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

Significance Our study demonstrates that ovarian tumor cell debris generated by front-line chemotherapy promotes tumor growth by stimulating the release of proinflammatory cytokines and lipid mediators in the tumor microenvironment. Targeting the debris-mediated surge of protumorigenic factors provides a strategy for enhancing the efficacy of cytotoxic therapies. Here, we show that the dual cyclooxygenase-2 (COX-2) and soluble epoxide hydrolase (sEH) inhibitor PTUPB prevented the chemotherapy-induced cytokine/lipid surge and suppressed debris-stimulated ovarian tumor growth. Dual COX-2/sEH inhibition may have clinical implications for use in combination with cytotoxic cancer therapies to alleviate debris-mediated inflammation. Our results indicate that PTUPB may act as a “surge protector” against therapy-induced protumorigenic mediators to improve patient survival by preventing tumor recurrence. 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.