Cyclovirobuxine D inhibits the growth of osteosarcoma cells through the induction of autophagy flux arrest by promoting lysosomal acidification

Osteosarcoma (OS) is an aggressive primary tumor with the highest incidence in children and adolescents. Natural plant compounds (NPCs) have long been promising resources in the field of antitumor drug discovery because of their high efficacy and low toxicity. Here, the aim of this study is to investigate the potential inhibitory effects of Cyclovirobuxine D (CVB-D), a natural bioactive isolated from the traditional Chinese medicinal herb Huangyang, on OS cells. We showed that CVB-D reduced OS cell growth in vitro and in vivo. Mechanistically, CVB-D inhibited PI3K-AKT-mTOR pathway and initiated autophagy. On the other hand, CVB-D induced lysosomal over-acidification by interacting with the V-type proton ATPase 116 kDa subunit a1 (ATP6V0A1), ultimately leading to autophagy flux arrest which might be related to the inhibitory effect of CVB-D on OS cells. Conclusively, our results propose a potential foundation for CVB-D to be developed into an anti-OS drug and an autophagy inhibitor.