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)

Fatty acid amide hydrolase (FAAH) catalyzes the hydrolysis of bioactive fatty acid amides and esters such as the endogenous cannabinoid receptor ligands, anandamide (N-arachidonoyl-ethanolamine) and 2-arachidonoylglycerol, and the putative sleep inducing factor cis-9-octadecenoamide (oleamide). Most FAAH blockers developed to date also inhibit cytosolic phospholipase A2 (cPLA2) and/or bind to the CB1 cannabinoid receptor subtype. Here we report the finding of four novel FAAH inhibitors, two of which, malhamensilipin A and grenadadiene, were screened out of a series of thirty-two different algal natural products, and two others, arachidonoylethylene glycol (AEG) and arachidonoyl-serotonin (AA-5-HT) were selected out of five artificially functionalized polyunsaturated fatty acids. When using FAAH preparations from mouse neuroblastoma N18TG2 cells and [14C]anandamide as a substrate, the IC50s for these compounds ranged from 12.0 to 26 microM, the most active compound being AA-5-HT. This substance was also active on FAAH from rat basophilic leukaemia (RBL-2H3) cells (IC50 = 5.6 microM), and inhibited [14C]anandamide hydrolysis by both N18TG2 and RBL-2H3 intact cells without affecting [14C]anandamide uptake. While AEG behaved as a competitive inhibitor and was hydrolyzed to arachidonic acid (AA) by FAAH preparations, AA-5-HT was resistant to FAAH-catalyzed hydrolysis and behaved as a tight-binding, albeit non-covalent, mixed inhibitor. AA-5-HT did not interfere with cPLA2-mediated, ionomycin or antigen-induced release of [3H]AA from RBL-2H3 cells, nor with cPLA2 activity in cell-free experiments. Finally, AA-5-HT did not activate CB1 cannabinoid receptors since it acted as a very weak ligand in in vitro binding assays, and, at 10-15 mg/kg body weight, it was not active in the 'open field', 'hot plate' and rectal hypothermia tests carried out in mice. Conversely AEG behaved as a cannabimimetic substance in these tests as well as in the 'ring' immobility test where AA-5-HT was also active. AA-5-HT is the first FAAH inhibitor reported to date which is inactive both against cPLA2 and at CB1 receptors, whereas AEG represents a new type of cannabinoid receptor agonist.
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PMID:Arachidonoylserotonin and other novel inhibitors of fatty acid amide hydrolase. 970 57

Apoptosis was induced by treating L1210 leukaemia cells with mechlorethamine, and SW620 colorectal cells with doxorubicin. The onset and progression of apoptosis were monitored by assessing caspase activation, mitochondrial transmembrane potential, phosphatidylserine externalization, DNA fragmentation and cell morphology. In parallel, 31P magnetic resonance (MR) spectra of cell extracts were recorded. In L1210 cells, caspase activation was detected at 4 h. By 3 h, the MR spectra showed a steady decrease in NTP and NAD, and a significant build-up of fructose 1,6-bisphosphate (F-1,6-P) dihydroxyacetonephosphate and glycerol-3-phosphate, indicating modulation of glycolysis. Treatment with iodoacetate also induced a build-up of F-1,6-P, while preincubation with two poly(ADP-ribose) polymerase inhibitors, 3-aminobenzamide and nicotinamide, prevented the drop in NAD and the build-up of glycolytic intermediates. This suggested that our results were due to inhibition of glyceraldehyde-3-phosphate dehydrogenase, possibly as a consequence of NAD depletion following poly(ADP-ribose) polymerase activation. Doxorubicin treatment of the adherent SW620 cells caused cells committed to apoptosis to detach. F-1,6-P was observed in detached cells, but not in treated cells that remained attached. This indicated that our observations were not cell line- or treatment-specific, but were correlated with the appearance of apoptotic cells following drug treatment. The 31P MR spectrum of tumours responding to chemotherapy could be modulated by similar effects.
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PMID:Magnetic resonance detects metabolic changes associated with chemotherapy-induced apoptosis. 1036 12

