Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.37 (neutrophil elastase)
 4,078 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Flavanols--a class of plant polyphenols abundant in tea leaves and grape seeds and skins--have been found to inhibit some matrix-proteases instrumental in inflammation and cancer invasion, such as leukocyte elastase (LE) and gelatinases. In order to establish the relationship between chemical structure and activity, 27 different flavonoids (antocyanidins, dihydrochalcones, dihydroflavonols, flavanolignans, flavanols, flavones, flavonols and isoflavones) and other compounds with anti-oxidant properties were evaluated for their potential in blocking LE and gelatinase activities. LE activity was measured using a chromogenic substrate: from comparison of the different levels of inhibition, it was deduced that a crucial role in inhibition might be played by a galloyl moiety or hydroxyl group at C3, three hydroxyl groups at B ring, one hydroxyl group at C4', and a 2,3-double bond. Gelatinase activity was measured using the gelatin-zymography assay, and its inhibition showed that three hydroxyl groups at the A or B ring, or, for non-planar molecules, a galloyl moiety at C3 could be determinant. This comparative study is proposed as a basis for designing new molecules with enhanced anti-proteolytic activities, and no or reduced side-effects, for use in hindering inflammation, cancer invasion and angiogenesis.
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PMID:Inhibition of matrix-proteases by polyphenols: chemical insights for anti-inflammatory and anti-invasion drug design. 1212 43

There are several common themes that are emerging from our expanding knowledge about the inherited bone marrow failure syndromes. Patients have a spectrum of birth defects, which are relatively characteristic for each syndrome. but overlap in features such as poor growth. radial ray anomalies, and involvement of skin, eyes, renal, cardiac, skeletal, and other organs. Within each syndrome the composition and severity of the physical phenotype varies widely, and it may require the astute observer to make the correct diagnoses in the milder cases. There is also a wide spectrum to the hematologic picture. These range from single cytopenias such as DBA, SCN, and TAR, which do not develop pancytopenia, to SD and Amega patients who begin with deficiency of a specific single lineage, but evolve to aplastic anemia, to patients with FA or DC, who may present with a deficiency of any one of the cell lines, but almost inevitably end up with full-blown aplastic anemia. Acute myeloid leukemia has been observed in FA, DBA, DC, SD, SCN, and Amega, although not yet in TAR patients. MDS has also been reported in all of the same disorders as AML, although whether it is a preleukemic condition or an independent bone marrow dyspoiesis is not yet clear. Solid tumors are also now appearing in patients whose underlying disease involves hematopoiesis and physical development. These tumors occur at much younger ages than in the general population, in patients who do not appear to have the usual risk factors, and have patterns that are characteristic to the syndrome, such as head and neck and gynecologic cancers in FA and DC, and osteogenic sarcomas in DBA. The other syndromes have not yet been reported to have a propensity for solid tumors. Several genes have been identified that are mutant in some of the syndromes, although the pathophysiology is still not entirely clear. The inheritance patterns include X-linked recessive, autosomal dominant, autosomal recessive, and even mitochondrial. The FA gene products appear to cooperate, and are important in the pathways involved in response to DNA damage. However, the role of this pathway in developmental defects, hematopoietic failure, and the specific malignancies in FA is not fully elucidated. The DC gene products are important for maintenance of telomere length, which may have relevance to development of aplastic anemia and malignancies, but the relation to the physical phenotype is less apparent. The role of mutations in c-mpl in Amega is more straightforward. since the gene codes for the receptor for thrombopoietin. which is the hormone required for megakaryocyte and platelet development; patients with mutant c-mpl do not have birth defects. The role of mutations in RPS19 in erythropoiesis or developmental defects in DBA patients is not obvious, and the increased frequency of osteogenic sarcomas suggests that at least that subset of patients may have a mutant tumor suppressor gene (such as p53, the mutant gene in Li-Fraumeni syndrome) [68]. Although patients with SCN have mutations in neutrophil elastase, patients with similar mutations may have relatively benign cyclic neutropenia, or may even have normal neutrophil levels [69,70]. The mitochondrial gene deletions in Pearson's Syndrome result in variable degrees of acidosis, and varied organ involvement due to heteroplasmy. Thus, the disorders included under the rubric "inherited bone marrow failure syndromes" have clinical. hematologic, oncologic, and genetic diversity.
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PMID:Bone marrow failure syndromes in children. 1243 Jun 21

