DD-05 * GSK3BETA INHIBITORY DRUGS ATTENUATE INVASION OF GLIOBLASTOMA CELLS

Abstract

PURPOSE: Glycogen synthase kinase (GSK) 3beta is an emerging and attractive therapeutic target against glioblastoma (GBM). Here, we investigated the efficacy of existing approved drugs inhibiting GSK3beta activity in vitro and in vivo on the basis of drug repositioning. METHOD: The effects of GSK3beta inhibiting drugs, cimetidine, lithium carbonate, olanzapine, and valproic acid, on the invasive ability of glioma cells (U87, T98G, U251) were evaluated using migration and invasion assays. GSK3beta activity after adding GSK3b inhibiting drugs was evaluated by detecting phosphorylation of glycogen synthase (GS) that is the primary substrate for GSK3beta. Expression and activity of matrix metalloproteinase (MMP)-2 were examined with gelatin zymography. These drugs were administered orally to GBM mouse model at therapeutic doses once daily for 2 weeks. Tissue sections were stained by standard hematoxylin and eosin technique, and satellite lesions that did not connect tumor bulk were counted. Immunohistochemistry was performed to detect the phosphorylated GS and nestin. RESULTS: Inhibition of GSK3beta activity by each drug was confirmed in GBM cells in vitro and GBM mouse model. Each drug attenuated GBM cell migration and invasion in dose-dependent manner. Combination of all 4 drugs remarkably decreased MMP-2 expression and activity. All drugs reduced satellite lesions and nestin-positive cells in vivo. No adverse effect was observed in mice. CONCLUSION: GSK3beta-targeted therapy for GBM patients with approved 4 drugs showed promising effect to attenuate glioma invasion, possibly via suppression of stemness.