Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Numerous studies have suggested that iron (Fe) chelators such as desferrioxamine (DFO) may be useful antitumor agents (Blatt and Stitely, Cancer Res 47:1749, 1987; Becton and Bryles, Cancer Res 48:7189, 1988). Recent work with several analogues of the lipophilic Fe chelator, pyridoxal isonicotinoyl hydrazone (PIH), indicate that some of these ligands are considerably more efficient than DFO both in terms of their Fe chelation efficacy and at preventing 3H-thymidine incorporation by neuroblastoma (NB) cells (Richardson and Ponka, J Lab Clin Med 124:660, 1994). Considering this fact, the present study was designed to test the antiproliferative effect of a wide range of PIH analogues to identify the most active compounds. A total of 36 ligands have been examined that were synthesized by condensation of three types of aromatic aldehydes (pyridoxal, salicylaldehyde, and 2-hydroxy-1-naphthyladehyde) with a range of acid hydrazides. The effects of these chelators were assessed using the human NB cell line, SK-N-MC. Although PIH was far more effective than DFO at preventing Fe uptake from transferrin, it was less effective than DFO at preventing cellular proliferation (DFO ID50 = 22 mumol/L; PIH ID50 = 75 mumol/L). In contrast, 14 PIH analogues were far more efficient than DFO at preventing proliferation (ID50 = 1 to 7 mumol/L) and may have potential as antitumor agents. The most effective compounds were those hydrazones derived from 2-hydroxy-1-naphthylaldehyde. Most of the PIH analogues were considerably more effective than DFO at both preventing 59Fe uptake from 59Fe-transferrin and in mobilizing 59Fe from prelabeled NB cells. In addition, a linear relationship between Fe chelation efficacy and antiproliferative activity was found only for hydrazones derived from salicylaldehyde. Apart from gallium (Ga) nitrate having an antiproliferative effect by itself, this metal potentiated the antiproliferative effect of PIH but not that of DFO. Spectrophotometric studies showed that PIH could chelate Ga, and it can be suggested that, like the PIH-Fe complex that donates Fe to reticulocytes (Ponka et al, Biochim Biophys Acta 718:151, 1982), the PIH-Ga complex may efficiently bestow Ga to NB cells. The results suggest that analogues of PIH deserve further vigorous investigation because they may be useful therapeutic agents for the treatment of cancer.
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PMID:The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class as effective antiproliferative agents. 749 90

The mechanisms of iron uptake from transferrin and the effects of iron chelators on these processes were investigated in human neuroblastoma cells. This study was performed because numerous reports have indicated that neuroblastoma cells contain iron-rich ferritin and are also especially sensitive to iron chelation by deferoxamine. The mechanisms of iron and transferrin uptake were examined in the human neuroblastoma cell line SK-N-MC by using human transferrin labeled with iodine 125 and iron 59. Internalized and membrane-bound 59Fe and 125I-transferrin were separated with the protease pronase. Total internalized and membrane 125I-transferrin uptake was biphasic with time, whereas total and internalized 59Fe uptake was linear. Iron uptake from transferrin was prevented by incubation at 4 degrees C and also by lysosomotrophic agents. In addition, 59Fe uptake occurred by two processes. The first process was consistent with receptor-mediated endocytosis involving internalization of transferrin bound to specific binding sites. Iron uptake also occurred by a second process, which was not saturable up to a transferrin concentration of 0.06 mg/ml. In terms of quantitative iron uptake, however, the second process was far less important than receptor-mediated endocytosis. Deferoxamine (0.25 mmol/L) only slightly increased 59Fe release from prelabeled cells; the orally effective iron chelator pyridoxal isonicotinoyl hydrazone (0.25 mmol/L) was six times more effective. Moreover, when pyridoxal isonicotinoyl hydrazone (0.2 mmol/L) was added together with labeled transferrin over a 2-hour incubation, 59Fe uptake from transferrin decreased to 18% of the control value, whereas deferoxamine (0.2 mmol/L) had no appreciable effect. Even though deferoxamine (0.1 mmol/L) had little effect on 59Fe uptake or release, it reduced uptake of tritiated thymidine to 33% of the control value after a 24-hour incubation. Three analogs of pyridoxal isonicotinoyl hydrazone, pyridoxal benzoyl hydrazone (#101), pyridoxal p-methoxybenzoyl hydrazone (#107), and pyridoxal m-fluorobenzoyl hydrazone (#109), had chelation activities comparable to that of pyridoxal isonicotinoyl hydrazone and were more effective than either deferoxamine or pyridoxal isonicotinoyl hydrazone at preventing tritiated thymidine uptake. These results suggest that the pyridoxal isonicotinoyl hydrazone analogs have potential as effective antiproliferative agents and deserve further investigation.
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PMID:The iron metabolism of the human neuroblastoma cell: lack of relationship between the efficacy of iron chelation and the inhibition of DNA synthesis. 796 24

