Multiple roles of COX-2 in tumor angiogenesis: a target for antiangiogenic therapy.
Angiogenesis is required for multistage carcinogenesis. The inducible enzyme cyclooxygenase-2 (COX-2) is an important mediator of angiogenesis and tumor growth. COX-2 expression occurs in a wide range of preneoplastic and malignant conditions; and the enzyme has been localized to the neoplastic cells, endothelial cells, immune cells, and stromal fibroblasts within tumors. The proangiogenic effects of COX-2 are mediated primarily by three products of arachidonic metabolism: thromboxane A(2) (TXA(2)), prostaglandin E(2) (PGE(2)), and prostaglandin I(2) (PGI(2)). Downstream proangiogenic actions of these eicosanoid products include: (1) production of vascular endothelial growth factor; (2) promotion of vascular sprouting, migration, and tube formation; (3) enhanced endothelial cell survival via Bcl-2 expression and Akt signaling; (4) induction of matrix metalloproteinases; (5) activation of epidermal growth factor receptor-mediated angiogenesis; and (6) suppression of interleukin-12 production. Selective inhibition of COX-2 activity has been shown to suppress angiogenesis in vitro and in vivo. Because these agents are safe and well tolerated, selective COX-2 inhibitors could have clinical utility as antiangiogenic agents for cancer prevention, as well as for intervention in established disease alone or in combination with chemotherapy, radiation, and biological therapies.
Gately
Stephen
S
Department of Translational Medicine, NeoPharm Inc., 150 Field Drive, Suite 195, Lake Forest, IL 60045, USA.
Li
William W
WW
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000068579:Celecoxib; D002465:Cell Movement; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism; D011464:Epoprostenol / Q000378:metabolism; D006801:Humans; D018664:Interleukin-12 / Q000378:metabolism; D007527:Isoenzymes / Q000502:physiology*; D007783:Lactones / Q000494:pharmacology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008565:Membrane Proteins; D009369:Neoplasms / Q000098:blood supply / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D011720:Pyrazoles; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D013450:Sulfones; D013928:Thromboxane A2 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D016588:Anticarcinogenic Agents; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D007783:Lactones; D008565:Membrane Proteins; D011720:Pyrazoles; D013449:Sulfonamides; D013450:Sulfones; D042461:Vascular Endothelial Growth Factor A; C116926:rofecoxib; D018664:Interleukin-12; D013928:Thromboxane A2; D004815:Epidermal Growth Factor; D011464:Epoprostenol; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D020782:Matrix Metalloproteinases; D000068579:Celecoxib; D015232:Dinoprostone