Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.14.99.3 (heme oxygenase)
 4,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The preferential retention of the arginine allele at the p53 codon 72 locus is commonly observed in tumours from arginine/proline heterozygotes. Considering that cancer cells are harboured in a hypoxic environment in vivo, we here tested the hypothesis that the p53 codon 72 proline allele confers a survival disadvantage in presence of hypoxia. Here, we show that the transient transfection of the proline allele in p53 null cancer cells exposed to low oxygen tension or to the hypoxia-mimetic drug Desferoxamine induces a higher amount of cell death than the arginine allele. Accordingly, proline allele transiently transfected cell lines express lower levels of hypoxia pro-survival genes (HIF-1alpha, carbonic anhydrase IX, vascular endothelial growth factor, heme oxygenase-I, hepatocyte growth factor receptor, vascular endothelial growth factor receptor 2), compared to those transiently transfected with the arginine allele. Further, we report that the exposure of the arginine/proline heterozygote MCF-7 breast cancer cell line to cytotoxic concentration of Desferoxamine for several weeks, gives raise to hypoxia-resistant clones, carrying the arginine, but not the proline allele. These data indicate that the p53 codon 72 proline allele is less permissive for the growth of cancer cells in a hypoxic environment, and suggest that the preferential retention of the arginine allele in the tumour tissues of arginine/proline heterozygous patients may depend upon its lowered capacity to induce cell death in a hypoxic tumour environment.
Br J Cancer 2007 Apr 23
PMID:The p53 codon 72 proline allele is endowed with enhanced cell-death inducing potential in cancer cells exposed to hypoxia. 1740 54

The isothiocyanate sulforaphane was isolated from broccoli extracts in a bioactivity-guided fractionation as the principal and very potent inducer of cytoprotective phase 2 enzymes and subsequently shown to inhibit tumor development in animal models that involve various carcinogens and target organs. Because broccoli and broccoli sprouts are widely consumed, extracts obtained from them are viewed as convenient vehicles for sulforaphane delivery to humans. In relation to our current interest in devising strategies for protection against UV light-induced skin cancer, it was necessary to examine the safety and efficacy of topical application of sulforaphane-containing broccoli sprout extracts as single and multiple doses in both mice and humans. Topical application of an extract delivering 100 nmol sulforaphane/cm(2) increased the protein levels of NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione S-transferase A1, and heme oxygenase 1, three representative phase 2 enzymes, in mouse skin epidermis. Quantitative assessment of the activity of NQO1 24 h after dosing showed increases of 1.5- and 2.7-fold after application of single and multiple (thrice, every 24 h) doses, respectively. A dose-escalation safety study in healthy human subjects revealed no adverse reactions when doses as high as 340 nmol of sulforaphane in the form of broccoli sprout extracts were applied topically to the center of a 1-cm-diameter circle drawn on the volar forearm. A subsequent efficacy study showed that despite the interindividual differences in basal levels, the enzyme activity of NQO1 in homogenates of 3-mm full thickness skin punch biopsies increased in a dose-dependent manner, with maximum increases of 1.5- and 4.5-fold after application of 150 nmol doses, once or three times (at 24 h-intervals), respectively, thus providing direct evidence for induction of the phase 2 response in humans.
Cancer Epidemiol Biomarkers Prev 2007 Apr
PMID:Induction of the phase 2 response in mouse and human skin by sulforaphane-containing broccoli sprout extracts. 1741 83

