 1.5 microM respectively. This effect was strictly related to the ability to inhibit cell growth and [3H]thymidine incorporation. The suppression of cell growth was also associated with apoptosis. The addition of bacterial sphingomyelinase resulted in a significant, but limited, reduction of ODC induction and [3H]thymidine incorporation. Bacterial lipopolysaccharide, which may act as a ceramide analogue, also inhibited the induction of the enzyme. Moreover, C6-ceramide largely prevented the accumulation of ODC mRNA and its precursor, ODC heterogeneous nuclear RNA, that accompanied the induction of ODC activity. A slight increase in ODC turnover was also observed. The DNA-binding activity of some transcription factors known to bind and transactivate the ODC gene was investigated by gel mobility-shift assay under the same experimental conditions. However, only the binding of Myc/Max was negatively affected by the treatment with C6-ceramide. Furthermore, the amount of immunoreactive c-Myc, which increased after stimulation of the cells to growth, was strongly reduced by C6-ceramide. These results suggest that the inhibition of c-Myc and ODC expression may be early events in the response of leukaemia cells to ceramide.
 ...
PMID:Inhibition of the expression of ornithine decarboxylase and c-Myc by cell-permeant ceramide in difluoromethylornithine-resistant leukaemia cells. 921 Apr 1

The degradation of ornithine decarboxylase (ODC) is mediated by antizyme, a protein regulated by the end-products of ODC activity, the polyamines. High levels of polyamines induce a +1 ribosomal frameshift in the translation of the rat antizyme message leading to the expression of a full-length protein. We have studied whether the regulation of antizyme expression occurs only at the level of translation or whether polyamine levels also affect the transcription of the antizyme gene. Thus, we have cloned and sequenced the mouse homologues of the rat ODC-antizyme gene and cDNA. Northern blot analysis shows that although high concentrations of polyamines do not affect the steady-state levels of antizyme message in L1210 leukemia cells, polyamine depletion using 2-(difluoromethyl)ornithine [Orn(F2Me)] leads to a marked decrease in mRNA levels. Results of transient transfections of luciferase-reporter-gene constructs driven by antizyme promoter fragments in untreated and Orn(F2Me)-treated Balb/C 3T3 cells indicate that the transcription of the antizyme gene is altered upon polyamine depletion. The amount of antizyme protein on Western blots was also altered by polyamine depletion and addition, and the polysomal distribution of antizyme message suggests a general translational increase of the message when polyamine concentrations are high. These results indicate a role for polyamines in the transcriptional and translational regulation of ornithine decarboxylase antizyme.
 ...
PMID:Polyamines regulate both transcription and translation of the gene encoding ornithine decarboxylase antizyme in mouse. 942 68

Starting with an extract derived from the stem of Macleaya cordata (Papaveraceae) that was active in the process of inhibiting phorbol 12,13-dibutyrate binding to partially purified protein kinase C (PKC), the benzophenanthridine alkaloid angoline was isolated and identified. This discovery appeared in context, as a related benzophenanthridine alkaloid, chelerythrine, has been reported to mediate a variety of biological activities, including potent and selective inhibition of protein kinase C (PKC). However, in our studies, angoline was not observed to function as a potent inhibitor of PKC. Moreover, we were unable to confirm the reported inhibitory activity of chelerythrine. In a comprehensive series of studies performed with various PKC isozymes derived from a variety of mammalian species, neither chelerythrine nor angoline inhibited activity with high potency. To the contrary, chelerythrine stimulated PKC activity in the cytosolic fractions of rat and mouse brain in concentrations up to 100 microM. In addition, chelerythrine and angoline did not inhibit [3H]phorbol 12,13-dibutyrate binding to the regulatory domain of PKC at concentrations up to 40 microg/ml, and no significant alteration of PKC-alpha, -beta, or -gamma translocation was observed with human leukemia (HL-60) cells in culture. Further, chelerythrine did not inhibit 12-O-tetradecanoylphorbol 13-acetate-induced ornithine decarboxylase activity with cultured mouse 308 cells, but angoline was active in this capacity with an IC50 value of 1.0 microg/ml. A relatively large number of biological responses have been reported in studies conducted with chelerythrine, and alteration of PKC activity has been considered as a potential mechanism of action. In light of the current report, mechanisms independent of PKC inhibition should be considered as responsible for these effects.
 ...
PMID:Angoline and chelerythrine, benzophenanthridine alkaloids that do not inhibit protein kinase C. 967 17

Polyamine oxidase functions in the polyamine catabolic pathway, converting N1-acetyl-spermidine and -spermine into putrescine (Put) and spermidine (Spd), respectively, thereby facilitating homeostasis of intracellular polyamine pools. Inhibition of polyamine oxidase in hematopoietic cells by a specific inhibitor, N,N'-bis(2,3-butadienyl)-1,4-butanediamine (MDL-72,527), reduces the levels of Put and Spd and induces the accumulation of N1-acetylated Spd. Although previously thought to be relatively nontoxic, we now report that this inhibitor overrides survival factors to induce cell death of several immortal and malignant murine and human hematopoietic cells, but not of primary myeloid progenitors. Cells treated with MDL-72,527 displayed biochemical changes typical of apoptosis, and cell death was associated with the down-regulation of the antiapoptotic protein Bcl-X(L). However, enforced overexpression of Bcl-X(L), or treatment with the universal caspase inhibitor zVAD-fmk, failed to block MDL-72,527-induced apoptosis in these hematopoietic cells. Despite decreases in Put and Spd pools, MDL-72,527-induced apoptosis was not blocked by cotreatment with exogenous Put or Spd, nor was it influenced by overexpression or inhibition of the polyamine biosynthetic enzyme ornithine decarboxylase. Significantly, MDL-72,527-induced apoptosis was associated with the rapid formation of numerous lysosomally derived vacuoles. Malignant leukemia cells were variably sensitive to the lysosomotropic effects of MDL-72,527, yet pretreatment with the ornithine decarboxylase inhibitor L-alpha-difluoromethylornithine sensitized all of these leukemia cells to the deleterious effects of the inhibitor by stimulating its intracellular accumulation. The lysosomotropic nature of select polyamine analogues may, thus, provide a novel chemotherapeutic strategy to selectively induce apoptosis of malignant hematopoietic cells.
 ...
PMID:The polyamine oxidase inhibitor MDL-72,527 selectively induces apoptosis of transformed hematopoietic cells through lysosomotropic effects. 1051 8


<< Previous 1 2 3 4 5 6 7 8 9 Next >>