EXTH-23. EFFECT OF EVOGLIPTIN AND TEMOZOLOMIDE COMBINATION THERAPY FOR THE TREATMENT OF GLIOBLASTOMA, IN VITRO AND IN VIVO

Abstract A recent study showed that high dipeptidyl-peptidase IV (DPP4) expression affects glioma progression. The purpose of this study is to investigate the synergistic effect of a DDP4 inhibitor, evogliptin and temzolomide (TMZ) combination therapy for glioblastoma (GBM) in vitro and in vivo. U87, U252, and A172 cells were treated with 50, 250, and 500 uM TMZ or with 5, 10, and 20 mM evogliptin for 24, 48 and 72 hrs. For in vivo experiment, GBM xenograft models were used. Three groups (n=5 mice) were treated with TMZ(15mg/kg/day), evogliptin (2mg/25g/day), and combination of TMZ and evogliptin via i.p. injection for 4 weeks. For evaluating the relevant mechanism, Affymetrix miRNA arrays are used. The MTT assay revealed that the combination treatment had higher cytotoxicity against U87, U251, and A172 cells than the monotherapy had after 48 and 72-hr treatment. mRNA DDP4 levels were much more decreased after combination administration. The median survival of each group was 43.6, 55.2, 53.2, 65.2, and 71.3 days in the control, evogliptin, TMZ, the first combination therapy with low-dose evogliptin (2mg/25g/day) and TMZ, and the second combination therapy with high-dose evogliptin (10mg/25g/day) and TMZ, respectively. In Affymetrix miRNA arrays, miR-1246, miR-149-3p, miR-3148, miR-4440, miR-4484, miR-4535, miR-6126, miR-6780b-5p, and miR-7110-5p were increased after evogliptin treatment. miR-149-5p, miR-23a-5p, miR-3195, miR-4330, miR-4497, miR-4669, miR-671-3p, and miR-744-5p were decreased. miR-4440 and miR-6780b-5p were also increased following combination therapy. In the TCGA dataset, the survival of glioma patients with low DPP4 expression is longer than that in patients with high DPP4. A DDP4 inhibitor, evoglipin regulates miRNA in GBM cell lines. The combination of evogliptin and TMZ had a moderate effect on the treatment of GBM in vitro and in vivo. miR-4440 and miR-6780b-5p could be associated with inhibiting the proliferation of GBM cells by targeting DPP4.