Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q86TM3 (cage)
 29,987 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The trace element nutrient selenium (Se) has been shown to possess cancer-preventive activity in both animal models and humans, but the mechanisms by which this occurs remain to be elucidated. Because angiogenesis is obligatory for the genesis and growth of solid cancers, we investigated, in the study presented here, the hypothesis that Se may exert its cancer-preventive activity, at least in part, by inhibiting cancer-associated angiogenesis. The effects of chemopreventive levels of Se on the intra-tumoral microvessel density and the expression of vascular endothelial growth factor in 1-methyl-1-nitrosourea-induced rat mammary carcinomas and on the proliferation and survival and matrix metalloproteinase activity of human umbilical vein endothelial cells in vitro were examined. Increased Se intake as Se-enriched garlic, sodium selenite, or Se-methylselenocysteine led to a significant reduction of intra-tumoral microvessel density in mammary carcinomas, irrespective of the manner by which Se was provided: continuous exposure (7-wk feeding) with a chemoprevention protocol or acute bolus exposure (3 d) after carcinomas had established. Compared with the untreated controls, significantly lower levels of vascular endothelial growth factor expression were observed in a sizeable proportion of the Se-treated carcinomas. In contrast to the mammary carcinomas, the microvessel density of the uninvolved mammary glands was not altered by Se treatment. In cell culture, direct exposure of human umbilical vein endothelial cells to Se induced cell death predominantly through apoptosis, decreased the gelatinolytic activities of matrix metalloproteinase-2, or both. These results indicate a potential for Se metabolites to inhibit key attributes (proliferation, survival, and matrix degradation) of endothelial cells critical for angiogenic sprouting. Therefore, inhibition of angiogenesis associated with cancer may be a novel mechanism for the anticancer activity of Se in vivo, and multiple mechanisms are probably involved in mediating the anti-angiogenic activity.
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PMID:Selenium-induced inhibition of angiogenesis in mammary cancer at chemopreventive levels of intake. 1056 99

Inhibition of matrix metalloproteinases (MMPs), a family of proteolytic enzymes linked to many aspects of cancer progression, has been explored as a therapeutic goal for almost two decades. Thus far, all tested MMP inhibitors (MMPIs) have failed to reach primary end points in Phase III clinical trials, although secondary analyses suggest benefits in particular patient groups. The clinical development of these agents has been hampered by problems related to determination of effective dosages and side effects that necessitate dose lowering or drug holidays. Imaging technologies offer hope as a means to measure enzyme activity and hence effective enzyme inhibition in vivo. Meanwhile, recent results from genetic studies of both mice and man have given some clues to possible causes of musculoskeletal side effects. Future progress in the therapeutic use of MMPIs is dependent on the ability to selectively target cancer-associated MMPs at the correct stage in tumour progression and the development of surrogate markers of in vivo efficacy.
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PMID:Matrix metalloproteinase inhibitors for cancer therapy:the current situation and future prospects. 1278 74

Caffeic acid phenethyl ester (CAPE) derived from honeybee propolis has been used as a folk medicine and has several proven biological activities. The present study investigated the effect of CAPE on angiogenesis, tumor invasion, and metastasis. A cytotoxicity assay of CAPE in CT26 colon adenocarcinoma cells showed a dose-dependent decrease in cell viability but no significant influence on the growth of human umbilical vein epithelial cells (HUVEC). A low concentration of CAPE (1.5 microg/mL) inhibited 52.7% of capillary-like tube formation in HUVEC culture on Matrigel. CAPE (6 microg/mL)-treated CT26 cells showed not only inhibited cell invasion by 47.8% but also decreased expression of matrix metalloproteinase (MMP)-2 and -9. Vascular endothelial growth factor (VEGF) production from CT26 cells was also inhibited by treatment with CAPE (6 microg/mL). Intraperitoneal injection of CAPE (10 mg/kg/day) in BALB/c mice reduced the pulmonary metastatic capacity of CT26 cells accompanied with a decreased plasma VEGF level. CAPE treatment also prolonged the survival of mice implanted with CT26 cells. These results indicate that CAPE has potential as an antimetastatic agent.
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PMID:Inhibitory effect of caffeic acid phenethyl ester on angiogenesis, tumor invasion, and metastasis. 1469 Mar 72

