title: Cyclooxygenase 2-mediated apoptotic and inflammatory responses in photodynamic therapy treated breast adenocarcinoma cells and xenografts.
abstract: 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 E2 (PGE2). Pretreatment with N-acetylcysteine (NAC) reduced COX-2 expression and PGE2 release induced by PDT. The elevated COX-2 level and PGE2 release following PDT were inhibited by NADPH oxidase inhibitor and NF-κB inhibitor. Inhibition of COX-2 attenuated the levels of PGE2 and vascular endothelial growth factor (VEGF) following PDT in treated tumors, and also decreased the expression of proinflammatory mediators interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). 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.
authors.affiliation: MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China.
authors.forename: Jiaxing
authors.initials: J
authors.lastname: Song
authors.affiliation: MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China.
authors.forename: Yanchun
authors.initials: Y
authors.lastname: Wei
authors.affiliation: MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China; Joint Laboratory of Laser Oncology with Cancer Center of Sun Yat-sen University, South China Normal University, Guangzhou 510631, China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Chen
authors.affiliation: MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China; Joint Laboratory of Laser Oncology with Cancer Center of Sun Yat-sen University, South China Normal University, Guangzhou 510631, China. Electronic address: xingda@scnu.edu.cn.
authors.forename: Da
authors.initials: D
authors.lastname: Xing
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D053583:Interleukin-1beta / Q000378:metabolism; D008027:Light; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D017319:Photosensitizing Agents / Q000494:pharmacology* / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D014183:Transplantation, Heterologous; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D007093:Imidazoles; D053583:Interleukin-1beta; D017319:Photosensitizing Agents; D011725:Pyridines; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D051546:Cyclooxygenase 2; D015232:Dinoprostone; C093642:SB 203580; D000111:Acetylcysteine