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)

We recently identified the cis-regulatory element and its specific nuclear binding factors for delta 12-prostaglandin (PG) J2-induced expression of the rat heme oxygenase, HO-1 [Koizumi, T., Odani, N., Okuyama, T., Ichikawa, A. and Negishi, M. (1995) J. Biol. Chem. 270, in press]. Here we further examined the molecular mechanism underlying the delta 12-PGJ2-induced HO-1 gene expression. Protein kinase inhibitors, 2-aminopurine and staurosporine, suppressed the delta 12-PGJ2-induced HO-1 mRNA and the nuclear protein binding to the delta 12-PGJ2-responsive cis-regulatory element in rat basophilic leukemia cells. Furthermore, the nuclear protein binding to the element was suppressed by in vitro phosphatase treatment of the nuclear proteins from delta 12-PGJ2-treated cells. These findings suggest that delta 12-PGJ2 induces the expression of the HO-1 gene through phosphorylation of the nuclear proteins which bind to the delta 12-PGJ2-responsive element.
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PMID:Involvement of protein kinase in delta 12-prostaglandin J2-induced expression of rat heme oxygenase-1 gene. 755 84

We recently reported that delta 12-prostaglandin (PG) J2 caused various cells to synthesize heme oxygenase, HO-1 (Koizumi, T., Negishi, M., and Ichikawa, A. (1992) Prostaglandins 43, 121-131). Here we examined the molecular mechanism underlying the delta 12-PGJ2-induced HO-1 synthesis. delta 12-PGJ2 markedly stimulated the promoter activity of the 5'-flanking region of the rat HO-1 gene from -810 to +101 in rat basophilic leukemia cells. From functional analysis of various deletion mutant genes we found that the delta 12-PGJ2-responsive element was localized in a region from -690 to -660, containing an E-box motif, which was essential for the delta 12-PGJ2-stimulated promoter activity. When the region containing the delta 12-PGJ2-responsive element was combined with a heterologous promoter, SV40 promoter, in the sense and antisense direction, the element showed an enhancer activity in response to delta 12-PGJ2. Gel mobility shift assays demonstrated that delta 12-PGJ2 specifically stimulated the binding of two nuclear proteins to the E-box motif of this region. These results indicate that delta 12-PGJ2 induces the expression of the rat HO-1 gene through nuclear protein binding to a specific element having an E-box motif.
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PMID:Identification of a cis-regulatory element for delta 12-prostaglandin J2-induced expression of the rat heme oxygenase gene. 766 98

Merocyanine 540 (MC540)-mediated photodynamic action is a novel approach for purging tumor cells from autologous remission bone marrow explants. The purpose of this study was to evaluate the effects of hemin (ferriprotoporphyrin IX), a potential source of pro-oxidant iron in bone marrow, on in vitro photodynamic inactivation of leukemia cells. Murine L1210 cells exhibited a progressive loss of clonogenicity when irradiated with broad-band visible light in the presence of MC540. Hemin had strikingly different effects on photokilling, depending on its contact time with cells, eliciting a sizable decrease in resistance after short-term (30-min) contact but a marked increase in resistance after long-term (24-h) contact. Similar trends were observed when cells were challenged with glucose/glucose oxidase, indicating that the responses apply to more than one type of oxidative stress. Immunoblot analyses revealed that the levels of inducible heme oxygenase (HO-1) and ferritin heavy (H) chain were substantially elevated 24 h after hemin addition. HO-1 increased relatively rapidly and maximized within 4 h after adding hemin, whereas H-ferritin increased more slowly in parallel with the development of hyperresistance, maximizing after 24-36 h. Desferrioxamine, an avid iron chelator, had no effect on HO-1 induction but inhibited both ferritin induction and the increase in cell resistance, suggesting that HO-mediated release of iron from hemin was necessary for triggering these responses. Spleen apoferritin was taken up by L1210 cells and strongly inhibited photokilling, further implicating ferritin involvement in hyperresistance. Photokilling was accompanied by free radical-mediated lipid peroxidation (thiobarbituric acid reactivity), which could be suppressed substantially by 24-h hemin preincubation. A plausible explanation for the long-term effects of hemin is that excess H-ferritin generated as a result of iron-regulatory protein deactivation sequesters toxic iron, which might otherwise catalyze damaging lipid peroxidation. Chronic oxidative release of hemin from bone marrow erythroid cells could compromise the efficacy of photopurging by making tumor cells more tolerant to photooxidative insult.
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PMID:Hyperresistance of leukemia cells to photodynamic inactivation after long-term exposure to hemin. 884 Sep 77

