VS-5584 Inhibits Human Osteosarcoma Cells Growth by Induction of G1- phase Arrest through Regulating PI3K/mTOR and MAPK Pathways.

Abstract

Activation of the PI3K/mTOR signaling pathway plays a key role in the progression of human osteosarcoma. Studies have confirmed that VS-5584 was a novel inhibitor of the PI3K/mTOR pathway, and displayed potential anticancer activity. To explore the anticancer effect and underlying mechanism of VS-5584 against the growth of human osteosarcoma cells. U2OS and MG-63 human osteosarcoma cells were cultured and the cytotoxicity, cell apoptosis in VS-5584-treated cells were explored by the CCK8 assay, flow cytometric analysis and western blot. Cell migration and tube formation were also employed to examine the anticancer potential. The results showed that VS-5584 treatment dose-dependently inhibited the growth of U2OS and MG-63 cells by induction of G1-phase arrest through regulating p21, p27, Cyclin B1 and Cdc2. Further investigation revealed that VS-5584 treatment effectively inhibited the PI3K/mTOR signaling pathway and triggered MAPK phosphorylation. Moreover, VS-5584 treatment dramatically suppressed cell migration and tube formation of HUVECs, followed by the down-regulation of HIF-1α and VEGF. Our findings validated that VS-5584 may be a promising anticancer agent with potential application in the chemotherapy and chemoprevention of human osteosarcoma.