NVP-BEZ235 synergizes cisplatin sensitivity in osteosarcoma.

ABSTRACT

Osteosarcoma(OS) remains a major health concern in childhood and adolescence, although cisplatin is one of the gold standard chemotherapeutic drugs in the treatment of OS, chemoresistant to cisplatin is common. Phosphoinositide 3-kinase (PI3K)-Akt-mammalian target of rapamycin inhibitor (mTOR) pathway and autophagy regulates chemosensitivity incancer cells. In this study, we hypothesized that NVP-BEZ235, a dual inhibitor of PI3K/mTOR, could synergize cisplatin sensitivity in OS. In vitro, NVP-BEZ235 plus cisplatinexerted a synergistic effect on cell proliferation inhibition and apoptosis induction. Cisplatin could activate PI3K-Akt-mTOR pathway activity in early times, whereas, NVP-BEZ235 could inhibit PI3K-Akt -mTOR pathway activity all the times alone or combined with cisplatin. What's more, NVP-BEZ235 could switch function of autophagy induced by cisplatin to synergize cisplatin sensitivity. In vivo, pronounced decrease in tumor cell proliferation and increase in apoptosisin combination-treated mouse xenograft models compared with cisplatin or NVP-BEZ235 treated models. All these results suggest NVP-BEZ235 could synergize cisplatin sensitivity in OS, combination of NVP-BEZ235 with cisplatin could represent a novel therapeutic strategy for treatment of OS.