Synergy between Celecoxib and Radiotherapy Results from Inhibition of Cyclooxygenase-2-Derived Prostaglandin E2, a Survival Factor for Tumor and Associated Vasculature

Abstract

Previous work has demonstrated that selective cyclooxygenase-2 (COX-2) inhibitors can act synergistically with radiotherapy to improve tumor debulking and control in preclinical models. The underlying mechanism of this remarkable activity has not yet been determined. Here, we report that radiation can elevate intratumoral levels of COX-2 protein and its products, particularly prostaglandin E 2 (PGE 2 ). Furthermore, inhibition of COX-2 activity or neutralization of PGE 2 activity enhances radiotherapy even in tumors where COX-2 expression is restricted to the tumor neovasculature. Direct assessment of vascular function by direct contrast enhancement-magnetic resonance imaging showed that the combination of radiation and celecoxib lead to enhanced vascular permeability. These observations suggest that an important mechanism of celecoxibinduced radiosensitization involves inhibition of COX-2-derived PGE 2 , thus removing a survival factor for the tumor and its vasculature.

Dimethyl-Celecoxib (DMC), a derivative of celecoxib that lacks cyclooxygenase-2-Inhibitory function, potently mimics the anti-tumor effects of celecoxib on burkitt’s lymphoma in vitro and in vivo

“…84 Thus, it is conceivable that in order to effect suppression of tumor growth in vivo, all that is required is for NSAIDs to suppress COX-2 activity in endothelial cells-independent of their effects in tumor cells. A recent report 85 appears to support the possibility of such a scenario: celecoxib was shown to enhance the anti-tumor effects of ionizing radiation on colon tumors grown in the footpad of mice; intriguingly, this cooperative effect was dependent on the presence of COX-2 in the tumor vasculature, but independent of the COX-2 status of the tumor cells.…”

Cyclooxygenase in the Treatment of Glioma: Its Complex Role in Signal Transduction

“…Also, the subsequent maintenance of inhibition of COX-2 activity and PG-E 2 synthesis after acute therapy may impair neovascularization and the regrowth of tumor. 115 Thus, COX-2-derived PG-E 2 seems to have an important role in tumor survival after radiation damage, and these effects appear to be most important in angiogenesis. COX-2 inhibition is a logical method to manipulate these changes and improve the impact of radiotherapy.…”

Tumor Cyclooxygenase-2/Prostaglandin E2–Dependent Promotion of FOXP3 Expression and CD4+CD25+ T Regulatory Cell Activities in Lung Cancer

“…Although multiple genetic alterations are necessary for lung cancer invasion and metastasis, mounting evidence from numerous studies indicates that tumor COX-2 activity has a multifaceted role in conferring the malignant and metastatic phenotypes (4,5). Overexpression of tumor COX-2 is associated with apoptosis resistance (6,7), increased angiogenesis (8,9), decreased host immunity (2,10), and enhanced invasion and metastasis (11)(12)(13). In murine lung cancer models, we found that specific genetic or pharmacologic inhibition of COX-2 reduced tumor growth (10).…”