Glucocorticoids are known to promote apoptosis of eosinophils, normal and neoplastic lymphoid cells, and blastic cells in some patients with acute myeloid leukemia. We investigated the biochemical signal transduction pathways, in particular, the generation of reactive oxygen species (ROS) and activation of caspases in dexamethasone (DEX)-induced apoptosis of eosinophils, and we compared them with those in DEX-sensitive myeloid and lymphoid leukemia cell lines. The GC-receptor antagonist completely abolished DEX-induced apoptosis of eosinophils and leukemia cells. Among inhibitors related to the ROS system, diphenylene iodonium (DPI), a nicotinamide adenine dinucleotide diphosphate (NADPH) oxidase inhibitor, strongly inhibited both spontaneous and DEX-induced apoptosis of eosinophils at concentrations as low as 0.2 to 2 mumol/L, while promoting apoptosis of leukemia cells in a dose-dependent manner. Apocynin, another NADPH oxidase inhibitor, and antioxidants did not affect the apoptosis of eosinophils or leukemia cells. DEX treatment did not change intracellular production of O2- and H2O2, and it decreased the extracellular release of O2- in both cells. These results suggest little or no involvement of ROS generation in DEX-induced apoptosis of both cells. Although among peptide-based caspase inhibitors, only z-VAD-FMK, a broad caspase inhibitor, partially inhibited the apoptosis of eosinophils and leukemia cells, DEX treatment increased the activities of caspases 2-, 3-, 6-, and 8-like proteases assessed by colorimetry in both cells, suggesting the involvement of a similar caspase activation pathway in DEX-induced apoptosis in both cells. DPI markedly reduced caspase 3-like activity in eosinophils, while augmenting the activity in leukemia cells, indicating that DPI acts upstream of caspase 3 activation opposingly in both cells. Thus, the action of DPI in eosinophils seems peculiar in respect to apoptosis induction, and DPI appears to exert an influence on unknown targets rather than those involved in NADPH oxidase inhibition.
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PMID:Glucocorticoid-induced apoptotic pathways in eosinophils: comparison with glucocorticoid-sensitive leukemia cells. 1090 53

In response to high levels of DNA damage, catalytic activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) triggers necrotic death because of rapid consumption of its substrate beta-nicotinamide adenine dinucleotide and consequent depletion of ATP. We examined whether there are other consequences of PARP activation that could contribute to cell death. Here, we show that PARP activation reaction in vitro becomes acidic with release of protons during hydrolysis of beta-nicotinamide adenine dinucleotide. In the cellular context, we show that Molt 3 cells respond to DNA damage by the alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) with a dose-dependent acidification within 30 min. Whereas acidification by 0.15 pH units induced by 10 microM MNNG is reversed within 1 h, 100 , microinduced acidification by 0.5-0.6 pH units is persistent up to 7 h. Acidification is a general DNA damage response because H(2)O(2) exposure also acidifies Molt 3 cells, and MNNG causes acidification in Jurkat, U937, or HL-60 leukemia cells and in PARP(+/+) fibroblasts. Acidification is significantly decreased in the presence of PARP inhibitors or in PARP(-/-) fibroblasts, suggesting a major role for PARP activation in acidification. Inhibition of proton export through ATP-dependent Na(+)/H(+) exchanger is another major cause of acidification. Using the pH clamp method to either suppress or introduce changes in cellular pH, we show that brief acidification by 0.5-0.6 pH units may be a negative regulator of apoptosis while permitting necrotic death of cells with extensively damaged DNA.
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PMID:Role of poly(ADP-ribose) polymerase in rapid intracellular acidification induced by alkylating DNA damage. 1175 65

A selected suite of cytochemical parameters in Mytilus edulis are altered in response to field and laboratory exposure to chemical contaminants. These biomarkers include lysosomal stability, nicotinamide adenine dinucleotide phosphate (NADPH)-ferrihemoprotein reductase activity, liposfuscin deposition, and accumulation of lysosomal and cytoplasmic unsaturated neutral lipid. Normal variations in physiological processes (influenced by exogenous seasonal changes in temperature, salinity, food availability, etc.) may alter the sensitivity of these biomarkers to contaminant exposure. To address this issue, M. edulis (complex) were sampled monthly from a reference nonurban site (Coupeville, Penn Cove) and a polluted urban site (Seacrest, Elliott Bay) in Puget Sound, WA, for a period of 15 months. Physiological measurements including total length, total weight, somatic and mantle weights (an indication of gonadal development and reproductive status), condition index, and the presence or absence of hemic neoplasia (HN, or leukemia) were recorded. Significant differences in lysosomal stability, lysosomal and cytoplasmic unsaturated neutral lipids, lipofuscin deposition, and NADPH-ferrihemoprotein reductase activity in cells of the digestive gland or digestive tubules were generally found in mussels taken throughout the year from Seacrest compared to mussels sampled from Coupeville, consistent with exposure to chemical contaminants. No seasonally influenced suppression of the entire suite of parameters as measures of contaminant exposure was evident. Therefore these biomarkers can be used to evaluate contaminant exposure in mussels throughout the entire year.
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PMID:Assessment of seasonal variability of cytochemical responses to contaminant exposure in the blue mussel Mytilus edulis (complex). 1243 18

