Buformin suppresses osteosarcoma via targeting AMPK signaling pathway

Abstract

AbstractBackgroundBuformin has been reported to be a powerful anticancer drug by activating the AMPK signal. Herein, we aimed to investigate the effects of buformin on osteosarcoma.Material and methodsCellular proliferative abilities were determined by cell counting kit-8 and colony formation assays. Cellular invasion was investigated using a transwell system. Cell cycle was examined by flow cytometry. Western blot was performed to measure the expression of key proteins. Synergistic effects of buformin and cisplatin were validated in seven fresh osteosarcoma tissues.ResultsBuformin suppressed the growth of U-2 OS cells in a dose-dependent manner (IC50 = 69.1 µM). Moreover, buformin induced cell cycle arrest (P < 0.001) and impaired cellular invasion (P = 0.038). Phosphorylation of AMPK was upregulated by buformin, while phosphorylation of S6, cyclin D1, and MMP9 were significantly downregulated. In addition, buformin notably induced accumulation of reactive oxygen species and lactate and eventually decreased ATP production. In both U-2 OS cells and the primary cultured osteosarcoma tissues, buformin increased tumor sensitivity to cisplatin.ConclusionsBuformin could suppress tumor growth and invasion of osteosarcoma through directly targeting the AMPK signaling pathway. Moreover, buformin inhibited the abnormal metabolism and notably increased the cytotoxicity of cisplatin, and therefore represents a new potential treatment option for osteosarcoma.