Proceedings of the National Academy of Sciences - PNAS, 2019-01, Vol.116 (5), p.1698-1703
2019
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- Autor(en) / Beteiligte
- Titel
- Suppression of chemotherapy-induced cytokine/lipid mediator surge and ovarian cancer by a dual COX-2/sEH inhibitor
- Ist Teil von
- Proceedings of the National Academy of Sciences - PNAS, 2019-01, Vol.116 (5), p.1698-1703
- Ort / Verlag
- United States: National Academy of Sciences
- Erscheinungsjahr
- 2019
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0027-8424eISSN: 1091-6490DOI: 10.1073/pnas.1803999116Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6358686
- Format
- –
- Schlagworte
- Animal models, Animals, Antineoplastic Agents - adverse effects, Antineoplastic Agents - pharmacology, Ascites, Biological Sciences, Bridged-Ring Compounds - pharmacology, Cancer, Carcinoma, Ovarian Epithelial - drug therapy, Carcinoma, Ovarian Epithelial - metabolism, Cell Proliferation - drug effects, Chemotherapy, Cyclooxygenase 2 - metabolism, Cyclooxygenase 2 Inhibitors - pharmacology, Cyclooxygenase-2, Cytokines, Cytokines - metabolism, Debris, Detritus, Disease Models, Animal, Disease Progression, Epoxide hydrolase, Epoxide Hydrolases - antagonists & inhibitors, Female, Inflammation, Inflammation - drug therapy, Inflammation - metabolism, Inhibitors, Lipids, Macrophages, Macrophages - drug effects, Macrophages - metabolism, Mice, Mice, Inbred C57BL, Mice, SCID, Ovarian cancer, Ovarian Neoplasms - drug therapy, Ovarian Neoplasms - metabolism, Pharmacology, Platinum, Platinum - pharmacology, Signal Transduction - drug effects, Staphylococcal enterotoxin H, Taxanes, Taxoids - pharmacology, Tumors