Sarco-endoplasmic reticulum calcium ATPase (SERCA) enzymes control calcium-induced cellular activation by accumulating calcium from the cytosol into the endoplasmic reticulum (ER). To better understand the role of SERCA proteins and cellular calcium homeostasis in all-trans retinoic acid (ATRA)-induced differentiation, we investigated the effect of pharmacologic inhibition of SERCA-dependent calcium uptake into the ER on ATRA-induced differentiation of the HL-60 myelogenous and the NB4 promyelocytic cell lines. SERCA inhibitors di-tert-butyl-benzohydroquinone (tBHQ), thapsigargin, and cyclopiazonic acid significantly enhanced the induction of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and CD11b marker expression induced by suboptimal concentrations of ATRA (50 nM) in both cell lines. Analysis of cellular calcium homeostasis revealed that a 60% mobilization of the total SERCA-dependent intracellular calcium pool was necessary to obtain enhancement of ATRA-dependent differentiation by tBHQ. Moreover, after 3 days of ATRA treatment in combination with tBHQ, NB4 cells showed a significantly decreased calcium mobilization compared with treatments with tBHQ or ATRA alone, suggesting that enhanced differentiation and calcium mobilization are causally related. Interestingly, several ATRA-resistant NB4-derived cell lines were partially responsive to the differentiation-inducing effect of the combination of the 2 drugs. In addition, we found that retinoic acid receptor alpha (RAR alpha) and PML-RAR alpha proteins are protected from ATRA-induced proteolytic degradation by SERCA inhibition, indicating that cellular calcium homeostasis may interact with signaling systems involved in the control of ATRA-dependent transcriptional activity. By linking calcium to ATRA-dependent signaling, our data open new avenues in the understanding of the mechanisms of differentiation-induction therapy of leukemia.
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PMID:Enhancement of ATRA-induced cell differentiation by inhibition of calcium accumulation into the endoplasmic reticulum: cross-talk between RAR alpha and calcium-dependent signaling. 1251 18

Deregulation of apoptosis, the physiological form of cell death, is closely associated with immunological diseases and cancer. Apoptosis is activated either by death receptor-driven or mitochondrial pathways, both of which may provide potential targets for novel anticancer drugs. Although several ligands stimulating death receptors have been described, the actual molecular events triggering the mitochondrial pathway are largely unknown. Here, we show initiation of apoptosis by gradual depletion of the intracellular coenzyme NAD+. We identified the first low molecular weight compound, designated FK866, which induces apoptosis by highly specific, noncompetitive inhibition of nicotinamide phosphoribosyltransferase (NAPRT), a key enzyme in the regulation of NAD+ biosynthesis from the natural precursor nicotinamide. Interference with this enzyme does not primarily intoxicate cells because the mitochondrial respiratory activity and the NAD+ -dependent redox reactions involved remain unaffected as long as NAD+ is not effectively depleted by catabolic reactions. Certain tissues, however, have a high turnover of NAD+ through its cleavage by enzymes like poly(ADP-ribose) polymerase. Such cells often rely on the more readily available nicotinamide pathway for NAD+ synthesis and undergo apoptosis after inhibition of NAPRT, whereas cells effectively using the nicotinic acid pathway for NAD+ synthesis remain unaffected. In support of this concept, FK866 effectively induced delayed cell death by apoptosis in HepG2 human liver carcinoma cells with an IC(50) of approximately 1 nM, did not directly inhibit mitochondrial respiratory activity, but caused gradual NAD+ depletion through specific inhibition of NAPRT. This enzyme, when partially purified from K562 human leukemia cells, was noncompetitively inhibited by FK866, and the inhibitor constants were calculated to be 0.4 nM for the enzyme/substrate complex (K(i)) and 0.3 nM for the free enzyme (K(i)'), respectively. Nicotinic acid and nicotinamide were both found to have antidote potential for the cellular effects of FK866. FK866 may be used for treatment of diseases implicating deregulated apoptosis such as cancer for immunosuppression or as a sensitizer for genotoxic agents. Furthermore, it may provide an important tool for investigation of the molecular triggers of the mitochondrial pathway leading to apoptosis through enabling temporal separation of NAD+ decrease from ATP breakdown and apoptosis by several days.
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PMID:FK866, a highly specific noncompetitive inhibitor of nicotinamide phosphoribosyltransferase, represents a novel mechanism for induction of tumor cell apoptosis. 1461 43

