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Glioblastoma (GBM) is the most common and lethal primary brain tumor in adults, but there is no effective drug available for GBM. Avasimibe is a potent inhibitor of acyl-coenzyme A: cholesterol acyltransferase-1 (ACAT-1), which was used to treat atherosclerosis. Experimental evidence and bioinformatics have shown that avasimibe has anticancer activity. In this study we investigated the anticancer effects of avasimibe on human glioblastoma cells and the underlying mechanisms. Our results showed that avasimibe dose-dependently inhibited the proliferation of U251 and U87 human glioblastoma cells with IC 50 values of 20.29 and 28.27 μM, respectively, at 48 h. Avasimibe (7.5, 15, 30 μM) decreased the DNA synthesis, and inhibited the colony formation of the tumor cells. Treatment of avasimibe also dose-dependently increased the apoptotic rate of tumor cells, decreased the mitochondrial membrane potential, induced the activity of caspase-3/7, and increased the protein expression of cleaved caspase-9, cleaved PARP and Bax in U251 and U87 cells. RNA-sequencing analyses revealed that avasimibe suppressed the expression of CDK2, cyclin E1, CDK4, cyclin D, CDK1, cyclin B1, Aurora A, and PLK1, while induced the expression of p53, p21, p27, and GADD45A, which was validated by Western blot analysis. These results demonstrated that avasimibe induced mitochondria-dependent apoptosis in glioblastoma cells, which was associated with arresting the cell cycle at G0/G1 phase and G2/M phase by regulating the p53/p21 pathway, p53/GADD45A and Aurora A/PLK1 signaling pathways. In U87 xenograft nude mice model, administration of avasimibe (15, 30 mg·kg -1 ·d -1 , ip, for 18 days) dose-dependently inhibit the tumor growth. Taken together, our results demonstrated that avasimibe might be a promising chemotherapy drug in the treatment of GBM.

Avasimibe exerts anticancer effects on human glioblastoma cells via inducing cell apoptosis and cell cycle arrest