Activity-based protein profiling (ABPP) is a chemical method that utilizes active-site-directed probes to determine the functional state of enzymes in complex proteomes. Probe-labeled enzymes are typically detected by in-gel fluorescence scanning, a robust technique that nonetheless exhibits some key deficiencies, including limited sensitivity and resolution, as well as ambiguity regarding the molecular identity of the enzymes under investigation. Here, we report a microarray platform for ABPP that addresses these limitations. In this platform, proteomes are treated with ABPP probes in solution, after which labeled enzymes are captured and visualized on glass slides displaying an array of anti-enzyme antibodies. We show that ABPP microarrays exhibit superior sensitivity and resolution compared to gel-based methods, permitting the parallel analysis of several enzyme activities in proteomes, including cancer-associated proteases such as urokinase, matrix metalloproteinase-9, and prostate-specific antigen.
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PMID:Microarray platform for profiling enzyme activities in complex proteomes. 1557 75

Norcantharidin (NCTD), a potential anti-cancer drug, is the demethylated analog of cantharidin isolated from blister beetles. The present study investigated the effect of NCTD on tumor invasion and metastasis. A cytotoxicity assay of NCTD in CT26 colorectal adenocarcinoma cells showed a dose- and time-dependent decrease in cell viability. NCTD (50 microM)-treated CT26 cells not only showed an inhibited cell invasion of 65.6%, but also decreased the activity of matrix metalloproteinase-2 and -9. NCTD decreased the adhesive ability of CT26 cells in a dose-dependent manner. At a concentration of 100 microM, NCTD showed a down-expression of several cadherin-catenin adhesion molecules, including Desmoglein, N-cadherin, and alpha- and beta-catenin, while there were no obvious changes in E-cadherin and gamma-catenin. Intraperitoneal injection of NCTD (2 mg/kg/day) in BALB/c mice reduced both the pulmonary metastatic capacity of CT26 cells and prolonged the survival day of the mice. These results demonstrated that it was effective in blocking both tumor invasion and metastasis.
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PMID:Inhibitory effect of norcantharidin, a derivative compound from blister beetles, on tumor invasion and metastasis in CT26 colorectal adenocarcinoma cells. 1571 Nov 81

Coordinate cell-surface expression of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) on cancer cells, tumor-infiltrating lymphocytes (TIL) and cancer-associated myofibroblasts has been shown to play an important role in tumor invasion and metastasis in organ tissues. However, precise localization of tumor cell lines in vitro has remained obscure. The aim of this study was to investigate the spatial localization of these proteolytic enzymes in 21 tumor cell lines consisting of 8 gastric, 4 pancreatic, 2 gallbladder, 1 extrahepatic bile duct cancer and 6 T- or B-cell tumors. The cell-surface and/or intracellular localization of MMP-2, -7, and -9, membrane type-1 (MT1)-MMP and TIMP-2 and -4 was quantitatively determined by flow cytometry in living (non-permeabilized) and permeabilized tumor cell lines. As a result, all of the tumor cell lines showed a high level of intracellular expression, but a low or undetectable level of cell-surface expression of MMPs and TIMPs. The findings revealed that intracellular MMPs and TIMPs in tumor cell lines were preserved as latent pro-enzymes.
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PMID:Intracellular localization of matrix metalloproteinases and their inhibitors in cultured tumor cell lines: flow cytometric analysis. 1646 38

Xenon-129 biosensors offer an attractive alternative to conventional MRI contrast agents due to the chemical shift sensitivity and large nuclear magnetic signal of hyperpolarized (129)Xe. Here, we report the first enzyme-responsive (129)Xe NMR biosensor. This compound was synthesized in 13 steps by attaching the consensus peptide substrate for matrix metalloproteinase-7 (MMP-7), an enzyme that is upregulated in many cancers, to the xenon-binding organic cage, cryptophane-A. The final coupling step was achieved on solid support in 80-92% yield via a copper (I)-catalyzed [3+2] cycloaddition. In vitro enzymatic cleavage assays were monitored by HPLC and fluorescence spectroscopy. The biosensor was determined to be an excellent substrate for MMP-7 (K(M) = 43 microM, V(max) = 1.3 x 10(-)(8) M s(-1), k(cat)/K(M) = 7,200 M(-1) s(-1)). Enzymatic cleavage of the tryptophan-containing peptide led to a dramatic decrease in Trp fluorescence, lambda(max) = 358 nm. Stern-Volmer analysis gave an association constant of 9000 +/- 1,000 M(-1) at 298 K between the cage and Trp-containing hexapeptide under enzymatic assay conditions. Most promisingly, (129)Xe NMR spectroscopy distinguished between the intact and cleaved biosensors with a 0.5 ppm difference in chemical shift. This difference most likely reflected a change in the electrostatic environment of (129)Xe, caused by the cleavage of three positively charged residues from the C-terminus. This work provides guidelines for the design and application of new enzyme-responsive (129)Xe NMR biosensors.
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PMID:Designing 129Xe NMR biosensors for matrix metalloproteinase detection. 1701 9