The catabolism of heme, generating biliverdin, carbon monoxide, and free iron, is mediated by heme oxygenase (HO). One form of this of this enzyme, heme oxygenase-1, is inducible by numerous agents which promote oxidative stress, and is now known to provide important antioxidant protection, as demonstrated in many rodent models of free radical-mediated pathogenesis, and suggested by epidemiology observing favorable health outcomes in individuals carrying high-expression alleles of the HO-1 gene. The antioxidant impact of HO-1 appears to be mediated by bilirubin, generated rapidly from biliverdin by ubiquitously expressed biliverdin reductase. Bilirubin efficiently scavenges a wide range of physiological oxidants by electron donation. In the process, it is often reconverted to biliverdin, but biliverdin reductase quickly regenerates bilirubin, thereby greatly boosting its antioxidant potential. There is also suggestive evidence that bilirubin inhibits the activity or activation of NADPH oxidase. Increased serum bilirubin is associated with reduced risk for atherogenic disease in epidemiological studies, and more limited data show an inverse correlation between serum bilirubin and cancer risk. Gilbert syndrome, a genetic variant characterized by moderate hyperbilirubinemia attributable to reduced hepatic expression of the UDP-glucuronosyltransferase which conjugates bilirubin, has been associated with a greatly reduced risk for ischemic heart disease and hypertension in a recent study. Feasible strategies for boosting serum bilirubin levels may include administration of HO-1 inducers, supplementation with bilirubin or biliverdin, and administration of drugs which decrease the efficiency of hepatic bilirubin conjugation. The well-tolerated uricosuric drug probenecid achieves non-competitive inhibition of hepatic glucuronidation reactions by inhibiting the transport of UDP-glucuronic acid into endoplasmic reticulum; probenecid therapy is included in the differential diagnosis of hyperbilirubinemia, and presumably could be used to induce an ''iatrogenic Gilbert syndrome''. Other drugs, such as rifampin, can raise serum bilirubin through competitive inhibition of hepatocyte bilirubin uptake--although unfortunately rifampin is not as safe as probenecid. Measures which can safely achieve moderate serum elevations of bilirubin may prove to have value in the prevention and/or treatment of a wide range of disorders in which oxidants play a prominent pathogenic role, including many vascular diseases, cancer, and inflammatory syndromes. Phycobilins, algal biliverdin metabolites that are good substrates for biliverdin reductase, may prove to have clinical antioxidant potential comparable to that of bilirubin.
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PMID:''Iatrogenic Gilbert syndrome''--a strategy for reducing vascular and cancer risk by increasing plasma unconjugated bilirubin. 1782 97

Interleukin-11 (IL-11) is a cytokine which interacts with a variety of haemopoietic and non-haemopoietic cell types. Recombinant human IL-11 (rhIL-11; oprelvekin) is produced in Escherichia coli and differs from the naturally occurring protein only in the absence of the amino-terminal proline residue. In synergy with other factors, rhIL-11 stimulates the growth of myeloid, erythroid, and megakaryocyte progenitor cells in vitro. In vivo, rhIL-11 is active in mice, rats, dogs, guinea pigs, hamsters and non-human primates, where the principal activity measured was stimulation of megakaryocytopoiesis and thrombopoiesis. rhIL-11 has shown benefit in 2 clinical trials by significantly reducing severe chemotherapy-induced thrombocytopenia. In addition to its thrombopoietic activity, rhIL-11 has also shown activity in models of acute gastrointestinal mucosal damage. rhIL-11 enhanced survival in mice following cytoablative therapy and in a hamster model of chemotherapy-induced oral mucositis, where treatment with rhIL-11 was associated with decreased mucosal damage, accelerated healing and reduced numbers of deaths. rhIL-11 is currently in clinical trials for the treatment of chemotherapy-induced mucositis. In rat models of acute colonic injury and inflammatory bowel disease, rhIL-11 treatment reduced intestinal mucosal damage and alleviated clinical signs. rhIL-11 has direct effects on activated macrophages to reduce the production of pro-inflammatory mediators. In animal models of endotoxaemia, rhIL-11 treatment reduced serum levels of pro-inflammatory cytokines and blocked hypotension. rhIL-11 increased survival in models of Gram-negative sepsis and toxic shock. Based on these studies, rhIL-11 is currently in clinical trials for treatment of Crohn's disease. Other inflammatory conditions are being further evaluated. Mechanistically, rhIL-11 functions at many levels to control inflammation, ameliorate tissue damage and maintain haemostasis in the face of trauma or infection. rhIL-11 has direct effects on hepatocytes, inducing the production of acute phase reactant proteins, haem oxygenase and tissue inhibitor of metalloproteinase-1 (TIMP-1). TIMP-1 expression can also be induced in synoviocytes and chondrocytes by treatment with rhIL-11. rhIL-11 administration has been associated with increased plasma levels of von Willebrand factor and fibrinogen. rhIL-11 treatment potentially offers multiple benefits for cancer chemotherapy patients, such as prevention of thrombocytopenia, gastrointestinal epithelial protection and subsequent reduction of mucositis, and amelioration of inflammatory complications. In addition, rhIL-11 is being evaluated further in the treatment of inflammatory disorders such as inflammatory bowel disease, rheumatoid arthritis and sepsis.
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PMID:Interleukin-11. 1803 Nov 4