Gene transfer or gene therapy has advantages in the treatment of a variety of disorders due to its selective expression within specific mammalian cells. IFN-alpha has been used in the management of leukemia, and gene transfer of the IFN-alpha gene into hematopoietic progenitor cells may have great potential for the treatment of chronic myelogenous leukemia (CML). Therefore, we examined the ability of adenovirus (Ad)-IFN-alpha gene construct to transfect normal bone marrow hematopoietic CD34+ stem cells and the production of IFN-alpha protein by these cells. Ad-cytomegalovirus (CMV) promoter-driven IFN-alpha at multiple doses was assessed to transfect highly purified CD34+ cells in liquid culture. Optimal transduction of CD34+ cells with the AdCMV-IFN-alpha construct was achieved using 120 plaque forming units (pfu). Flow cytometric determinations revealed that there was no significant difference in CD34+ cell viability for the 8 or 12-h transfection periods. Immunoassay of IFN-alpha produced by CD34+ cells shows that IFN-alpha levels increased several fold in transfected cells and this was not seen in CD34+ cells transfected with the heme oxygenase gene (HO-1). These in vitro data suggest that adenovirus-mediated gene transfer of IFN-alpha into hematopoietic stem cells can be achieved and that the IFN-alpha protein is produced by viable CD34 progenitor cells.
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PMID:Gene transfer of alpha interferon into hematopoietic stem cells. 959 68

Transient reduction in coronary perfusion pressure in the isolated mouse heart increases microvascular resistance (paradoxical vasoconstriction) by an endothelium-mediated mechanism. To assess the presence and extent of paradoxical vasoconstriction in hearts from normal and diabetic rats and to determine whether increased heme oxygenase (HO)-1 expression and HO activity, using cobalt protoporphyrin (CoPP), attenuates coronary microvascular response, male Wistar rats were rendered diabetic with nicotinamide/streptozotocin for 2 wk and either CoPP or vehicle was administered by intraperitoneal injection weekly for 3 wk (0.5 mg/100 g body wt). The isolated beating nonworking heart was submitted to transient low perfusion pressure (20 mmHg), and coronary resistance (CR) was measured. During low perfusion pressure, CR increased and was associated with increased lactate release. In diabetic rats, CR was higher, HO-1 expression and endothelial nitric oxide synthase were downregulated, and inducible nitric oxide synthase and O(2)(-) were upregulated. After 3 wk of CoPP treatment, HO activity was significantly increased in the heart. Upregulation of HO-1 expression and HO activity by CoPP resulted in the abolition of paradoxical vasoconstriction and a reduction in oxidative ischemic damage. In addition, there was a marked increase in serum adiponectin. Elevated HO-1 expression was associated with increased expression of cardiac endothelial nitric oxide synthase, B-cell leukemia/lymphoma extra long, and phospho activator protein kinase levels and decreased levels of inducible nitric oxide synthase and malondialdehyde. These results suggest a critical role for HO-1 in microvascular tone control and myocardial protection during ischemia in both normal and mildly diabetic rats through the modulation of constitutive and inducible nitric oxide synthase expression and activity, and an increase in serum adiponectin.
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PMID:Beneficial effect of heme oxygenase-1 expression on myocardial ischemia-reperfusion involves an increase in adiponectin in mildly diabetic rats. 1790 3