Iron (Fe) is known to be necessary for cellular proliferation. Previous studies have suggested that neuroblastoma cells appear to be relatively sensitive to growth inhibition by a specific Fe chelator, deferrioxamine (DFO), in vitro. Also, DFO has been recently used for the treatment of neuroblastoma patients. In this paper we demonstrate that neuroblastoma cell proliferation in vitro is extremely sensitive to inhibition by DFO as compared to another cell line with almost identical growth kinetics. Neuroblastoma cells treated with DFO adapt appropriately to Fe chelation as measured by marked upregulation of transferrin receptor mRNA, increased functional transferrin receptor, and decreased cellular ferritin concentration. Further studies that quantitated cellular incorporation of 59Fe from added transferrin-59Fe in the presence of DFO indicated that neuroblastoma cells were more sensitive to inhibition of Fe incorporation by the chelator as compared to the other cell line. Neuroblastoma cells treated with DFO showed a consistent arrest in the G1 phase of the cell cycle. For cells taken from the "resting" state this block occurred before the vast majority of cells had entered S or G2-M phases of the cell cycle. Further evidence that neuroblastoma cells were arrested before the G1-S interface was provided when cells inhibited by DFO and released into aphidicolin exhibit arrest at the G1-S interface, whereas release from aphidicolin into DFO resulted in entry into S phase. Also, DFO-treated cells exhibited a decrease in both p34cdc2 immunoreactive protein as well as kinase activity. The results of these latter studies strongly indicate evidence for a Fe requirement for malignant cell proliferation before the onset of DNA synthesis. Our results also provide a basis for further studies that will better define a therapeutic approach to patients with neuroblastoma utilizing DFO treatment.
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PMID:Neuroblastoma sensitivity to growth inhibition by deferrioxamine: evidence for a block in G1 phase of the cell cycle. 835 25

The efficacy and cytotoxic properties of immunotoxin conjugates directed against the transferrin receptor were examined in cell lines and operative specimens from pediatric brain tumors. Dose-response relationships were assessed for immunotoxin-mediated inhibition of protein synthesis for two immunotoxins, 454A12-rRA and anti-tfnR-CRM 107. Three target medulloblastoma cell lines (DAOY, D283MED, and D341MED), a glioblastoma (U373), and a neuroblastoma (SH-SY5Y) cell line exhibited similar sensitivity to both immunotoxins with IC50s in the 10(-9)-10(-10) M range. The time course of protein synthesis inhibition by the immunotoxins in DAOY cells showed that inhibition by anti-tfnR-CRM 107 was rapid and apparent by 6 h of incubation. In contrast, a response to 454A12-rRA was not observed until 16 h. Cell viability was decreased 30-40% by 24 h after removing 454A12-rRA (1 x 10(-9) M) and was maximally decreased 70-80% after 3 days. The efficacy of the immunotoxins on a variety of fresh specimens of pediatric brain tumors was also examined. The more aggressive and malignant tumor types such as glioblastoma multiforme and medulloblastoma had low IC50 values (10(-12) M), indicating that these tumors were extremely sensitive to transferrin receptor-targeted immunotoxins. In general, protein synthesis in slow-growing and benign tumors was not as greatly affected by immunotoxins. Immunoblots showed expression of transferrin receptors on the cell lines and tumors which correlated with in vitro sensitivity to immunotoxin. The results demonstrate that two immunotoxins targeted to the transferrin receptor are efficacious in killing brain tumor cell lines and primary tumor cultures at very low concentrations and that highly malignant tumors are especially sensitive to this cytotoxic response.
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PMID:Efficacy of transferrin receptor-targeted immunotoxins in brain tumor cell lines and pediatric brain tumors. 844 15

