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

• Type of Material: Article
• Authors: Allison Gartung, Harvard Medical School; Jun Yang, University of California Davis; Vikas Sukhatme, Emory University; Diane R. Bielenberg, Harvard Medical School; Djanira Fernandes, Harvard Medical School; Jaimie Chang, Harvard Medical School; Birgitta A. Schmidt, Harvard Medical School; Sung Hee Hwang, University of California Davis; David Zurakowski, Harvard Medical School; Sui Huang, Institute for Systems Biology; Mark W. Kieran, Harvard Medical School; Bruce D. Hammock, University of California Davis; Dipak Panigrahy, Harvard Medical School
• Language: English
• Date: 2019-01-29
• Publisher: National Academy of Sciences
• Publication Version: Final Published Version
• Copyright Statement: © 2019 National Academy of Sciences. All Rights Reserved.
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.1803999116
• Title of Journal or Parent Work: Proceedings of the National Academy of Sciences
• ISSN: 0027-8424
• Volume: 116
• Issue: 5
• Start Page: 1698
• End Page: 1703
• Grant/Funding Information: This work was supported by the National Cancer Institute Grants R01 01CA170549-02 and ROCA148633-01A4 (to D.P.); National Institute on Environmental Health Sciences Superfund Research Program P42 ES004699 and Grant R01 ES002710 (to B.D.H.); the Stop and Shop Pediatric Brain Tumor Fund (M.W.K.); the CJ Buckley Pediatric Brain Tumor Fund (M.W.K.); Alex Lemonade Stand (M.W.K.); Molly’s Magic Wand for Pediatric Brain Tumors (M.W.K.); the Markoff Foundation Art-In-Giving Foundation (M.W.K.); the Kamen Foundation (M.W.K.); Jared Branfman Sunflowers For Life (M.W.K.); the Joe Andruzzi Foundation (M.W.K.); and the Credit Unions Kids at Heart (D.P.).
• Keywords: BONE-MARROW; CYCLOOXYGENASE-2; cyclooxygenase; TUMOR-GROWTH; inflammation; BIOACTIVE LIPIDS; TISSUE-LEVELS INCREASE; Science & Technology - Other Topics; THERAPEUTIC TARGET; Science & Technology; CELL REPOPULATION; Multidisciplinary Sciences; debris; RECEPTIVE MICROENVIRONMENT; oxylipins; SOLUBLE EPOXIDE HYDROLASE; soluble epoxide hydrolase; PROMETASTATIC FACTORS
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Oncology; Health Sciences, Pathology

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.