Angiostatic role of the selective cyclooxygenase-2 inhibitor etoricoxib (MK0663) in experimental lung cancer.
Lung cancer was induced in Sprague-Dawley rats by a single intra-tracheal instillation of 9,10-dimethybenz(a)anthracene (DMBA) and evaluated the anti-angiogenic action of etoricoxib, which is a selective cyclooxygenase-2 (COX-2) inhibitor. The animals were divided into four groups. Group 1 (Control) received 0.9% (w/v) normal saline intra-tracheal and 0.5% (w/v) carboxymethyl cellulose per oral daily as the vehicle of the drug, Group 2 received DMBA (20 mg/kg) intra-tracheal once, Group 3 received a daily oral dose of etoricoxib (0.6 mg/kg bw) in addition to the DMBA while Group 4 received etoricoxib alone. Morphological and histological analysis confirmed the presence of lung tumors 20 weeks after the administration of DMBA. Expressions of COX-2, MMP-2, MMP-9, MCP-1, MIP-1β and VEGF were studied by immunofluorescence, Western immunoblot and mRNA studies, which showed a higher expression of these proteins in the DMBA-treated animals but much lower in DMBA+etoricoxib. Gelatin zymography as applied for the detection of the extracellular protein degrading enzymes, matrix metalloproteinases showed more intense activity in DMBA-treated rats as compared to the other groups. Also, the isolated alveolar macrophages were stained with Merocyanine540 (MC540) to study the membrane fluidity and lipid packing effect. DMBA treatment resulted in a significant increase in the number of lung cells exhibiting a high intensity of MC540 staining, which was reduced by the co-administration of etoricoxib. Thus the effects of etoricoxib on the expression of the angiogenic proteins have been observed, which clearly shows an anti-angiogenic mechanism of action of etoricoxib in lung cancer chemoprevention.
Department of Biophysics, Panjab University, Chandigarh 160014, India.
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D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use*; D000077613:Etoricoxib; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D008168:Lung / Q000098:blood supply / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D008175:Lung Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D053505:Matrix Metalloproteinases, Secreted / Q000235:genetics / Q000378:metabolism; D008560:Membrane Fluidity / Q000187:drug effects; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D011725:Pyridines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013450:Sulfones / Q000627:therapeutic use*; D047368:Tumor Burden / Q000187:drug effects
D020533:Angiogenesis Inhibitors; D016588:Anticarcinogenic Agents; D018925:Chemokines; D052246:Cyclooxygenase 2 Inhibitors; D011725:Pyridines; D012333:RNA, Messenger; D013450:Sulfones; D053505:Matrix Metalloproteinases, Secreted; D000077613:Etoricoxib