Exposure to manganese compounds often occurs as the result of industrial production or mining. Although manganese appears in traces in animal and human tissue and is essential to certain biological processes, it is also toxic. In humans and animals, toxicity is mainly associated with the nervous system. The mechanism underlying behavioral and biochemical alterations observed after manganese intoxication is not fully understood. We have shown that the manganese present in serum after exposure to manganese oxide is bound to transferrin as trivalent manganic ion. In this study of manganese uptake and storage we used a clone of human neuroblastoma cells (SHSY5Y). These cells differentiate and express catecholaminergic properties. Saturation binding analysis of the transferrin-manganese complex to the cells revealed a single class of binding sites, with an apparent KD of 13 +/- 1 nM and a density of 11,000 +/- 2,000 binding sites per cell. The complex was internalized in a temperature-dependent way and reached saturation after 2 h when approximately 2% of the added manganese had been internalized. About 80% of the internalized manganese was found in ferritin after 24 h of exposure. The results demonstrate that the transferrin receptor on SHSY5Y cells can bind and internalize a manganese-transferrin complex as efficiently as an iron-transferrin complex, although a saturation of the manganese uptake was achieved.
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PMID:Receptor-mediated endocytosis of a manganese complex of transferrin into neuroblastoma (SHSY5Y) cells in culture. 851 58

We have recently screened 36 analogues of the lipophilic iron (Fe) chelator, pyridoxal isonicotinoyl hydrazone (PIH), for their antiproliferative effect (Richardson et al, Blood 86:4295, 1995). Of these compounds, 1 chelator derived from salicylaldehyde benzoyl hydrazone (206) and 4 ligands derived from 2-hydroxy-1-naphthylaldehyde benzoyl hydrazone (308, 309, 311, and 315) showed pronounced antiproliferative activity, being far more effective than desferrioxamine (DFO). The present study was designed to investigate in detail the mechanism of action of these PIH analogues in a variety of neoplastic cell lines. This investigation showed that the analogues were far more active than DFO at inhibiting cellular proliferation and 3H-thymidine, 3H-leucine, and 3H-uridine incorporation. Additional experiments showed that, in contrast to DFO, the 5 analogues were potent at preventing 59Fe uptake from transferrin (Tf) and increasing 59Fe release from cells at concentrations as low as 10 micromol/L. Examination of the distribution of 59Fe in neoplastic cells using native polyacrylamide gel electrophoresis (PAGE)/59Fe-autoradiography showed that most of the 59Fe taken up from Tf was incorporated into ferritin, although 3 other previously unrecognized components (bands A, B, and C) were also identified. Band C comigrated with 59Fe-citrate and was chelated on incubation of neuroblastoma cells with DFO, PIH, or the PIH analogues, with this compartment being the main intracellular target of these ligands. Further work showed that the effects of the chelators at inducing characteristics consistent with apoptosis or necrosis were cell line-specific, and while DFO increased the percentage of cells in the G0/G1 phases in all cell types, the effect of analogue 311 on the cell cycle was variable depending on the cell line. This study provides further evidence for the potential use of these Fe chelators as anticancer agents.
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PMID:The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class as effective antiproliferative agents II: the mechanism of action of ligands derived from salicylaldehyde benzoyl hydrazone and 2-hydroxy-1-naphthylaldehyde benzoyl hydrazone. 910 24

