Celecoxib inhibits angiogenesis by inducing endothelial cell apoptosis in human pancreatic tumor xenografts

Abstract

Previous studies suggest that antagonists of cyclooxygenases 1 and 2 (COX-1, -2) inhibit angiogenesis in tumor xenografts, but the molecular mechanisms involved remain unclear. Here we characterized the effects of non-selective (indomethacin) and selective (NS398, celecoxib) cyclooxygenase inhibitors on parameters of angiogenesis in human pancreatic adenocarcinoma cells. COX-1 expression was constitutive in 9/9 pancreatic cancer cell lines, whereas COX-2 and cytosolic phospholipase A 2 (cPLA 2 ) expression were observed in 4/9 cell lines (BxPC3, Capan2, Cfpac1 and L3.6 pl). Production of the COX product, prostaglandin E2, correlated with expression of cPLA 2 and COX-2 and was blocked by non-steroidal anti-inflammatory drugs (NSAIDs, indomethacin or NS398). In contrast to the findings of others, neither indomethacin nor NS398 affected tumor cell secretion of angiogenic factors (VEGF, bFGF, IL-8) at concentrations that produced maximal inhibition of PGE 2 production, and higher concentrations increased angiogenic factor production. We also studied the effects of celecoxib in orthotopic L3.6 pl xenografts. Immunofluorescence analysis revealed high-level expression of COX-2 in endothelial cells in L3.6 pl xenografts that increased following therapy with celecoxib, whereas the tumor cells expressed uniformly low levels of COX-2. Celecoxib did not decrease tumor-associated VEGF levels in orthotopic human L3.6 pl xenografts, but the drug did decrease tumor microvessel density (MVD) and increase apoptosis in tumor-associated endothelial cells in a dose-dependent fashion. Together, our results demonstrate that the anti-angiogeneic effects of NSAIDs in human pancreatic cancer cells are exerted via direct effects on endothelial cells.

Effects of Capecitabine and Celecoxib in Experimental Pancreatic Cancer

“…The inducible cyclo-oxygenase type II (Cox 2) is overexpressed in many malignancies [12]. Cox 2 overexpressing cells secreted high levels of VEGF, which is related to increased tumoral cell invasion, bad prognostic and low survival rates of patients [13]. Cox 2 inhibitory therapy reduces tumor growth and metastasis in colon cancer [14].…”

Tumor Size Significantly Correlates with Postoperative Liver Metastases and COX-2 Expression in Patients with Resectable Pancreatic Cancer

“…Recently, anti-COX-2 agents have been documented to have antitumor activity, and some are now being tested as therapies for various cancers [26-29, 31, 35-37] . The antitumor effect of anti-COX-2 agents has also been confirmed in experimental research on pancreatic cancer cells [38][39][40][41] , and clinical investigations have already started [42][43][44] .…”

Mechanical Analysis of Tumor Growth Regression by the Cyclooxygenase-2 Inhibitor, DFU, in a Walker256 Rat Tumor Model: Importance of Monocyte Chemoattractant Protein-1 Modulation

“…The importance of VEGF on the mobilization and recruitment of bone marrow -derived EPCs toward an ischemic lesion has already been clarified (35), and it is documented that SDF-1 and MCP-1 exhibit a potent stimulatory effect on EPC kinetics and enhance the neovascularization of ischemic tissues (26, 36 -39); however, little is known about the details in the malignant diseases. DFU showed no direct chemotactic and no anti -cell proliferation activity to TR-BME-2 cells, which might indicate a unique profile of DFU, because it is reported that celecoxib can induce endothelial cell apoptosis and inhibit endothelial cell proliferation (23). In the in vitro chemotaxis assay, the serum from the rats treated with DFU showed less chemotactic activity compared with that from control tumor-bearing rats.…”