IL1 Receptor Antagonist Inhibits Pancreatic Cancer Growth by Abrogating NF-κB Activation

Abstract

Purpose: Constitutive NF-kB activation is identified in about 70% of pancreatic ductal adenocarcinoma (PDAC) cases and is required for oncogenic KRAS-induced PDAC development in mouse models. We sought to determine whether targeting IL-1a pathway would inhibit NF-kB activity and thus suppress PDAC cell growth.Experimental Design: We determined whether anakinra, a human IL-1 receptor (rhIL-1R) antagonist, inhibited NF-kB activation. Assays for cell proliferation, migration, and invasion were performed with rhIL-1R antagonist using the human PDAC cell lines AsPc1, Colo357, MiaPaCa-2, and HPNE/K-ras G12V

Inhibition of the NF-κB pathway by nafamostat mesilate suppresses colorectal cancer growth and metastasis

“…We recently reported that inhibition of the NF-κB upstream inducer, IL-1α, using a clinically available antagonist (anakinra) suppressed pancreatic cancer in vitro and in vivo [27]. In this study, we focused on nafamostat mesilate, an anti-inflammatory drug used to treat pancreatitis.…”

“…Emerging evidence suggests that several conventional cancer chemotherapeutic agents that activate NF-κB/p65 lead to unfavorable clinical outcome [27,32,33], and the DNA-binding ability of NF-κB/ p65 has been proposed as a major mechanism contributing to chemoresistance in CRC [9,22,34]. The naturally occurring compound thymoquinone could abrogate oxaliplatin-induced activation of NF-κB/p65 and enhance sensitivity to oxaliplatin in pancreatic cancer [32].…”

Interleukin-1 and Related Cytokines in the Regulation of Inflammation and Immunity

“…IL-1-mediated tumor promotion has been identified in different murine and human tumor types, including sarcomas, melanoma, pancreatic ductal adenocarcinoma (Ling et al, 2012;Melisi et al, 2009;Tjomsland et al, 2013;Zhuang et al, 2016), myelomas (Lust et al, 2016), and breast carcinomas and involves different mechanisms ( Figure 4A). IL-1 has been shown to sustain the expansion and immunosuppressive function of myeloid cells in tumor-bearing mice (Elkabets et al, 2010;Kaplanov et al, 2019;Pan et al, 2017).…”

Pancreatic Cancer and Obesity: Some Molecular Perspectives

“…Data from mouse models of PC showed that NF-kB is required for oncogenic K-Ras-induced tumor development. Treatments with Gemcitabine alone or in combination with IL-1 inhibitors decreased IL-1α-induced NF-kB activity, and reduced PC growth [29].…”