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)

Initially the impetus to develop iron (Fe) chelators for clinical use was based upon the need for a drug to treat Fe-overload diseases such as beta-thalassemia. However, it has become clear that Fe chelators may be useful for the treatment of a wide variety of disease states, including cancer, malaria, and free radical mediated injury. In particular, over the last 10 years a number of studies have shown that Fe chelators may be of use in the treatment of a number of aggressive human cancers, including neuroblastoma and leukemia, and several clinical trials have substantiated their potential. In the current review the role of Fe in cellular proliferation will be discussed, followed by the possible sites and mechanism of action of some of the most effective ligands. Attention will then be turned to examine the Fe chelators shown to possess antiproliferative activity and the clinical trials performed to assess their efficacy.
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PMID:Potential of iron chelators as effective antiproliferative agents. 943 40

Neuroblastoma (NB) is a high risk tumor of childhood, and raised serum ferritin is an adverse prognostic factor. The hypothesis that iron chelation therapy impacts tumor status and patient prognosis through changes in iron metabolism has been systematically evaluated here in a xenograft model of human NB. One of two iron chelators was given in seven different regimens to nude mice xenografted s.c. with either IMR-32, an established cell line, or JBN-1, heterotransplanted directly from a patient. Nude mice (a total of 160 in 24 cohorts) were given: desferrioxamine (DFO) by s.c. bolus or reservoir; 1,2-dimethyl-3-hydroxypyridin-4-one (L1), i.p. or orally; or saline. Measurements of mean Hb and liver iron levels were compared with corresponding saline cohorts per regimen as well as for pooled cohorts per agent for both cell lines. For IMR-32 xenografts, significant differences in Hb were achieved with L1 (10.9 g/dl pooled versus 13.7 g/dl controls) and in liver iron with DFO and L1 (235 microg/g and 306 microg/g, respectively, versus 520 microg/g). For JBN-1, the pattern was similar. With L1, H6 was 10.2 g/dl and controls were 11.7 g/dl (individual DFO cohorts were also significant); liver iron with DFO was 303 microg/g, liver iron with L1 was 270 microg/g, and controls were 387 microg/g. Additional therapy prior to tumor injection (67 mice and 10 cohorts) did not increase the depletion. Despite documentation of iron depletion, no reductions in tumor engraftment, latency, or tumor size at end point were achieved in the chelator-treated mice, compared with controls populations. Accordingly, inclusion of these iron chelators in clinical trials for NB appears unwarranted.
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PMID:Failure of iron chelators to reduce tumor growth in human neuroblastoma xenografts. 945 92

Inductively coupled plasma atomic emission spectroscopy (ICP-AES) was used for routine analysis of small samples of human milk. The concentrations of calcium (Ca), copper (Cu), iron (Fe), magnesium (Mg), manganese (Mn), phosphorus (P), and zinc (Zn) were determined in 203 milk samples from postpartum women at different stages of lactation after stepwise digestion in HNO3, HClO4, and H2O2 under heat. Validation of the procedure was achieved using certified reference material of bovine liver (NBS 1577) with mean recoveries of 103.5%. The concentrations of the above elements in milk matrix were comparable with previously reported values. The analytical results from breast milk will provide reference information for mineral studies of Brazilian mothers and breast-fed infants.
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PMID:Multielement determination in small samples of human milk by inductively coupled plasma atomic emission spectrometry. 952 47

Cancer cells have a high requirement for iron (Fe) as it plays a crucial role in a variety of metabolic processes including energy production and DNA synthesis. Studies in vitro and in vivo have demonstrated that the Fe chelator in current clinical use, desferrioxamine (DFO), can effectively inhibit the growth of some neoplasms, including leukemia and neuroblastoma. Unfortunately, DFO suffers from a number of serious disadvantages, including its high cost, the need for prolonged subcutaneous infusion (12-24 h/day, 5-6 nights/week), and its poor intestinal absorption precluding oral administration. Hence, the development of more effective Fe chelators is necessary. The Fe chelator, pyridoxal isonicotinoyl hydrazone (PIH), was initially identified as a ligand that showed high activity at mobilizing Fe from cells. More recently, a range of PIH analogues have been examined for their anti-proliferative effect, with several classes of these compounds showing high activity at inhibiting tumor growth in vitro. In fact, some of these hydrazones, particularly those derived from 2-hydroxy-1-naphthylaldehyde, showed comparable activity to the cytotoxic drugs cis-platin and bleomycin. In this review the role of Fe in cellular proliferation will be examined followed by a description of the most recent studies using the PIH analogues as effective anti-proliferative agents. Further studies in vivo with these Fe chelators are essential to determine their potential as chemotherapeutic agents.
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PMID:Analogues of pyridoxal isonicotinoyl hydrazone (PIH) as potential iron chelators for the treatment of neoplasia. 972 Jul 14

