Linked Life Data

15647251

Source:http://linkedlifedata.com/resource/pubmed/id/15647251

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
13
pubmed:dateCreated
2005-3-28
pubmed:abstractText
Heparanase is an endo-beta-glucuronidase that cleaves heparan sulfate (HS) chains of heparan sulfate proteoglycans on cell surfaces and in the extracellular matrix (ECM). Heparanase, overexpressed by most cancer cells, facilitates extravasation of blood-borne tumor cells and causes release of growth factors sequestered by HS chains, thus accelerating tumor growth and metastasis. Inhibition of heparanase with HS mimics is a promising target for a novel strategy in cancer therapy. In this study, in vitro inhibition of recombinant heparanase was determined for heparin derivatives differing in degrees of 2-O- and 6-O-sulfation, N-acetylation, and glycol splitting of nonsulfated uronic acid residues. The contemporaneous presence of sulfate groups at O-2 of IdoA and at O-6 of GlcN was found to be non-essential for effective inhibition of heparanase activity provided that one of the two positions retains a high degree of sulfation. N-Desulfation/ N-acetylation involved a marked decrease in the inhibitory activity for degrees of N-acetylation higher than 50%, suggesting that at least one NSO3 group per disaccharide unit is involved in interaction with the enzyme. On the other hand, glycol splitting of preexisting or of both preexisting and chemically generated nonsulfated uronic acids dramatically increased the heparanase-inhibiting activity irrespective of the degree of N-acetylation. Indeed N-acetylated heparins in their glycol-split forms inhibited heparanase as effectively as the corresponding N-sulfated derivatives. Whereas heparin and N-acetylheparins containing unmodified D-glucuronic acid residues inhibited heparanase by acting, at least in part, as substrates, their glycol-split derivatives were no more susceptible to cleavage by heparanase. Glycol-split N-acetylheparins did not release basic fibroblast growth factor from ECM and failed to stimulate its mitogenic activity. The combination of high inhibition of heparanase and low release/potentiation of ECM-bound growth factor indicates that N-acetylated, glycol-split heparins are potential antiangiogenic and antimetastatic agents that are more effective than their counterparts with unmodified backbones.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
1
pubmed:volume
280
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
12103-13
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:15647251-Acetylation, pubmed-meshheading:15647251-Animals, pubmed-meshheading:15647251-CHO Cells, pubmed-meshheading:15647251-Carbohydrate Sequence, pubmed-meshheading:15647251-Cattle, pubmed-meshheading:15647251-Cells, Cultured, pubmed-meshheading:15647251-Cornea, pubmed-meshheading:15647251-Cricetinae, pubmed-meshheading:15647251-Disaccharides, pubmed-meshheading:15647251-Dose-Response Relationship, Drug, pubmed-meshheading:15647251-Endothelium, Vascular, pubmed-meshheading:15647251-Fibroblast Growth Factor 2, pubmed-meshheading:15647251-Glucuronic Acid, pubmed-meshheading:15647251-Glucuronidase, pubmed-meshheading:15647251-Glycols, pubmed-meshheading:15647251-Heparin, pubmed-meshheading:15647251-Humans, pubmed-meshheading:15647251-Inhibitory Concentration 50, pubmed-meshheading:15647251-Kinetics, pubmed-meshheading:15647251-Magnetic Resonance Spectroscopy, pubmed-meshheading:15647251-Molecular Sequence Data, pubmed-meshheading:15647251-Protein Structure, Tertiary, pubmed-meshheading:15647251-Recombinant Proteins, pubmed-meshheading:15647251-Uronic Acids
pubmed:year
2005
pubmed:articleTitle
Modulation of the heparanase-inhibiting activity of heparin through selective desulfation, graded N-acetylation, and glycol splitting.
pubmed:affiliation
G. Ronzoni Institute for Chemical and Biochemical Research, via G. Colombo, 81, 20133 Milan, Italy.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't