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

Document Type

Article

Publication Date

1-29-2019

Publication Title

Proceedings of the National Academy of Sciences of the United States of America

Keywords

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

Abstract

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.

Clinical Institute

Cancer

Clinical Institute

Women & Children

Department

Institute for Systems Biology

Department

Oncology

Department

Obstetrics & Gynecology

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