The clinical utility of anthracycline anticancer agents, especially doxorubicin, is limited by a progressive toxic cardiomyopathy linked to mitochondrial damage and cardiomyocyte apoptosis. Here we demonstrate that the post-doxorubicin mouse heart fails to upregulate the nuclear program for mitochondrial biogenesis and its associated intrinsic antiapoptosis proteins, leading to severe mitochondrial DNA (mtDNA) depletion, sarcomere destruction, apoptosis, necrosis, and excessive wall stress and fibrosis. Furthermore, we exploited recent evidence that mitochondrial biogenesis is regulated by the CO/heme oxygenase (CO/HO) system to ameliorate doxorubicin cardiomyopathy in mice. We found that the myocardial pathology was averted by periodic CO inhalation, which restored mitochondrial biogenesis and circumvented intrinsic apoptosis through caspase-3 and apoptosis-inducing factor. Moreover, CO simultaneously reversed doxorubicin-induced loss of DNA binding by GATA-4 and restored critical sarcomeric proteins. In isolated rat cardiac cells, HO-1 enzyme overexpression prevented doxorubicin-induced mtDNA depletion and apoptosis via activation of Akt1/PKB and guanylate cyclase, while HO-1 gene silencing exacerbated doxorubicin-induced mtDNA depletion and apoptosis. Thus doxorubicin disrupts cardiac mitochondrial biogenesis, which promotes intrinsic apoptosis, while CO/HO promotes mitochondrial biogenesis and opposes apoptosis, forestalling fibrosis and cardiomyopathy. These findings imply that the therapeutic index of anthracycline cancer chemotherapeutics can be improved by the protection of cardiac mitochondrial biogenesis.
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PMID:The CO/HO system reverses inhibition of mitochondrial biogenesis and prevents murine doxorubicin cardiomyopathy. 1803 88

In the present study, we investigated the antitumor effects of the invasiveness and migration of heme oxygenase 1 (HO-1) in human breast carcinoma cells. 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced matrix metalloproteinase-9 (MMP-9) enzyme activity and gene expression at both protein and mRNA levels were examined in human breast carcinoma cells (MCF-7 and MDA-MB-231), and the addition of the MMP-9 inhibitor, SB3CT, significantly suppressed TPA-induced invasion and migration according to the in vitro Transwell assay. Elevation of HO-1 gene expression by ferric protoporphyrin IX inhibited TPA-induced invasion of MCF-7 cells, which was blocked by adding the heme oxygenase inhibitor, tin protoporphyrin IX, or transfection of cells with HO-1 short hairpin RNA. MCF-7 cells overexpressing HO-1 (MCF-7/HO-1) were established in the present study, and TPA-induced MMP-9 gene expression, tumor invasion, and colony formation were significantly reduced in MCF-7/HO-1 cells, compared with those in Neo-transfected cells. Activation of protein kinase Calpha/extracellular signal-regulated kinases/AP-1 with stimulation of reactive oxygen species production was involved in TPA-induced invasion of MCF-7 cells, which was attenuated by HO-1 protein induced by ferric protoporphyrin IX or transfection of HO-1 expression vectors. Additionally, the addition of carbon monoxide, but not ferric ions, biliverdin, or bilirubin, inhibited TPA-induced invasion through suppressing MMP-9, extracellular signal-regulated kinases, and AP-1 activation stimulated by TPA. The beneficial role of HO-1 in blocking tumor invasion was first identified in this study.
Mol Cancer Ther 2008 May
PMID:Heme oxygenase-1 inhibits breast cancer invasion via suppressing the expression of matrix metalloproteinase-9. 1848 7

Endogenous overexpression of the antiapoptotic protein heme oxygenase 1 (HO-1) has been shown to occur in various cancer diseases and might contribute to cancer progression. We compared the expression levels of HO-1 in human liver to expression levels in hepatocellular carcinoma (HCC), as well as the effect of HO-1 inhibition by small interfering RNA (siRNA) on cellular survival and apoptosis in the mouse hepatoma cell lines Hepa129 and Hepa1-6 and on orthotopic tumor growth in immune-competent C3H/HeN mice. Our results show that HO-1 is frequently overexpressed in human HCC. Downmodulation of HO-1 by siRNA resulted in increased cellular damage and apoptosis, reduced proliferation, reduced growth of orthotopic HCC and reduced angiogenesis. Livers and kidneys of treated animals did not reveal signs of damage by this treatment. In conclusion, a specific knockdown of HO-1 might represent a novel therapeutic approach in HCC therapy.
Int J Cancer 2008 Sep 15
PMID:Inhibition of heme oxygenase 1 expression by small interfering RNA decreases orthotopic tumor growth in livers of mice. 1941 48

