ET-12 ANTI-VEGF THERAPY WITH KETOGENIC DIET AGAINST GLIOBLASTOMA IN MOUSE MODEL

Abstract

NTRODUCTUIONMalignant glioma cells critically depend on glucose as the main energy source to survive and sustain their aggressive properties. The ketogenic diet (KD) has been proposed as a complementary therapy for treatment of malignant gliomas. VEGF inhibitor (bevacizumab) decreases blood supply to tumor and clinically used for glioblastoma treatment. Therefore, we examined anti-tumor effect of the combination of bevacizumab (Bev) and KD using mouse model.METHODSU87MG cells were implanted into the right brain of nude mice. One week after the implantation, mice were randomized into four treatment groups: control group, KD group, Bev group, and combination (K+B) group. KetoCal 4:1 was administered to the mice for KD. Bev (10mg/kg) was injected from tail vein twice a week. Metabolic and histological analysis of the tumor, and survival analysis of the mice were performed.RESULTS3-hydroxy-butyrate, one of the ketone bodies, was significantly increased in the tumor of KD group, however, the metabolic enzymes of ketone bodies were not found an increased expression in immunostaining experiments. Principal component analysis (PCA) analysis demonstrated distinct clustering or a clear separation of the four groups. In K+B group, several TCA cycle-related enzymes (succinate dehydrogenase (SDH), fumarate-hydratase (FH)) were decreased, suggesting a repression of TCA cycle. In addition, several amino acids (tyrosine, valine, alanine, glutamic acid) were decreased in K+B tumor, however, alpha-ketoglutarate was significantly increased, suggesting dynamic metabolic remodeling. Histologically, Ki-67 index was most decreased in the K+B tumor among four groups. In survival analysis, Bev group had significant longer survival than control group (p=0.0016), and the K+B group had most longer survival time among four groups.CONCLUSIONSDrastic metabolic remodeling in the tumor occurred in the combination of Bev and KD This combination may be potentially useful for glioblastoma therapy.