The antimalarial drug artemisinin and its derivatives display neurotoxicity in animal studies in vivo and in neuronal cells in vitro. Their toxicity may be due to an interaction of iron with the endoperoxide bridge of the derivative to produce toxic free radicals and/or other toxic metabolites. In this study, 0.3 microM artemether (AEM) in the presence of 2 microM haemin significantly inhibited the outgrowth of neurites from differentiating NB2a neuroblastoma cells by up to 76%. The antioxidants ascorbic acid and glutathione completely protected against this toxicity at a concentration of 100 microM. AEM was found to be partially converted to two isomeric products, which were identified as the tetrahydrofuran acetate isomer of AEM and 3alpha-hydroxydesoxyartemether.
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PMID:The role of iron in neurotoxicity: a study of novel antimalarial drugs. 974 11

Oxidative stress is considered an important pathophysiological mechanism contributing to promote cell death in a broad variety of diseases including cardiovascular and neurodegenerative disorders. The so-called scavestrogens J811 and J861, structurally derived from 17alpha-estradiol, are potent radical scavengers and inhibitors of iron-induced cell damage in vitro. In this study the potential cytoprotective effects of the scavestrogens J811 and J861 against Fenton reagent-induced cell damage (50 microM FeSO4 plus 200 microM H2O2) were compared with those of 17alpha- and 17beta-estradiol. Cell viability studies using Trypan blue staining showed that estradiols and scavestrogens at concentrations ranging from 0.1 to 10 microM are able to protect IMR 32 neuroblastoma cells from Fenton-mediated death. In addition, these compounds decreased lipid peroxidation measured as thiobarbituric acid reactive substances and renormalize oxidative stress-increased intracellular glutathione levels. When given 6 h after the toxic stimulus, J811 and J861 rescued 60% of cells, whereas 17alpha- and 17beta-estradiol were ineffective. These results suggest that the scavestrogens J811 and J861 are powerful antioxidants capable of interfering with radical-mediated cell death in diseases known to be aggravated by reactive oxygen species. Such compounds may be useful in the development of novel treatments for stroke or neurodegenerative disorders.
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PMID:Scavestrogens protect IMR 32 cells from oxidative stress-induced cell death. 977 99

Aluminum (Al) and iron (Fe) have been implicated as playing a toxic role in the pathologic lesions of Alzheimer's disease. In the following report we describe the uptake and toxicity of Al, the effect of Al on Fe uptake, and the expression of neurofibrillary tangle (NFT) protein in murine neuroblastoma cells (Neuro 2A). Significant cell Al uptake and inhibition of cell growth were seen in Neuro 2A cells at 24, 48, 72, and 96 h after plating in medium containing Al transferrin (Al-Tf) and Al citrate. Al-loaded Neuro 2A cells showed increased rates of 59Fe and 125I-Tf uptake and total cellular Fe content at 24, 48, 72, and 96 h after plating compared with control cultures. Significant increases in NFT protein staining were detected in Al-exposed cells at 72 and 96 h in culture compared with controls. The intensity of NFT staining in Al-loaded cells was directly proportional to the time in culture. There was no difference in malonyldialdehyde levels measured in control versus Al-loaded Neuro 2A cells. These results suggest that the accumulation of Al in Neuro 2A cells resulted in increased uptake of Fe, inhibition of cell growth, and expression of NFT protein, partially mimicking the pathological hallmarks of Alzheimer's disease. This model system may also be applicable for Al-induced dialysis dementia, because the Al concentrations at which cell toxicity occurred can be found in dialysis patients.
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PMID:Aluminum enhances iron uptake and expression of neurofibrillary tangle protein in neuroblastoma cells. 1021 85

We have identified specific iron (Fe) chelators of the pyridoxal isonicotinoyl hydrazone (PIH) class that are far more effective ligands than desferrioxamine (DFO; Richardson et al, Blood 86:4295, 1995; Richardson and Milnes, Blood 89:3025, 1997). In the present study, we have compared the effect of DFO and one of the most active chelators (2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone; 311) on molecular targets involved in proliferation. This was performed to further understand the mechanisms involved in the antitumor activity of Fe chelators. Ligand 311 was far more active than DFO at increasing Fe release from SK-N-MC neuroepithelioma and BE-2 neuroblastoma cells and preventing Fe uptake from transferrin. Like DFO, 311 increased the RNA-binding activity of the iron-regulatory proteins (IRPs). However, despite the far greater Fe chelation efficacy of 311 compared with DFO, a similar increase in IRP-RNA binding activity occurred after 2 to 4 hours of incubation with either chelator, and the binding activity was not inhibited by cycloheximide. These results suggest that, irrespective of the Fe chelation efficacy of a ligand, an increase IRP-RNA binding activity occurred via a time-dependent step that did not require protein synthesis. Further studies examined the effect of 311 and DFO on the expression of p53-transactivated genes that are crucial for cell cycle control and DNA repair, namely WAF1, GADD45, and mdm-2. Incubation of 3 different cell lines with DFO or 311 caused a pronounced concentration- and time-dependent increase in the expression of WAF1 and GADD45 mRNA, but not mdm-2 mRNA. In accordance with the distinct differences in Fe chelation efficacy and antiproliferative activity of DFO and 311, much higher concentrations of DFO (150 micromol/L) than 311 (2.5 to 5 micromol/L) were required to markedly increase GADD45 and WAF1 mRNA levels. The increase in GADD45 and WAF1 mRNA expression was seen only after 20 hours of incubation with the chelators and was reversible after removal of the ligands. In contrast to the chelators, the Fe(III) complexes of DFO and 311 had no effect on increasing GADD45 and WAF1 mRNA levels, suggesting that Fe chelation was required. Finally, the increase in GADD45 and WAF1 mRNAs appeared to occur by a p53-independent pathway in SK-N-MC and K562 cells, because these cell lines lack functional p53. Our results suggest that GADD45 and WAF1 may play important roles in the cell cycle arrest observed after exposure to these chelators.
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PMID:The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class as effective antiproliferative agents III: the effect of the ligands on molecular targets involved in proliferation. 1039 46