Heme plays an important biomodulating role in various cell functions. In this study, we examined the effects of hemin on cellular sensitivity to imatinib and other anti-leukemia reagents. Hemin treatment of human BCR/ABL-positive KCL22 leukemia cells increased IC(50) values of imatinib, that is, the drug resistance, in a dose-dependent manner without any change in the BCR/ABL kinase activity. Imatinib-induced apoptosis was also suppressed by hemin treatment in KCL22 cells. Hemin treatment increased the activity of gamma-glutamylcysteine synthetase (gamma-GCS) light subunit gene promoter, which contains a Maf recognition element (MARE). Protein levels of gamma-GCS and heme oxygenase-1 (HO-1), two MARE-containing genes, were also increased after hemin treatment. Knockdown of Nrf2 expression by RNA interference largely abolished the effect of hemin on imatinib-treated cells, suggesting that Nrf2 recognition of MARE is essential for the hemin-mediated protective effect. Similar to hemin, treatment of cells with delta-aminolevulinic acid (delta-ALA), the obligatory heme precursor, also increased IC(50) values of imatinib. In contrast, inhibition of cellular heme synthesis by succinylacetone increased the sensitivity of cells to imatinib in two imatinib-resistant cell lines, KCL22/SR and KU812/SR. Hemin treatment also decreased the sensitivity of cells to four anthracyclins, daunorubicin, idarubicin, doxorubicin, and mitoxantrone, in BCR/ABL-negative leukemia U937 and THP-1 cells, as well as in KCL22 cells. These findings thus indicate that cellular heme level plays an important role in determining the sensitivity of cells to imatinib and certain other anti-leukemia drugs and that the effect of heme may be mediated via its ability to upregulate Nrf2 activity.
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PMID:Hemin reduces cellular sensitivity to imatinib and anthracyclins via Nrf2. 1817 53

The expression of heme oxygenase-1 (HO-1), stress-related enzyme, is induced in leukaemia and some cancer tissues, but relatively little is known about the differential pattern of HO-1 expression and proliferation in premalignant lesions of the epithelial oral mucosa. The purpose of this study was to evaluate whether HO-1 expression and proliferation were increased in preneoplastic lesions compared to normal and oral cancer tissues. Immunohistochemical staining was used to examine the expression patterns of HO-1 and proliferating cell nuclear antigen (PCNA) in a series of normal mucosa and mild-to-severe cases of oral epithelial dysplasia (OED) and oral squamous cell carcinoma. Both HO-1 and PCNA are expressed in the basal cells of normal oral mucosa. In patients with OED and carcinoma in situ, immunostaining for PCNA and HO-1 was more intense, and gradually extended into the superficial layers of the mucosa. HO-1 and PCNA expression was correlated with the degree of epithelial dysplasia. Oral squamous cell carcinoma also showed elevated expression of HO-1, but this level was not higher than in severe OED or carcinoma in situ. These results suggest that the up-regulation of HO-1 in premalignant oral lesions is part of an early cytoprotection mechanism against carcinogenesis in the oral mucosa.
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PMID:Upregulation of heme oxygenase-1 in oral epithelial dysplasias. 1827 47

Kaempferol is one of the most commonly found dietary flavonoids. The exposure to kaempferol is known to inhibit degranulation from mast cells, but the inhibitory mechanism of degranulation has not been clarified yet. In this study, we investigated the involvement of heme oxygenase (HO)-1 in the anti-allergic action of kaempferol against degranulation in rat basophilic leukemia (RBL-2H3) cells. Our results demonstrate upregulation of HO enzymatic activity after short (15 min) exposure to kaempferol, followed by the induction of HO-1 expression in protein. The involvement of HO-1 in the kaempferol-induced inhibition of degranulation was confirmed using tin protoporphyrin IX (SnPP), a HO-1 inhibitor. These findings strongly suggest that kaempferol exerts anti-allergic actions via activation of the HO-1.
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PMID:Involvement of heme oxygenase-1 in kaempferol-induced anti-allergic actions in RBL-2H3 cells. 1921 25

