Abstract
Modulation of β-catenin signaling has attractive therapeutic potential in cancer immunotherapy. Several studies have found that β-catenin can mediate immune evasion in cancer and promote anti-inflammatory features of antigen-presenting dendritic cells. Many small molecular compounds that inhibit Wnt/β-catenin signaling are currently in clinical development, but none have entered routine clinical use. New inhibitors of β-catenin signaling are consequently desirable. Here, we have tested, in monocyte-derived dendritic cells, the effects of two small molecular compounds, axitinib and nitazoxanide, that previously have been discovered to inhibit β-catenin signaling in colon cancer cells. Immature and lipopolysaccharide-matured dendritic cells prepared from healthy blood donor buffy coats were stimulated with 6-bromoindirubin-3′-oxime (6-BIO) to boost basal β-catenin activity, and the effects of axitinib and nitazoxanide were compared with the commercial β-catenin inhibitor ICG-001. Assays, including genome-wide RNA-sequencing, indicated that neither axitinib nor nitazoxanide demonstrated considerable β-catenin inhibition. Both compounds were found to be less toxic to monocyte-derived dendritic cells than either 6-BIO or ICG-001. Axitinib stimulated several aspects of dendritic cell function, such as IL12-p70 secretion, and counteracted IL-10 secretion, according to the present study. However, neither axitinib nor nitazoxanide were found to be efficient β-catenin inhibitors in monocyte-derived dendritic cells.
Highlights
ICG-001 showed a toxic effect at 40 μM, but the effects were minimal at concentrations up to 10 μM (Figure 1B)
The β-catenin inhibitors nitazoxanide and axitinib showed no toxic effects on monocyte-derived dendritic cells (moDCs) up to 40 μM and 20 μM, respectively (Figure 1C,D)
Utilizing this model system in the present work, we aimed to investigate the ability of the two small molecular compounds axitinib and nitazoxanide to inhibit β-catenin compared with the β-catenin inhibitor ICG-001
Summary
Utilizing this model system in the present work, we aimed to investigate the ability of the two small molecular compounds axitinib and nitazoxanide to inhibit β-catenin compared with the β-catenin inhibitor ICG-001
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