The process of iron (Fe) release from cells plays an important role in health and disease, although the mechanisms responsible remain unclear. In this study we have examined the process of Fe efflux from HepG2 cells, including the possible roles of Cp and ascorbate in this process. Recently, it has been suggested that Cp plays no role in Fe release but can increase Fe uptake by Fe-deficient HepG2 cells (Mukhopadhyay et al. Science 1998;279:714-7). However, this latter study used a nonphysiologically relevant Fe complex (iron 59-NTA) to label cells with 59Fe at a nonphysiologic temperature (25 degrees C) and Cp concentration (<100 microg/mL). Because of these problems, the experiments have been repeated by maintaining physiologic conditions and labeling cells with the physiologic Fe donor diferric Tf. When cells were labeled at 37 degrees C with 59Fe-Tf in the presence of a physiologically relevant Cp concentration (300 microg/mL), this latter protein had no effect on the uptake of 59Fe in control cells or in cells depleted of Fe by using desferrioxamine. In addition, when Fe-replete or Fe-depleted cells were incubated with 59Fe-NTA at 25 degrees C or 37 degrees C, Cp had no effect on 59Fe uptake compared with the control. When the effect of Cp (10-500 microg/mL) on 59Fe release was examined in cells prelabeled with 59Fe-Tf, a concentration-dependent increase in 59Fe efflux was observed, whereas BSA had no effect. However, in contrast to membrane-permeable Fe chelators that caused a marked increase in Fe release, the effect of Cp on Fe efflux was less impressive. To further investigate the mechanism of 59Fe mobilization, we compared 59Fe efflux among HepG2 cells, SK-Mel-28 melanoma cells, and SK-N-MC neuroblastoma cells. These studies demonstrated that 59Fe release was dependent on the incubation time with 59Fe-Tf, the cell line, and the reincubation temperature. Although 59Fe mobilization from cells was markedly temperature dependent, a range of metabolic inhibitors did not affect 59Fe release. Additional experiments showed that physiologic concentrations of ascorbate reduced 59Fe efflux, whereas glutathione had no effect. This study provides further evidence that Cp is involved in Fe mobilization but does not appear to affect Fe uptake from Tf or NTA.
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PMID:Role of ceruloplasmin and ascorbate in cellular iron release. 1056 Sep 33

Free radical scavenging and antioxidant activities of baicalein, baicalin, wogonin and wogonoside, the four major flavonoids in the radix of Scutellaria baicalensis Georgi, were examined in different systems. ESR results showed that baicalein and baicalin scavenged hydroxyl radical, DPPH radical and alkyl radical in a dose-dependent manner, while wogonin and wogonoside showed subtle or no effect on these radicals. Ten micromol/l of baicalein and baicalin effectively inhibited lipid peroxidation of rat brain cortex mitochondria induced by Fe(2+)-ascorbic acid, AAPH or NADPH, while wogonin and wogonoside showed significant effects only on NADPH-induced lipid peroxidation. In a study on cultured human neuroblastoma SH-SY5Y cells system, it was found that 10 micromol/l of baicalein and baicalin significantly protected cells against H(2)O(2)-induced injury. Baicalein was the most effective antioxidant among the four tested compounds in every system due to its o-tri-hydroxyl structure in the A ring. Compared with a well-known flavonoid, quercetin, the antioxidant activity of baicalein was lower in DPPH or AAPH system, but a little higher in those systems which might associate with iron ion. These results suggest that flavonoids in the radix of Scutellaria baicalensis with o-di-hydroxyl group in A the ring, such as baicalein and baicalin, could be good free radical scavengers and might be used to cure head injury associated with free radical assault.
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PMID:Free radical scavenging and antioxidant activities of flavonoids extracted from the radix of Scutellaria baicalensis Georgi. 1056 78


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