Suppression of chemotherapy-induced cytokine/lipid mediator surge and ovarian cancer by a dual COX-2/sEH inhibitor.
Proceedings of the National Academy of Sciences of the United States of America
Animals; Antineoplastic Agents; Bridged-Ring Compounds; Carcinoma, Ovarian Epithelial; Cell Proliferation; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cytokines; Disease Models, Animal; Disease Progression; Epoxide Hydrolases; Female; Inflammation; Lipids; Macrophages; Mice; Mice, Inbred C57BL; Mice, SCID; Ovarian Neoplasms; Platinum; Signal Transduction; Taxoids
Although chemotherapy is a conventional cancer treatment, it may induce a protumorigenic microenvironment by triggering the release of proinflammatory mediators. In this study, we demonstrate that ovarian tumor cell debris generated by first-line platinum- and taxane-based chemotherapy accelerates tumor progression by stimulating a macrophage-derived "surge" of proinflammatory cytokines and bioactive lipids. Thus, targeting a single inflammatory mediator or pathway is unlikely to prevent therapy-induced tumor progression. Here, we show that combined pharmacological abrogation of the cyclooxygenase-2 (COX-2) and soluble epoxide hydrolase (sEH) pathways prevented the debris-induced surge of both cytokines and lipid mediators by macrophages. In animal models, the dual COX-2/sEH inhibitor PTUPB delayed the onset of debris-stimulated ovarian tumor growth and ascites leading to sustained survival over 120 days postinjection. Therefore, dual inhibition of COX-2/sEH may be an approach to suppress debris-stimulated ovarian tumor growth by preventing the therapy-induced surge of cytokines and lipid mediators.
Women & Children
Institute for Systems Biology
Obstetrics & Gynecology
Gartung, Allison; Yang, Jun; Sukhatme, Vikas P; Bielenberg, Diane R; Fernandes, Djanira; Chang, Jaimie; Schmidt, Birgitta A; Hwang, Sung Hee; Zurakowski, David; Huang, Sui; Kieran, Mark W; Hammock, Bruce D; and Panigrahy, Dipak, "Suppression of chemotherapy-induced cytokine/lipid mediator surge and ovarian cancer by a dual COX-2/sEH inhibitor." (2019). Articles, Abstracts, and Reports. 1179.