S100B suppression alters polarization of infiltrating myeloid-derived cells in gliomas and inhibits tumor growth

Abstract

S100B, a member of the multigene family of Ca 2+ -binding proteins, is overexpressed by most malignant gliomas but its biological role in gliomagenesis is unclear. Recently, we demonstrated that low concentrations of S100B attenuated microglia activation through the induction of STAT3. Furthermore, S100B downregulation in a murine glioma model inhibited macrophage trafficking and tumor growth. Based on these observations, we hypothesized that S100B inhibitors may have antiglioma properties through modulation of tumor microenvironment. To discover novel S100B inhibitors, we developed a high-throughput screening cell-based S100B promoter-driven luciferase reporter assay. Initial screening of 768 compounds in the NIH library identified 36 hits with >85% S100B inhibitory activity. Duloxetine (Dul, an SNRI) was selected for the initial proof-of-concept studies. At low concentrations (1–5 μM) Dul inhibited S100B and CCL2 production in mouse GL261 glioma cells, but had minimal cytotoxic activity in vitro . In vivo , however, Dul (30 mg/kg/14 days) inhibited S100B production, altered the polarization and trafficking of tumor-associated myeloid-derived cells, and inhibited the growth of intracranial GL261 gliomas. Dul therapeutic efficacy, however, was not observed in the K-Luc glioma model that expresses low levels of S100B. These findings affirm the role of S100B in gliomagenesis and justify the development of more potent S100B inhibitors for glioma therapy. • S100B is overexpressed by most malignant gliomas but its biological role in gliomagenesis is unclear. • S100B downregulation in a murine glioma model inhibits macrophage trafficking and tumor growth. • High-throughput screening assay was developed to discover novel S100B inhibitors. • Duloxetine, a serotonin-norepinephrine reuptake inhibitor, was identified as an inhibitor of S100B. • In a murine glioma model, duloxetine inhibited S100B production and tumor growth, and altered polarization of macrophages.