Journal Article

Suppression of chemotherapy-induced cytokine/lipid mediator surge and ovarian cancer by a dual COX-2/sEH inhibitor

Sukhatme, Vikas P., Bielenberg, Diane R., Yang, Jun, Panigrahy, Dipak, Hwang, Sung Hee, Huang, Sui, Gartung, Allison, Schmidt, Birgitta A., Fernandes, Djanira, Kieran, Mark W., Hammock, Bruce D., Chang, Jaimie, Zurakowski, David

2019

Overview

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.

• Publisher: National Academy of Sciences
• Subject: Animal models / Ascites / Biological Sciences / Cancer / Chemotherapy / Cyclooxygenase-2 / Cytokines / Debris / Detritus / Epoxide hydrolase / Inflammation / Inhibitors / Lipids / Macrophages / Medical Sciences / Ovarian cancer / Pharmacology / Platinum / Staphylococcal enterotoxin H / Taxanes / Tumors