High expression of the inducible isoform of heme oxygenase (HO-1) is well known in various solid tumors in human and experimental animal models. To investigate the relationship between HO-1 and nasopharyngeal carcinomas, especially its involvement in the response of nasopharyngeal carcinomas to radiotherapy, thirty-two nasopharyngeal carcinomas were semi-quantitatively analyzed by RT-PCR, and the expression of HO-1 was correlated with the consequence after novel radiotherapy, which was evaluated by the reduction of tumor size. Among 32 nasopharyngeal carcinomas, HO-1 expression was found in 19 samples (59.4%), in which 9 patients (47.4%) showed no response to radiotherapy. Interestingly, in 13 nasopharyngeal carcinoma patients with negative expression of HO-1, radiotherapy exhibited to be effective (9 patients, 69.2%) or responsive (3 patients, 23.1%). In this study, we first demonstrated the expression of HO-1 in nasopharyngeal carcinomas, and more important, these findings strongly suggest the potential of HO-1 as a useful index in identifying patients with well response to radiotherapy, further these data indicate a new therapeutic for nasopharyngeal carcinoma by inhibiting HO-1 activity, which warrants further investigation.
J Exp Clin Cancer Res 2008 Jun 26
PMID:Implication of heme oxygenase-1 in the sensitivity of nasopharyngeal carcinomas to radiotherapy. 1858 67

The inhibitory effects of a novel prodrug, 3-(4'-geranyloxy-3'-methoxyphenyl)-2-trans-propenoyl-L-alanyl-L-proline (GAP), of the secondary metabolite 4'-geranyloxy-3'-methoxyphenyl)-2-trans-propenoic acid (4'-geranyloxy-ferulic acid), on colon carcinogenesis was investigated using an azoxymetahen (AOM)/dextran sodium sulfate (DSS) model. GAP was synthetically derived from ferulic acid. Male CD-1 (ICR) mice initiated with a single intraperitoneal injection of azoxymethane (10 mg/kg body weight) were promoted by 1% (wt/vol) DSS in drinking water for 7 days. They were then given modified AIN-76A diet containing 0.01% or 0.05% GAP for 17 wk. At Week 20, the development of colonic adenocarcinoma was significantly inhibited by GAP feeding at dose levels of 0.01% [60% incidence (P = 0.0158) with a multiplicity of and 1.13 +/- 1.13 (P < 0.05)] and 0.05% [53% incidence (P = 0.0057) with a multiplicity of 0.08 +/- 1.08 (P < 0.01)], when compared to the AOM/DSS group (95% incidence with a multiplicity of 3.10 +/- 3.06). Dietary GAP modulated the mitotic and apoptotic indexes in the crypt cells and lowered 8-hydroxy-2'-deoxyguanosine (8-OHdG)-positive cells in the colonic mucosa. Urinary level of 8-OHdG was lowered by GAP feeding. Additionally, dietary GAP elevated the immunoreactivity of an inducible form of heme oxygenase 1 in the colonic mucosa. Our results indicate that GAP is able to inhibit colitis-related colon carcinogenesis by modulating proliferation and oxidative stress in mice.
Nutr Cancer 2008
PMID:A novel prodrug of 4'-geranyloxy-ferulic acid suppresses colitis-related colon carcinogenesis in mice. 1879 32

This review will discuss some issues related to the risk/benefit profile of the use of dietary antioxidants. Thus, recent progress regarding the potential benefit of dietary antioxidants in the treatment of chronic diseases with a special focus on immune system and neurodegenerative disorders will be discussed here. It is well established that reactive oxygen species (ROS) play an important role in the etiology of numerous diseases, such as atherosclerosis, diabetes and cancer. Among the physiological defense system of the cell, the relevance of antioxidant molecules, such as glutathione and vitamins is quite well established. Recently, the interest of researchers has, for example, been conveyed on antioxidant enzyme systems, such as the heme oxygenase/biliverdin reductase system, which appears modulated by dietary antioxidant molecules, including polyphenols and beta-carotene. These systems possibly counteract oxidative damage very efficiently and finally modulate the activity of oxidative phenomena occurring, for instance, during pathophysiological processes. Although evidence shows that antioxidant treatment results in cytoprotection, the potential clinical benefit deriving from both nutritional and supplemental antioxidants is still under wide debate. In this line, the inappropriate assumption of some lipophylic vitamins has been associated with increased incidence of cancer rather than with beneficial effects.
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PMID:The role of antioxidant supplement in immune system, neoplastic, and neurodegenerative disorders: a point of view for an assessment of the risk/benefit profile. 1882 65


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