Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.11.18 (MAP)
 7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inhibitors of ornithine decarboxylase (ODC), such as alpha-difluoromethylornithine (DFMO), may influence the cytotoxicity of anti-tumour agents that interact with DNA. Intracellular levels of putrescine and spermidine were markedly reduced by ODC inhibitors while the level of spermine, which is the main polyamine in nuclei, was unchanged. By combining a novel inhibitor of ODC, such as (2R, 5R)-6-heptyne-2,5-diamine (MDL 72.175, MAP), with an inhibitor of S-adenosylmethionine decarboxylase (SAMDC), such as 5'-[[(Z)-4-aminobut-2-enyl]methylamino]-5'-deoxyadenosine (MDL 73.811, AbeAdo), spermine was selectively depleted in a human ovarian cancer cell line OVCAR-3 (i.e. spermine became almost undetectable whereas the levels of spermidine and putrescine were not affected). The depletion of spermine blocked DNA synthesis with a consequent accumulation of cells in the G1 phase of the cell cycle. Pretreatment with MAP plus AbeAdo did not change the cytotoxicity of alkylating agents, such as L-phenylalanine mustard (L-PAM), 1,4-bis(2'-chloroethyl)-1,4-diazabicyclo-[2.2.1] heptane diperchlorate (DABIS), 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), cis-diamminedichloroplatinum (II) (cis-DDP), N-deformyl-N-[4-N-N,N-bis (2-chloroethylamino)benzoyl] (tallimustine) or CC-1065, whereas it markedly reduced the cytotoxicity of DNA topoisomerase II inhibitors, such as doxorubicin (DX) and 4'-demethylepipodophyllotoxin-5-(4,6-O)-ethylidene- beta-D-glycopyranoside (VP-16). The addition of spermine before drug treatment restored the sensitivity to the DNA topoisomerase II inhibitors, thus indicating that the reduced effect was related to the intracellular spermine level. The reason for the reduction in cytotoxicity is unclear, but it does not appear to be related to a cell cycle effect or to a decrease in the intracellular level of DNA topoisomerase II. Drugs that modify polyamine biosynthesis are under early clinical development as potential new anti-tumour agents. These findings illustrate the need for caution in combining such drugs with DNA topoisomerase II inhibitors.
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PMID:Treatment with inhibitors of polyamine biosynthesis, which selectively lower intracellular spermine, does not affect the activity of alkylating agents but antagonizes the cytotoxicity of DNA topoisomerase II inhibitors. 908 39

Reduced glutathione (GSH) is an essential, multifunctional tripepetide that controls redox-sensitive cellular processes, but its regulation in the heart is poorly understood. The present study used a pharmocological model of GSH depletion to examine cellular mechanisms controlling cardiac GSH. Inhibition of GSH metabolism was elicited in normal rats by daily injections of buthionine sulfoximine (BSO), a blocker of gamma-glutamylcysteine synthetase, plus 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU), an inhibitor of glutathione reductase. After 3 d of BSO/BCNU treatment, intracellular [GSH] was measured in isolated-ventricular myocytes by fluorescence microscopy using the probe monochlorobimane. Basal [GSH] in left-ventricular myocytes from BSO/BCNU-treated rats (2.0 +/- 0.05 amol/microm(3), n = 146) was 50% less than control (4.0 +/- 0.13 amol/microm(3), n = 116; P < 0.05). Incubation of myocytes from BSO/BCNU rats with 0.1 microM insulin normalized [GSH] after a delay of 3-4 h (3.6 +/- 0.29 amol/microm(3), n = 66). This effect of insulin was blocked by pre-treating myocytes with cycloheximide. A protein tyrosine phosphatase inhibitor, bis-peroxovanadium-1,10-phenanthroline (bpV(phen), 1 microM), elicited a similar effect as insulin, while neither agent altered [GSH] in myocytes from control rats. Moreover, the effect of insulin and bpV(phen) to up-regulate GSH was blocked by inhibitors of PI 3-kinase (wortmannin, LY294002), MEK (PD98059) and p38 MAP kinases (SB203580). These data suggest that the insulin-signaling cascade regulates [GSH] in ventricular myocytes by a coordinated activation of PI 3-kinase and MAP kinase pathways. These signaling mechanisms may play essential roles in controlling intracellular redox state and normal function of cardiac myocytes.
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PMID:Regulation of glutathione in cardiac myocytes. 1296 37

Electrical remodeling of the diseased heart contributes to contractile dysfunction and arrhythmias, and is characterized by down-regulation of K(+) channels that control action potential morphology. We have recently shown that remodeling of K(+) channels underlying the transient outward current (I(to)) involves a shift in cell redox balance that is reflected by a depletion of the endogenous redox buffer, glutathione (GSH). This study used a pharmacological model to further examine the role of redox-mediated mechanisms in regulating cardiac K(+) currents. Inhibition of major redox pathways was elicited in normal rats by daily injections of 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU), an inhibitor of thioredoxin and glutathione reductases, and buthionine sulfoximine (BSO), a blocker of GSH synthesis. Fluorescence microscopy studies showed that [GSH] in isolated ventricular myocytes was decreased ~50% from control after 3 days of BCNU/BSO treatment (P<0.05), consistent with a shift in cell redox state. In voltage-clamp experiments, maximum I(to) density was decreased 33% from control in left ventricular myocytes from BCNU/BSO-treated rats (P<0.05), while the inward rectifier and steady state outward currents were not significantly altered. Decreased I(to) density correlated with significant decreases in Kv4.2 mRNA and proteins levels of Kv4.2 and Kv1.4. Down-regulation of I(to) in myocytes from BCNU/BSO rats was reversed in vitro by exogenous GSH or N-acetylcysteine, a GSH precursor and antioxidant. I(to) density and [GSH] were also up-regulated by receptor tyrosine kinase activation with insulin or a tyrosine phosphatase inhibitor. The effect of these activators on I(to) was blocked by inhibitors of PI 3-kinase, MEK and p38 MAP kinases. These data suggest that expression of cardiac I(to) channels is regulated by endogenous oxidoreductase systems and that receptor tyrosine kinase signaling functionally impacts K(+) channel remodeling through its control of cell redox state.
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PMID:Redox control of K+ channel remodeling in rat ventricle. 1643 Sep 15