Metformin enhances anti-cancer effects of cisplatin in meningioma through AMPK-mTOR signaling pathways

Liemei Guo; Jing Cui; Herui Wang; Rogelio Medina; Shilei Zhang; Xiaohua Zhang; Zhengping Zhuang; Yingying Lin

doi:10.1016/j.omto.2020.11.004

Metformin enhances anti-cancer effects of cisplatin in meningioma through AMPK-mTOR signaling pathways

Mol Ther Oncolytics. 2020 Nov 20:20:119-131. doi: 10.1016/j.omto.2020.11.004. eCollection 2021 Mar 26.

Authors

Liemei Guo¹, Jing Cui², Herui Wang², Rogelio Medina², Shilei Zhang³, Xiaohua Zhang¹, Zhengping Zhuang², Yingying Lin¹

Affiliations

¹ Department of Neurosurgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, No. 160, Pujian Road, District Pudong, Shanghai 200127, China.
² Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
³ Department of Pathology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, No. 160, Pujian Road, District Pudong, Shanghai 200127, China.

Abstract

Cisplatin is currently used to treat inoperable recurrent meningiomas, but its side effects and drug resistance limit its use. Metformin has recently been identified as a chemosensitizing agent. However, the combined treatment of cisplatin and metformin in high-grade meningiomas has not been reported. Herein, our findings demonstrate metformin significantly enhanced cisplatin-induced inhibition of proliferation in meningioma cells, which was associated with the induction of G0/G1 cell cycle arrest. Additionally, metformin activated adenosine monophosphate activated protein kinase (AMPK) and repressed the mammalian target of rapamycin (mTOR) signaling pathways via an AMPK-dependent mechanism. Furthermore, our xenograft murine model confirmed that metformin enhanced cisplatin's anti-cancer effect by upregulation of AMPK and downregulation of mTOR signaling pathways. In addition, in 63 patients with atypical meningiomas, the activation of AMPK was significantly associated with tumor recurrence and short disease-free survival (DFS). These results demonstrate metformin enhanced the anti-cancer effect of cisplatin in meningioma in vitro and in vivo, an effect mediated through the activation of AMPK and repression of mTOR signaling pathways. Our study suggests the combined treatment of metformin and cisplatin is an effective and safe treatment for high-grade meningiomas.

Keywords: AMPK; cisplatin; mTOR; meningioma; metformin.