Science Translational Medicine

COX-2 Inhibition Potentiates Antiangiogenic Cancer Therapy and Prevents Metastasis in Preclinical Models

The cyclooxygenases (COXs) are a family of enzymes, which catalyze the rate-limiting step of prostaglandin biosynthesis. This family contains three members: ubiquitously expressed COX-1, which is involved in homeostasis; the inducible COX-2 isoform, which is upregulated during both inflammation and cancer; and COX-3, expressed in brain and spinal cord, whose functions remain to be elucidated.

Cyclooxygenase-2 (COX-2) is the inducible isoform, which is regulated by growth factors and different cytokines such as IL1ƒÀ, IL6, or TNFƒ¿, therefore overexpressed during inflammation.

Antiangiogenic agents that block vascular endothelial growth factor (VEGF) signaling are important components of current cancer treatment modalities but are limited by alternative ill-defined angiogenesis mechanisms that allow persistent tumor vascularization in the face of continued VEGF pathway blockade. COX-2 inhibition augmented VEGF pathway blockade to suppress angiogenesis and tumor growth, prevent metastasis, and increase overall survival. These results demonstrate the importance of the COX-2/PGE2 pathway in mediating resistance to VEGF pathway blockade and could aid in the rapid development of more efficacious anticancer therapies.

These findings prompt us to analyze here the effects of a combination of COX-2 inhibitors (celecoxib) together with different clinically used therapeutic strategies (thalidomide, valproic acid) in order to further improve the efficiency of future anticancer treatments.