Persistent drug seeking/taking behavior involves the consolidation of memory. With each drug use, the memory may be reactivated and reconsolidated to maintain the original memory. During reactivation, the memory may become labile and susceptible to disruption; thus, molecules involved in plasticity should influence acquisition and/or reconsolidation. Recently, matrix metalloproteinases (MMPs) have been shown to influence neuronal plasticity, presumably by their regulation of extracellular matrix (ECM) molecules involved in synaptic reorganization during learning. We hypothesized that inhibition of MMP activity would impair the acquisition and/or reconsolidation of cocaine-conditioned place preference (CPP) in rats. Intracerebral ventricular (i.c.v.) microinjection of a broad spectrum MMP inhibitor, FN-439, prior to cocaine training suppressed acquisition of CPP and attenuated cocaine-primed reinstatement in extinguished animals. In a separate experiment, the cocaine memory was reactivated on two consecutive days with a cocaine priming injection. On these two days, artificial cerebral spinal fluid (aCSF) or FN-439 was administered either 30 min prior to or 1 min after cocaine-primed reinstatement sessions. Infusion of FN-439 partially impaired retrieval of the cocaine-associated context when given 30 min prior to cocaine. In both groups, however, FN-439 suppressed reinstatement compared with controls on the third consecutive test for cocaine-primed reinstatement, when no FN-439 was given. Control experiments demonstrated that two injections of FN-439 + cocaine given in the home cage, or of FN-439 + saline priming injections in the CPP chambers did not disrupt subsequent cocaine-primed reinstatement. These results show for the first time that (1) MMPs play a critical role in acquisition and reconsolidation of cocaine-induced CPP, and (2) rats demonstrate apparent disruption of reconsolidation by an MMP inhibitor after extinction and while they are under the influence of cocaine during reinstatement.
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PMID:Role of matrix metalloproteinases in the acquisition and reconsolidation of cocaine-induced conditioned place preference. 1735 46

Molecular beacons are FRET-based target-activatable probes. They offer control of fluorescence emission in response to specific cancer targets, thus are useful tools for in vivo cancer imaging. Photodynamic therapy (PDT) is a cell-killing process by light activation of a photosensitizer (PS) in the presence of oxygen. The key cytotoxic agent is singlet oxygen ((1)O(2)). By combining these two principles (FRET and PDT), we have introduced a concept of photodynamic molecular beacons (PMB) for controlling the PS's ability to generate (1)O(2) and, ultimately, for controlling its PDT activity. The PMB comprises a disease-specific linker, a PS, and a (1)O(2) quencher, so that the PS's photoactivity is silenced until the linker interacts with a target molecule, such as a tumor-associated protease. Here, we report the full implementation of this concept by synthesizing a matrix metalloproteinase-7 (MMP7)-triggered PMB and achieving not only MMP7-triggered production of (1)O(2) in solution but also MMP7-mediated photodynamic cytotoxicity in cancer cells. Preliminary in vivo studies also reveal the MMP7-activated PDT efficacy of this PMB. This study validates the core principle of the PMB concept that selective PDT-induced cell death can be achieved by exerting precise control of the PS's ability to produce (1)O(2) by responding to specific cancer-associated biomarkers. Thus, PDT selectivity will no longer depend solely on how selectively the PS can be delivered to cancer cells. Rather, it will depend on how selective a biomarker is to cancer cells, and how selective the interaction of PMB is to this biomarker.
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PMID:Photodynamic molecular beacon as an activatable photosensitizer based on protease-controlled singlet oxygen quenching and activation. 1750 20

Recently we have shown that inhibition of matrix metalloproteinase (MMP) activity suppresses the reinstatement of cocaine-primed conditioned place preference (CPP) in rats. Here we explored whether cocaine-primed reinstatement was associated with increased activity of the gelatinases, MMP-2 or MMP-9, in the medial prefrontal cortex (mPFC) or dorsal hippocampus. Male Sprague-Dawley rats underwent training for cocaine-CPP followed by extinction sessions and either saline- or cocaine-priming injections. Cocaine-induced reinstatement produced significant increases in mPFC MMP-9 activity at 1, 3 and 24 hr after injection compared with saline controls. No changes in MMP-9 occurred in the hippocampus or in MMP-2 activity in either brain region. Also, no changes in mPFC MMP-9 activity were observed 1 hr after reinstatement in animals given no extinction sessions but equivalent time off in the home cage. Finally, MMP-3 protein levels were not different in either brain region at any of the three time points assessed. These results suggest that an elevation in MMP-9 activity in the mPFC may contribute to synaptic remodeling important for the reactivation of a cocaine memory, or alternatively, for the modification of a competing extinction memory during reinstatement.
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PMID:Increase in matrix metalloproteinase-9 levels in the rat medial prefrontal cortex after cocaine reinstatement of conditioned place preference. 1879 88


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