NVP-BEZ235 synergizes cisplatin sensitivity in osteosarcoma
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Jin-Cheng Huang1,2,*, Zhi-Fei Cui1,*, Shui-Mu Chen1,*, Lian-Jun Yang1, Hong-Kai Lian2, Bin Liu1, Zhi-Hai Su1, Jin-Shi Liu1, Min Wang1, Zheng-Bo Hu3, Jia-Yao Ouyang1, Qing-Chu Li1 and Hai Lu1
1Department of Orthopedics, The Third Affiliated Hospital of Southern Medical University, Academy of Orthopedics, Guangdong Province, Guangzhou 510665, China
2Department of Orthopedics, Zhengzhou Central Hospital, Zhengzhou University, Zhengzhou 450000, China
3Department of Orthopedics, The Affiliated Shaoguan Hospital, Southern Medical University, Orthopedic Institute of Shaoguan, Shaoguan 512000, China
Qing-Chu Li, email: [email protected]
Hai Lu, email: [email protected]
Keywords: osteosarcoma (OS); cisplatin; chemotherapy; autophagy
Abbreviations: OS: Osteosarcoma; PI3K: Phosphoinositide 3-kinase; mTOR: mammalian target of rapamycin; 3-MA : 3-Methyladenine; CQ: Chloroquine Phosphate.
Received: May 29, 2017 Accepted: December 13, 2017 Published: December 27, 2017
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.
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