Cyclooxygenase 2-mediated apoptotic and inflammatory responses in photodynamic therapy treated breast adenocarcinoma cells and xenografts

Cyclooxygenase 2 (COX-2) is an inducible enzyme that contributes to the generation of chronic inflammation and the development of cancer, and promotes neoplastic transformation, in response to chemical carcinogens and environmental stresses. In this study, we demonstrated that a sublethal dose photodynamic therapy (PDT) led to inflammatory response mediated by the induction of COX-2 and release of Prostaglandin E-2 (PGE(2)). Pretreatment with N-acetylcysteine (NAC) reduced COX-2 expression and PGE(2) release induced by PDT. The elevated COX-2 level and PGE(2) release following PDT were inhibited by NADPH oxidase inhibitor and NF-kappa B inhibitor. Inhibition of COX-2 attenuated the levels of PGE(2) and vascular endothelial growth factor (VEGF) following PDT in treated tumors, and also decreased the expression of proinflammatory mediators interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha). In addition, PDT led to an appreciable accumulation of pSer15-p53/COX-2 complexes, and this association of complexes was partially inhibited by SB203580, an inhibitor of p38. Blockage of COX-2 expression by siRNA enhanced the transcriptional activity of p53, and facilitated PDT-induced loss of mitochondrial membrane potential and cleavage of caspase 3, probably due to the elevated Noxa expression disrupting the interaction of Mcl-1/Bax. Together, this study highlights the important roles of COX-2 in PDT-induced apoptosis and inflammation and the specific COX-2-mediated responses to PDT initiated by reactive oxygen species (ROS) involving the regulation of the multiple signaling pathways. These results indicate the inflammatory mediator COX-2 as a potential therapeutic target for improving PDT efficacy. (C) 2014 Elsevier B.V. All rights reserved.