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COX inhibition with SC did not affect the angiogenic process at doses that clearly inhibited platelet COX activity.The traditional NSAID indomethacin inhibited both angiogenesis and COX activity.COX is apparently involved in the pathway to neovascularization, however, other studies suggest a possible role for COX in this process.For instance, tube formation by human umbilical vein endothelial cells in coculture with HCT colon cancer cells may be COX dependent. Tube formation is blocked by aspirin, and by a COX Ceftriaxone sodium antisense oligonucleotide, but not by an experimental COX inhibitor, or by a COX antisense oligonucleotide. COX inhibition, however, potently reduced proliferation and the production of angiogenic factors by a cancer cell line which does express COX.Indomethac in, a COX and COX inhibitor, also inhibited the angiogenic response, but the COX inhibitor SC had no effect.Indomethacin, a COX and COX inhibitor, and the COX inhibitor SC, potently inhibited mouse stomach COX and platelet COX.During activation, platelets release platelet derived growth factor which has angiogenic effects on endothelial cells. Activated platelets also cause the release of arachidonic acid from cell membranes, the substrate for COX enzymes.The main prostanoid that platelets produce is thromboxaneA via thromboxane synthase activity.TXA is a potent vasoconstrictor and is important for platelet aggregation.Thrombocytopenia reduces tumor vascularization sim ilar to what is observed after adm inistration of diclofenacsodium. W hether the reduced vascularization is due to the lack of TXA or PDGF is unclear, however, this study indicates that platelet activity may be important in angiogenesis.Platelets may also contribute to metastasis, since thrombocytopenicmice show decreased metastatic spread of tumor cells compared to platelet replete controls. It is thought that platelets aggregate around tumor cells in transport to distal capillary beds and aid in implantation.In fact, different cell types, enzymes, integrins, growth factors, and small molecules interact in a complex manner and temporal sequence.Basic FGF, a growth factor produced by many tumors, can induce COX messenger RNA expression and protein in several cell lines including bone derived endothelial cells. There have been few studies to date, however, that show a direct connection between bFGF and COX activity or expression in vascular endothelial cells.In tumor cells, COX derived prostaglandins upregulate the production of growth factors including VEGF which can act directly on endothelial cells, and bFGF which stimulates COX upregulation in fibroblasts.COX derived prostaglandins in fibroblasts stimulate VEGF production which acts on endothelial cells in a paracrine fashion to again upregulate COX and facilitate vascular permeability and angiogenesis.They rem a rk thatregu lationof PG I synthesis by growth factors is dependent on the species and on the type of Dorzolamide hydrochloride vasculature from which the cells are originated. However, another study reports that levels of COX or protein are unaffected by bFGF in bovine aortic endothelial cells, perhaps because they are not derived from fetal tissues as in the previously described work.Therefore, the difficulties in modeling angiogenesis in cell culture may be due to the variable diversity of endothelial cell types, length of culture, age of original cells, and whether the cells were derived from capillaries or larger vessels.

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