A variety of serine proteases, including urokinase-type plasminogen activator (uPA), plasmin,and polymorphonuclear leukocyte elastase (PMN-E), have been implicated in the processes of tumor cell invasion and metastasis. Besides degrading of matrix proteins, PMN-E has been shown to be able to cleave and inactivate plasminogen activator inhibitor-1 (PAI-1), the main inhibitor of uPA, and alpha2-antiplasmin, the natural inhibitor of plasmin, thus enabling an uncontrolled matrix degradation by the fibrinolytic enzymes. Because only limited data are available on a relationship between the tumor level of PMN-E and prognosis in primary breast cancer patients, in the present study we have measured with an ELISA the levels of PMN-E (in complex with alpha1-proteinase inhibitor) in cytosolic extracts of 1143 primary breast tumors. Levels of complexed PMN-E have been correlated with the lengths of metastasis-free survival (MFS), relapse-free survival, and overall survival, and a comparison was made with data previously obtained for uPA and PAI-1. Our results show that patients with a high PMN-E level in their primary tumor had a rapid relapse and an early death compared with patients with a low tumor level of PMN-E. This held true for node-negative and node-positive subgroups of patients as well. The relationship of PMN-E with a poor prognosis was especially obvious during short-term follow-up (0-60 months). In Cox multivariate regression analysis, corrected for the traditional prognostic factors, PMN-E was an independent prognostic factor, and high levels of PMN-E were associated with a poor MFS [hazard ratio (HR), 1.63; 95% confidence interval (CI), 1.23-2.16; P < 0.001], relapse-free survival (HR, 1.45; 95% CI, 1.10-1.89; P = 0.01), and overall survival (HR, 1.64; 95% CI, 1.20-2.23; P = 0.003). Furthermore, in all three multivariate models, PMN-E still added significantly to the model after the additional inclusion of the uPA. PMN-E was an independent prognostic factor for MFS even in the multivariate analysis including the traditional clinical prognostic factors and the strong established biochemical prognostic factors uPA and PAI-1. Our present study suggests that PMN-E is associated with breast cancer metastasis, and knowledge of the tumor PMN-E status might be helpful in selecting the appropriate individualized (adjuvant) treatment for patients with breast cancer.
Cancer Res 2003 Jan 15
PMID:The prognostic value of polymorphonuclear leukocyte elastase in patients with primary breast cancer. 1254 85

Besides a variety of other proteases, polymorphonuclear leukocyte elastase (PMN-E) is also suggested to play a role in the processes of tumour cell invasion and metastasis. Yet, there is only limited data available on the relation between the tumour level of PMN-E and prognosis in patients with primary breast cancer, and no published information exists on its relation with the efficacy of response to systemic therapy in patients with advanced breast cancer. In the present study, we have measured with enzyme-linked immunosorbent assay the levels of total PMN-E in cytosolic extracts of 463 primary breast tumours, and have correlated their levels with the rate and duration of response on first-line tamoxifen therapy (387 patients) or chemotherapy (76 patients) in patients with locally advanced and/or distant metastatic breast cancer. Furthermore, the probabilities of progression-free survival and postrelapse survival were studied in relation to the tumour levels of PMN-E. Our results show that in logistic regression analysis for response to tamoxifen treatment in patients with advanced disease, high PMN-E tumour levels were associated with a poor rate of response compared with those with low PMN-E levels (odds ratio: OR, 0.40; 95% CI, 0.22-0.73; P=0.003). After correction for the contribution of the traditional predictive factors in multivariate analysis, the tumour PMN-E status was an independent predictor of response (P=0.01). Furthermore, a high tumour PMN-E level was related with a poor progression-free survival (P<0.001) and postrelapse survival (P=0.002) in a time-dependent analysis. In contrast, the tumour level of PMN-E was not significantly related with the efficacy of response to first-line chemotherapy in patients with advanced breast cancer. Our present results suggest that PMN-E is an independent predictive marker for the efficacy of tamoxifen treatment in patients with advanced breast cancer.
Br J Cancer 2003 Apr 07
PMID:Elevated expression of polymorphonuclear leukocyte elastase in breast cancer tissue is associated with tamoxifen failure in patients with advanced disease. 1267 9

