IMPS-44S100B INHIBITION WITH DULOXETINE, A SEROTONIN-NOREPINEPHRINE REUPTAKE INHIBITOR, ALTERS MACROPHAGE POLARIZATION AND ABROGATES GLIOMA GROWTH IN MICE

Abstract

S100B, a member of the multigene family of Ca2 + -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-base S100B promoter-driven luciferase reporter assay. Initial screening of 25,904 compounds in NIH and ChemBridge libraries identified 1297 hits with >85% S100B inhibitory activity. One compound, duloxetine (Dul, a serotonin-norepinephrine reuptake inhibitor) was selected for the initial proof-of-concept studies. At low concentrations (1-5 □M) Dul inhibited S100B and CCL2 production by mouse GL261 glioma cell lines, but had minimal cytotoxic activity. In vivo, Dul (30 mg/kg/14 days) inhibited S100B production, altered polarization and trafficking of macrophages and abrogated 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 S100B inhibitors for glioma therapy.