Iron (Fe) chelators of the pyridoxal isonicotinoyl hydrazone (PIH) class may be useful agents to treat Fe overload disease and also cancer. These ligands possess high activity at mobilizing 59Fe from neoplastic cells, and the present study has been designed to examine whether their marked activity may be related to an energy-dependent transport process across the cell membrane. Initial experiments examined the release of 59Fe from SK-N-MC neuroblastoma (NB) cells prelabelled for 3 h at 37 degrees C with 59Fe-transferrin (1.25 microM) and then reincubated in the presence and absence of the chelators for 3 h at 4 degrees C or 37 degrees C. Prelabelled cells released 4-5% of total cellular 59Fe when reincubated in minimum essential medium at 4 degrees C or 37 degrees C. When the chelators desferrioxamine (DFO; 0.1 mM) or PIH (0.1 mM) were reincubated with labelled cells at 4 degrees C, they mobilized only 4-5% of cellular 59Fe, whereas as 37 degrees C, these ligands mobilized 21% and 48% of cell 59Fe, respectively. The lipophilic PIH analogue, 311 (2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone; 0.1 mM), which exhibits high anti-proliferative activity, released 10% and 53% of cellular 59Fe when reincubated with prelabelled cells at 4 degrees C and 37 degrees C, respectively. Almost identical results were obtained using the SK-Mel-28 melanoma cell line. These data suggest that perhaps temperature-dependent mechanisms are essential for 59Fe mobilization from these cells. Interestingly, the metabolic inhibitors, 2,4-dinitrophenol, oligomycin, rotenone, and sodium azide, markedly decreased 59Fe mobilization mediated by PIH, but had either no effect or much less effect on 59Fe release by 311. Considering that an ATP-dependent process was involved in 59Fe release by PIH, further studies examined 4 widely used inhibitors of the multi-drug efflux pump P-glycoprotein (P-gp). All of these inhibitors, namely, verapamil (Ver), cyclosporin A (CsA), reserpine (Res) and quinine (Qui), decreased 59Fe mobilization by PIH but had little or no effect on 59Fe release mediated by analogue 311. Further, both CsA and Ver increased the proportion of ethanol-soluble 59Fe within cells in the presence of PIH, suggesting inhibited transport of the 59Fe complex from the cell. However, when PIH-mediated 59Fe release was compared between a well characterized Chinese hamster ovary cell line (CHRB30) expressing high levels of P-gp and the relevant control cell line (AuxB1), no appreciable difference in the kinetics of 59Fe release were found. In contrast, it was intriguing that the CHRB30 cells released more 59Fe into control medium (i.e., without PIH) than the AuxB1 control line (16.7% compared to 5.9%, respectively). In summary, the results suggest that a temperature- and energy-dependent process was involved in the efflux of the PIH-59Fe complex from the cells. In contrast, 59Fe release mediated by 311 was temperature-dependent but not energy-dependent, and could occur by simple diffusion or passive transport. Further studies investigating the membrane transport of Fe chelators may be useful in designing regimes that potentiate their anti-neoplastic effects.
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PMID:Mobilization of iron from neoplastic cells by some iron chelators is an energy-dependent process. 918 79