Severe congenital neutropenia (SCN), a heterogeneous disorder that includes Kostmann syndrome, predisposes to myelodysplasia and acute myelogenous leukemia. Recently identified heterozygous mutations in the gene ELA2, encoding neutrophil elastase on human chromosome 19pter, account for the majority of autosomal dominant cases of SCN, including those demonstrating neoplastic progression. The involvement of the serine protease neutrophil elastase, localized to the granules of neutrophils and monocytes, implies an unexpected role for proteolytic regulation of hematopoiesis. Continued elucidation of the clinical features, molecular genetics, and biochemistry is likely to provide insight into novel pathways of leukemia induction with attendant prospects for new avenues of therapy.
Cancer Invest 2003
PMID:Leukemia in severe congenital neutropenia: defective proteolysis suggests new pathways to malignancy and opportunities for therapy. 1453 48

Two hereditary human leukemia syndromes are severe congenital neutropenia (SCN), caused by mutations in the gene ELA2, encoding the protease neutrophil elastase, and familial platelet disorder with acute myelogenous leukemia (AML), caused by mutations in the gene AML1, encoding the transcription factor core-binding factor alpha (CBFalpha). In mice, CBFalpha regulates the expression of ELA2, suggesting a common link for both diseases. However, gene-targeted mouse models have failed to reproduce either human disease, thus prohibiting further in vivo studies in mice. Here we investigate CBFalpha regulation of the human ELA2 promoter, taking advantage of bone marrow obtained from patients with either illness. In particular, we have identified novel ELA2 promoter substitutions (-199 C to A) within a potential motif for lymphoid enhancer factor-1 (LEF-1), a transcriptional mediator of Wnt/beta-catenin signaling, in SCN patients. The LEF-1 motif lies adjacent to a potential CBFalpha binding site that is in a different position in human compared with mouse ELA2. We find that LEF-1 and CBFalpha co-activate ELA2 expression. In vitro, the high mobility group domain of LEF-1 interacts with the runt DNA binding and proline-, serine-, threonine-rich activation domains of CBFalpha. ELA2 transcript levels are up-regulated in bone marrow of an SCN patient with the -199 C to A substitution. Conversely, a mutation of the CBFalpha activation domain, found in a patient with familial platelet disorder with AML, fails to stimulate the ELA2 promoter in vitro, and bone marrow correspondingly demonstrates reduced ELA2 transcript. Observations in these complementary patients indicate that LEF-1 cooperates with CBFalpha to activate ELA2 in vivo and also suggest the possibility that up-regulating promoter mutations can contribute to SCN. Two hereditary AML predisposition syndromes may therefore intersect via LEF-1, potentially linking them to more generalized cancer mechanisms.
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PMID:Lymphoid enhancer factor-1 links two hereditary leukemia syndromes through core-binding factor alpha regulation of ELA2. 1459 2

In addition to their antibiotic potency, beta-lactams have recently been investigated as inhibitors of serine proteinase such as leukocyte elastase (LE), released by inflammatory cells. We describe the synthesis of a series of 4-alkylidene-beta-lactams, and investigate how substitutions on C-3, C-4, and N-1 of the beta-lactam ring affect the activity of human LE and gelatinases MMP-2 and MMP-9. LE activity was measured using a chromogenic substrate, while gelatin-zymography assay was used to evaluate gelatinase activity. We demonstrate that C-4 unsaturation on the beta-lactam ring determines the degree of biological activity, with a selectivity over LE by 3-[1-(tert-butyldimethylsilyloxy)-ethyl] derivatives (lowest IC(50) was 4 microM), and over gelatinase MMP-2 by C-3-unsubstituted 4-[1-ethoxycarbonyl]-ethylidene-beta-lactams (lowest IC(50) was 60 microM). (3S)-3-[(1R)-1-hydroxyethyl]-4-(1-ethoxycarbonyl)-ethylidene-azetidin-2-one inhibits gelatinase MMP-9. The compounds tested showed no cytotoxicity against NIH-3T3 murine fibroblasts. This is the first example of beta-lactams inhibiting metallo-proteinases instrumental in cancer invasion and angiogenesis. These molecules are good candidates for prototype drugs showing selective antibiotic, anti-inflammatory, and anti-invasion properties.
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PMID:4-alkylidene-azetidin-2-ones: novel inhibitors of leukocyte elastase and gelatinase. 1464 83

