CSIG-14. REPURPOSING LOMERIZINE, T-TYPE CALCIUM CHANNEL BLOCKER, AS A THERAPEUTIC STRATEGY FOR GLIOBLASTOMA BY TARGETING THE IL-6/STAT3 PATHWAY

Abstract INTRODUCTION The presence of glioma stem/initiating cells (GICs) is known to cause strong treatment resistance of glioblastoma (GBM). To identify novel treatments for GBMs targeting GICs, we performed drug repurposing screening and identified several T-type calcium channel blockers, including lomerizine. OBJECTIVE The aim of this research was to investigate the therapeutic effect and the anti-GBM mechanism of lomerizine on GBM both in vitro and in vivo. METHODS We used three human patient-derived GICs, their differentiated cells, and four GBM cell lines. We performed proliferation assay with all cell lines, and sphere limiting dilution assay and sphere-forming assay with GICs. Induction of apoptosis and cell cycle arrest was evaluated using flow cytometry. Various signaling pathways altered by lomerizine were analyzed by Western blotting. Anti-GBM effects of lomerizine in vivo were assessed two mouse brain tumor models with different molecular subtypes. RESULTS Especially in GICs, lomerizine inhibited proliferation in all cell lines used, partially dependent on T-type calcium channel antagonism. Lomerizine induced apoptosis and G1 arrest. Furthermore, lomerizine suppressed sphere formation and self-renewal ability in all GICs. STAT3 was dephosphorylated by lomerizine in a dose-dependent manner in all cell lines for more than 24 hours. Interestingly, the inhibition of phospho-STAT3Y705 expression induced by lomerizine treatment was partially canceled by T-type calcium channel enhancer pretreatment in almost all GIC and glioma cell lines. AKT and ERK were deactivated in only GICs. In vivo experiments showed a significant tumor suppression and prolongation of overall survival in the group of mice treated with lomerizine in both mouse models. CONCLUSION Based on our data, lomerizine holds potential as a novel GBM therapeutic agent targeting both GICs and differentiated glioma cells.