J Cancer 2020; 11(19):5802-5811. doi:10.7150/jca.46697

Research Paper

Moxidectin induces Cytostatic Autophagic Cell Death of Glioma Cells through inhibiting the AKT/mTOR Signalling Pathway

Jingjing Liu1,5#, Hongsheng Liang2#, Saadia Khilji3, Haitao Li1, Dandan Song1, Chen Chen1, Xiaoxing Wang1, Yiwei Zhang2, Ning Zhao1, Xina Li4, Aili Gao1✉

1. School of Life Science, Northeast Agricultural University, Harbin, Heilongjiang, China.
2. Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
3. Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
4. Department of Pharmacy, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
5. College of Life and Health Sciences, Northeastern University, Shenyang, Liaoning, China.
#These authors contributed equally to this work.

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Citation:
Liu J, Liang H, Khilji S, Li H, Song D, Chen C, Wang X, Zhang Y, Zhao N, Li X, Gao A. Moxidectin induces Cytostatic Autophagic Cell Death of Glioma Cells through inhibiting the AKT/mTOR Signalling Pathway. J Cancer 2020; 11(19):5802-5811. doi:10.7150/jca.46697. Available from http://www.jcancer.org/v11p5802.htm

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Abstract

Moxidectin (MOX), a broad-spectrum antiparasitic drug, has been characterized as a potential anti-glioma agent. The main objective of this study was to explore autophagy induced by MOX in glioma U251 and C6 cells, and the deep underlying molecular mechanisms. In addition, the effects of autophagy on apoptosis in glioma cells were tested. Autophagy was measured by transmission electron microscopy (TEM), immunofluorescence, western blot and immunohistochemistry. Cell viability was detected with MTT and colony formation assay. The apoptosis rate was measured by flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL). Additonally, autophagy inhibition was achieved by using 3-Methyladenine (3-MA) and chloroquine (CQ). U251-derived xenografts were established for examination of MOX-induced autophagy on glioma in vivo. Firstly, our research found that MOX stimulated autophagy of glioma cells in a dose-dependent manner. Secondly, we found that MOX induced autophagy by inhibiting the AKT/mTOR signalling pathway. Thirdly, inhibition of autophagy could reduce apoptosis in MOX-treated glioma cells. Finally, MOX induced autophagy, and autophagy increased the apoptosis effect of MOX on U251 in vivo. In conclusion, our data provide evidence that MOX can induce autophagy in glioma cells, and autophagy could increase MOX-induced apoptosis through inhibiting the AKT/mTOR signalling pathway. These findings provided a new prospect for the application of MOX and a novel targeted therapy for the treatment of gliomas.

Keywords: Moxidectin, Glioma, Autophagy, AKT/mTOR