In the end-stage renal disease patient, certain uremic compounds could influence the cellular accumulation of aluminum (Al). In this study, we examined the effect of 15 uremic ultrafiltrate fractions obtained by HPLC on the uptake and toxicity of Al in mouse hepatocytes (MH) in culture, a model system in which Al is taken up bound to transferrin (Tf). Uremic fractions 4 to 8, 12, 14, and 15 increased cellular Al uptake and aspartate aminotransferase release and decreased cell growth when Tf-Al, not Al citrate, was added to culture media. Compounds that have been extracted previously from these ultrafiltrate fractions (p-cresol, xanthine, tryptophan, hippuric acid, and o-hydroxyhippuric acid) were then tested for their effect on Al uptake and toxicity in MH at concentrations found in uremic serum. Significant Al uptake by MH was observed only when p-cresol was added together with Tf-Al. Time-response curves showed increased Al uptake and toxicity at p-cresol concentrations of 3 mg/dl in culture media. Dose-response curves confirmed that Al uptake and cell toxicity were proportional to p-cresol from 1.5 mg/dl to 3 mg/dl in culture media. p-Cresol was not toxic to MH in the absence of Tf-Al in media. p-Cresol increased Tf-associated Al uptake only because there was no effect on Al uptake when Al citrate was substituted, and studies with Tf-I125-Al in the presence of this compound showed increased Tf-I125 taken up by MH. p-Cresol did not increase Tf saturation with Al. p-Cresol also increased Tf-Al uptake in Friend erythroleukemia and neuroblastoma cells in culture. Our studies suggest that p-cresol and uremic fractions 4 to 8, 12, 14, and 15 increase the uptake and toxicity of Al in cultured MH. These compounds may play a role in the accumulation and toxicity of Al in the liver of end-stage renal disease patients and possibly in all cells that express Tf receptors.
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PMID:P-Cresol, a uremic compound, enhances the uptake of aluminum in hepatocytes. 918 61

Recently the high transfection potential of the cationic polymer polyethylenimine (PEI) was described (Boussif O et al. Proc Natl Acad Sci USA 1995; 92: 7297-7301). To combine the promising DNA delivering activity of PEI with the concept of receptor-mediated gene delivery, cell-binding ligands (transferrin or antiCD3 antibody) were incorporated by covalent linkage to PEI. DNA complexes of PEI or ligand-PEI conjugates were tested for transfection of cultured neuroblastoma Neuro 2A cells, melanoma B16 or H225 cells, erythroid leukemic K562 cells and T cell leukemia Jurkat E6.1 cells. Depending on the cell line, incorporation of the cell-binding ligand resulted in an up to 1000-fold increased transfection efficiency. This activity depends on ligand-receptor interaction and was observed also at low PEI cation:DNA anion ratios where ligand-free PEI lacks efficiency. Depending on the cell-binding ligand, specific targeting (CD3 antibody, Jurkat cells) can be achieved. Gene transfer can be augmented by the addition of an endosome-destabilizing influenza peptide, but is not dependent on the presence of additional endosomolytic agents. Application of transferrin-PEI for the production of murine interleukin-2 in B16 cells resulted in exceptionally high secretion rates of 19 micrograms IL-2 protein per 10(6) cells per 24 h.
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PMID:Coupling of cell-binding ligands to polyethylenimine for targeted gene delivery. 927 17

The subcellular location of aluminium is unknown, probably because of difficulties in investigating aluminium biochemistry and the use of varied experimental approaches of uncertain sensitivity. We have studied levels of uptake and the localization of gallium and of aluminium in cultured human neuroblastoma cells treated with soluble metal complexes (mainly Al- or Ga-EDTA), radiolabeled with 26Al or 67Ga, respectively. Crude nuclei and cytoplasm were obtained by two separate methods, and DNA, RNA, and proteins were prepared from the nuclei by centrifugation in high salt; also, cytosol and noncytosol were separated using a nondissociating method. Levels of uptake were of similar order for the two metals-on average about 50 pmol/10(6) cells for aluminium and 120 pmol/10(6) cells for gallium, after 4 to 8 days treatment at 250 microM, and approximately 50 to 70% of the metal was found in the cytosol. About 20% of the aluminium and 10 to 25% of the gallium was associated with nuclear protein. A lower proportion was bound to DNA and to nuclear RNA. In cells treated with gallium-citrate/transferrin mixtures, 30 to 35% of the gallium in the cytosol was bound to protein, at least 35 being loosely bound; the main gallium-associated protein was probably intracellular transferrin. The remaining 65 to 70% of the metal in the cytosol was in low-molecular-weight form, and we suggest that the latter metal could affect structures such as the cytoskeleton and also metabolic processes in the cytoplasm. The similarity in distribution of the two metals supports the use of gallium as a "surrogate" for aluminium, at least in cell culture studies.
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PMID:Location of aluminium and gallium in human neuroblastoma cells treated with metal-chelating agent complexes. 977 10


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