Initial studies with angiogenesis inhibitors showed little clinical benefit. However, recently reported clinical studies in colorectal cancer have shown that bevacizumab, a vascular endothelial growth factor (VEGF) monoclonal antibody, in combination with cytotoxic therapy has positive effects on patient survival. Furthermore, the VEGF receptor kinase (VEGF-R) tyrosine kinase inhibitor, vatalanib, has also shown encouraging results in colorectal cancer, with molecular resonance imaging providing evidence that the anti-tumor efficacy was indeed the result of anti-angiogenic activity. Both of these agents are progressing in phase III trials. This proof of concept has stimulated the desire for second-generation VEGF-R inhibitors having an improved profile. Structural biology insight regarding the binding mode of protein kinase inhibitors is valuable for the design of molecules possessing superior selectivity, efficacy and tolerability. Towards this goal, we have developed a new series of VEGF-R2 kinase inhibitors, based upon an anthranilic acid amide scaffold. An X-ray crystal structure of a representative compound, AAL993 (ZK260253), in complex with the catalytic domain of diphosphorylated VEGF-R2 has revealed that this molecule binds to an inactive conformation of the protein. This binding mode, similar to that observed for the anti-leukemia drug, imatinib in complex with c-Abl kinase, may be responsible for the high selectivity of AAL993 and provides valuable insight for the design of further compounds.
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PMID:Advances in the structural biology, design and clinical development of VEGF-R kinase inhibitors for the treatment of angiogenesis. 1502 47

The B cell leukemia 11A protein (BCL11A/Evi9/CTIP1) has been implicated in hematopoietic cell development and malignancies. BCL11A is a transcriptional repressor that binds directly to a GC-rich motif and is also recruited to a promoter template via interaction with the orphan nuclear receptor, chicken ovalbumin upstream promoter transcription factor II. In both cases, BCL11A-mediated transcriptional repression is only minimally reversed by trichostatin A, suggesting the possible lack of involvement of class I or II histone deacetylases. Nonetheless, chromatin immunoprecipitation assays revealed that expression of BCL11A in mammalian cells resulted in deacetylation of histones H3 and/or H4 that were associated with the promoter region of a reporter gene. BCL11A-mediated transcriptional repression, as well as deacetylation of histone H3/H4 in BCL11A-transfected cells, was partially reversed by nicotinamide, an inhibitor of class III histone deacetylases such as SIRT1. SIRT1 was found to interact directly with BCL11A and was recruited to the promoter template in a BCL11A-dependent manner leading to transcriptional repression. These findings define a role for SIRT1 in transcriptional repression mediated by BCL11A in mammalian cells.
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PMID:BCL11A-dependent recruitment of SIRT1 to a promoter template in mammalian cells results in histone deacetylation and transcriptional repression. 1563 32

Two-photon laser scanning microscopy (TPLSM) of endogenous reduced nicotinamide adenine dinucleotide (NAD(P)H) provides important information regarding the cellular metabolic state. When imaging the punctate mitochondrial fluorescence originating from NAD(P)H in a rat basophilic leukemia (RBL) cell at low laser powers, no morphological changes are evident, and photobleaching is not observed when many images are taken. At higher powers, mitochondrial NAD(P)H fluorescence bleaches rapidly. To assess the limitations of this technique and to quantify the extent of photodamage, we have measured the effect of TPLSM on DNA synthesis. Although previous reports have indicated a threshold power for "safe" two-photon imaging, we find the laser power to be an insufficient indicator of photodamage. A more meaningful metric is a two-photon-absorbed dose that is proportional to the number of absorbed photon pairs. A temporary reduction of DNA synthesis in RBL cells occurs whenever a threshold dose of approximately 2 x 10(53) photon2 cm-4 s-1 is exceeded. This threshold is independent of laser intensity when imaging with average powers ranging from 5 to 17 mW at 740 nm. Beyond this threshold, the extent of the reduction is intensity dependent. DNA synthesis returns to control levels after a recovery period of several hours.
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PMID:Reduction in DNA synthesis during two-photon microscopy of intrinsic reduced nicotinamide adenine dinucleotide fluorescence. 1564


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