It has been proved that oxidative stress increases when leukemia is accompanied by depression. This fact may indicate the role of oxidative stress in the development of depression in cancer patients. The aim of this study was to determine whether the acute myeloid leukemia of Brown Norway rats, which is accompanied by oxidative stress, evoked behavioral and receptor changes resembling alterations characteristic of rat models of depression. The rats were divided into two groups: leukemic rats and healthy control. Leukemia was induced through intraperitoneal injection of 10(7) promyelocytic leukemia cells to the Brown Norway rats. Depression-like behavior was evaluated in the forced swim test at 30 or 34 days after leukemic cells injection. The rats were killed after the evaluation and the spleen, brain cortex and hippocampus were excised. The red-ox state was assessed in homogenates of tissues by measuring total glutathione (GSH) content, the ferric ion reducing ability of plasma (FRAP) level, expression of heme oxygenase-1 (HO-1), biliverdin reductase (BvR) and ferritin mRNA, superoxide dismutase (SOD) activity, as well as malondialdehyde (MDA) concentration. Radioligand binding assay was used to assess of the effect of leukemia on cortical receptors. Leukemic cells were identified using RM-124 antibody by FACS Calibur flow cytometry. Leukemia influenced locomotory activity as well as forced swim test behavior in a 34-day series of experiments. Signs of oxidative stress in leukemic rats were observed in each examined stage of leukemia development. The FRAP values and glutathione contents, were significantly lowered whereas HO-1 mRNA expression, and malonodialdehyde concentrations were significantly increased in the spleen and brain structures of leukemic rats in comparison with the healthy controls. A significant increase in the potency of glycine to displace [(3)H]L-689,560 from the strychnine-insensitive glycine site of the N-methyl-D-aspartic (NMDA) receptors receptor complex in cortical homogenates of the leukemic rats in 30- and 34-day experimental series was observed in comparison with the control. Upregulation of 5-HT(2A) receptors was observed in rat cortex after 30 days of leukemia development but not in 34-days series compared with the control. It is concluded that disturbances in antioxidant system in brain cortex were accompanied by an activation of glycine sites of the NMDA receptor complex, regardless of stage of leukemia development, which are characteristic of model of depression. Findings of our study demonstrate the link between glutamatergic activity, oxidative stress and leukemia.
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PMID:Evaluation of oxidative status and depression-like responses in Brown Norway rats with acute myeloid leukemia. 1926 4

Heat shock protein 32 (Hsp32), also known as heme oxygenase-1 (HO-1), is a stress-related anti-apoptotic molecule, that has been implicated in enhanced survival of neoplastic cells and in drug-resistance. We here show that Hsp32 is expressed in most solid tumors and hematopoietic neoplasms and may be employed as a new therapeutic target as evidenced by experiments using specific siRNA and a Hsp32-targeting pharmacologic inhibitor. This Hsp-32 targeting drug, SMA-ZnPP, was found to inhibit the proliferation of neoplastic cells with IC(50) values ranging between 1 and 50 microM. In addition, SMA-ZnPP induced apoptosis in all neoplastic cells examined. Furthermore, SMA-ZnPP was found to synergize with other targeted and conventional drugs in producing growth-inhibition. Resulting synergistic effects were observed in all tumor and leukemia cells examined. Interestingly, several of the drug partners, when applied as single agents, induced the expression of Hsp32 in neoplastic cells, suggesting that synergistic effects resulted from SMA-ZnPP-induced ablation of a Hsp32-mediated survival-pathway that is otherwise used by tumor cells to escape drug-induced apoptosis. Together, Hsp32 is an important survival factor and target in solid tumors and hematopoietic neoplasms, and may be used to optimize anticancer therapy by combining conventional or targeted drugs with Hsp32-inhibitors. Based on these data, it seems desirable to explore the value of Hsp32-targeting drugs as anti-cancer agents in clinical trials.
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PMID:Targeting of Hsp32 in solid tumors and leukemias: a novel approach to optimize anticancer therapy. 1950 70


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