title: Anticancer drug bortezomib increases interleukin-8 expression in human monocytes.
abstract: Bortezomib (BZ) is the first clinically approved proteasome inhibitor that has shown remarkable anticancer activity in patients with hematological malignancies. However, many patients relapse and develop resistance; yet, the molecular mechanisms of BZ resistance are not fully understood. We have recently shown that in solid tumors, BZ unexpectedly increases expression of the pro-inflammatory and pro-angiogenic chemokine interleukin-8 (IL-8), while it inhibits expression of other NFκB-regulated genes. Since monocytes and macrophages are major producers of IL-8, the goal of this study was to test the hypothesis that BZ increases the IL-8 expression in human monocytes and macrophages. Here, we show that BZ dramatically increases the IL-8 expression in lipopolysaccharide (LPS)-stimulated U937 macrophages as well as in unstimulated U937 monocytes and peripheral blood mononuclear cells, while it inhibits expression of IL-6, IL-1 and tumor necrosis factor-α. In addition, our results show that the underlying mechanisms involve p38 mitogen-activated protein kinase, which is required for the BZ-induced IL-8 expression. Together, these data suggest that the BZ-increased IL-8 expression in monocytes and macrophages may represent one of the mechanisms responsible for the BZ resistance and indicate that targeting the p38-mediated IL-8 expression could enhance the BZ effectiveness in cancer treatment.
authors: Department of Biological Sciences, St. John's University, New York, NY 11439, USA.
authors: Shannon
authors: S
authors: Sanacora
authors: Department of Biological Sciences, St. John's University, New York, NY 11439, USA.
authors: Joaquin
authors: J
authors: Urdinez
authors: Department of Biological Sciences, St. John's University, New York, NY 11439, USA.
authors: Tzu-Pei
authors: TP
authors: Chang
authors: Department of Biological Sciences, St. John's University, New York, NY 11439, USA. Electronic address: vancuroi@stjohns.edu.
authors: Ivana
authors: I
authors: Vancurova
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D020298:U937 Cells; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D016209:Interleukin-8; D011719:Pyrazines; D000069286:Bortezomib; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Bortezomib; Interleukin-8; Macrophages; Monocytes; NFκB; p38 MAPK