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

Proc Natl Acad Sci U S A. 2019 Jan 29;116(5):1698-1703. doi: 10.1073/pnas.1803999116. Epub 2019 Jan 15.


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.

Keywords: cyclooxygenase; debris; inflammation; oxylipins; soluble epoxide hydrolase.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / adverse effects*
  • Antineoplastic Agents / pharmacology*
  • Bridged-Ring Compounds / pharmacology
  • Carcinoma, Ovarian Epithelial / drug therapy
  • Carcinoma, Ovarian Epithelial / metabolism
  • Cell Proliferation / drug effects
  • Cyclooxygenase 2 / metabolism*
  • Cyclooxygenase 2 Inhibitors / pharmacology*
  • Cytokines / metabolism*
  • Disease Models, Animal
  • Disease Progression
  • Epoxide Hydrolases / antagonists & inhibitors*
  • Female
  • Inflammation / drug therapy
  • Inflammation / metabolism
  • Lipids
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, SCID
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / metabolism
  • Platinum / pharmacology
  • Signal Transduction / drug effects
  • Taxoids / pharmacology


  • Antineoplastic Agents
  • Bridged-Ring Compounds
  • Cyclooxygenase 2 Inhibitors
  • Cytokines
  • Lipids
  • Taxoids
  • taxane
  • Platinum
  • Cyclooxygenase 2
  • Epoxide Hydrolases