Neutrophil elastase and alpha 1-antitrypsin are a pair of protease and protease inhibitor counterparts. The imbalance between the two counterparts is generally thought to cause tissue damage, which could create a favourable tissue environment for carcinogens and tumour progression. Laboratory research and clinical findings have indicated that a deficiency in alpha1-antitrypsin is associated with increased risk of liver cancer, bladder cancer, gall bladder cancer, malignant lymphoma, and lung cancer. Conversely, raised concentrations of neutrophil elastase might promote the development, invasion, and metastasis of many cancers. Several mechanisms of carcinogenesis have been postulated. Excess neutrophil elastase might facilitate cancer development by causing tissue damage and air trapping, which foster longer carcinogen exposure, might promote cancer progression by degrading the intercellular matrix barrier, and might directly lead to cancer development through the tumour-necrosis-factor signalling pathway.
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PMID:Role of imbalance between neutrophil elastase and alpha 1-antitrypsin in cancer development and progression. 1500 2

The pleural space is a virtual compartment between the lung and chest wall that becomes filled with fluid and inflammatory cells during a variety of respiratory diseases. Here, we study the potential role of the eicosanoid metabolite leukotriene B4 (LTB4) in disparate diseases leading to acute (pneumonia) or chronic (tuberculosis, cancer) inflammation of the pleural space. LTB4 concentrations were significantly higher in pleural fluid due to pneumonia, tuberculosis and cancer with respect to congestive heart failure and correlated with neutrophil elastase, which is used as an indication of state of activation of neutrophils in the pleural space. Moreover, pleural LTB4 was biologically active, as an anti-LTB4 antibody partially neutralized the chemotactic activity of parapneumonic, tuberculous and cancer effusions. Macrophages, neutrophils, lymphocytes, mesothelial cells and cancer cells all expressed mRNA for 5-lipoxygenase, the enzyme that initiates leukotriene synthesis leading to the production of LTB4, in exudative pleural effusions. Upon stimulation in transudative pleural effusions, pleural macrophages produced, in a time-dependent fashion, a significantly higher concentration of LTB4 than mesothelial cells. These studies demonstrate that different cell types are capable of producing LTB4 in the inflamed pleural space and that this mediator may play a crucial role in the recruitment of neutrophils into the pleural space.
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PMID:LTB4 is present in exudative pleural effusions and contributes actively to neutrophil recruitment in the inflamed pleural space. 1500 88

Hyperforin (Hyp), the major lipophilic constituent of St. John's wort, was assayed as a stable dicyclohexylammonium salt (Hyp-DCHA) for cytotoxicity and inhibition of matrix proteinases, tumor invasion, and metastasis. Hyp-DCHA triggered apoptosis-associated cytotoxic effect in both murine (C-26, B16-LU8, and TRAMP-C1) and human (HT-1080 and SK-N-BE) tumor cells; its effect varied, with B16-LU8, HT-1080, and C-26 the most sensitive (IC50 = 5 to 8 micromol/L). At these concentrations, a marked and progressive decline of growth was observed in HT-1080 cells, whereas untransformed endothelial cells were only marginally affected. Hyp-DCHA inhibited in a dose-dependent and noncompetitive manner various proteinases instrumental to extracellular matrix degradation; the activity of leukocyte elastase was inhibited the most (IC50 = 3 micromol/L), followed by cathepsin G and urokinase-type plasminogen activator, whereas that of the matrix metalloproteinases (MMPs) 2 and 9 showed an IC50 > 100 micromol/L. Nevertheless, inhibition of extracellular signal-regulated kinase 1/2 constitutive activity and reduction of MMP-2 and MMP-9 secretion was triggered by 0.5 micromol/L Hyp-DCHA to various degrees in different cell lines, the most in C-26. Inhibition of C-26 and HT-1080 cell chemoinvasion (80 and 54%, respectively) through reconstituted basement membrane was observed at these doses. Finally, in mice that received i.v. injections of C-26 or B16-LU8 cells, daily i.p. administration of Hyp-DCHA-without reaching tumor-cytotoxic blood levels-remarkably reduced inflammatory infiltration, neovascularization, lung weight (-48%), and size of experimental metastases with C-26 (-38%) and number of lung metastases with B16-LU8 (-22%), with preservation of apparently healthy and active behavior. These observations qualify Hyp-DCHA as an interesting lead compound to prevent and contrast cancer spread and metastatic growth.
Cancer Res 2004 Sep 01
PMID:Hyperforin inhibits cancer invasion and metastasis. 1534 8


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