Selective Cyclooxygenase-2 Inhibitor Etoricoxib Attenuated Hypoxic Cancer Milieu induced M2-Polarization of Macrophages and Acquisition of Pro-angiogenic and Pro-invasive Attributes

Abstract

Cyclooxygenase-2 (COX-2) inhibitors have been found to reduce the relative risk of breast cancer in several experimental and clinical studies. Various mechanisms of anti-tumor activity of COX-2 inhibition have been reported viz. anti-proliferation, apoptosis, preventing invasion and metastasis, and potentiation of anti-tumor immune responses. In addition to this, previous work indicated that attenuation of pro-tumoral M2 polarization of macrophages could be another mechanism of anti-cancer activity of COX-2 inhibitors. This prompted our investigation of the pro-tumoral M2 polarization inhibitory potential of Etoricoxib, a selective COX-2 blocker. Treatment with Etoricoxib markedly inhibited hypoxic breast cancer cell induced macrophage M2 polarization to a greater extent compared to Flunixin meglumine, a preferential COX-2 inhibitor. Moreover, we found that Etoricoxib treatment results in suppression of pro-angiogenic and pro-invasive functions of tumor associated macrophages (TAMs). Our study provides evidence for potential applicability of Etoricoxib as an anti-breast cancer modality via targeting M2 polarization of macrophages.