title: Indomethacin sensitizes resistant transformed cells to macrophage cytotoxicity.
abstract: Activated macrophages are well known to exhibit anti-tumor properties. However, certain cell types show intrinsic resistance. Searching for a mechanism that could explain this phenomenon, we observed that the supernatant of resistant cells could confer resistance to otherwise sensitive tumor cells, suggesting the presence of a secreted suppressor factor. The effect was abolished upon dialysis, indicating that the suppressor factor has a low molecular weight. Further studies showed that prostaglandin E2 (PGE2) is secreted by the resistant tumor cells and that inhibition of PGE2 production by indomethacin, a cyclooxygenase (COX) inhibitor, eliminated the macrophage suppression factor from the supernatant, and sensitized the resistant tumor cells to macrophage cytotoxicity. This study emphasizes the important role of tumor-secreted PGE2 in escaping macrophage surveillance and justifies the use of COX inhibitors as an adjuvant for improving tumor immunotherapy.
authors.affiliation: Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA. Electronic address: totaryjainh@health.usf.edu.
authors.forename: Hana
authors.initials: H
authors.lastname: Totary-Jain
authors.affiliation: Department of Developmental Biology and Cancer Research, IMRIC, The Hadassah Medical School-Hebrew University of Jerusalem, Israel. Electronic address: ronit.sionov@mail.huji.ac.il.
authors.forename: Ronit Vogt
authors.initials: RV
authors.lastname: Sionov
authors.affiliation: The Lautenberg Center for General and Tumor Immunology, The Hadassah Medical School-Hebrew University of Jerusalem, Israel. Electronic address: ruthg@ekmd.huji.ac.il.
authors.forename: Ruth
authors.initials: R
authors.lastname: Gallily
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D015232:Dinoprostone / Q000378:metabolism; D005260:Female; D007167:Immunotherapy / Q000379:methods*; D007213:Indomethacin / Q000494:pharmacology*; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D019899:Paracrine Communication; D019139:Tumor Escape
chemical_list: D016861:Cyclooxygenase Inhibitors; D015232:Dinoprostone; D007213:Indomethacin
keywords: Indomethacin; Macrophage cytotoxicity; PGE(2); TNFα; Tumor cell resistance