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Antiglioma effects of cytarabine on leptomeningeal metastasis of high-grade glioma by targeting the PI3K/Akt/mTOR pathway

Authors Zhao KH, Zhang C, Bai Y, Li Y, Kang X, Chen JX, Yao K, Jiang T, Zhong XS, Li WB

Received 27 February 2017

Accepted for publication 5 May 2017

Published 26 June 2017 Volume 2017:11 Pages 1905—1915

DOI https://doi.org/10.2147/DDDT.S135711

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Salvatore Bongarzone

Peer reviewer comments 3

Editor who approved publication: Dr Qiongyu Guo

Kai-Hong Zhao,1 Can Zhang,2 Yue Bai,1 Yan Li,1 Xun Kang,1 Jian-Xin Chen,1 Kun Yao,3 Tao Jiang,4 Xiao-Song Zhong,2 Wen-Bin Li1

1Department of Glioma, 2Clinical Center of Gene And Cell Engineering, Beijing Shijitan Hospital, 3Department of Neurosurgery, Beijing Tiantan Hospital, 4Department of Pathology, Sanbo Brain Hospital, Capital Medical University, Beijing, People’s Republic of China

Abstract: Leptomeningeal metastasis (LM) of high-grade glioma is a highly lethal disease requiring new effective therapeutic measures. For both de novo or relapsed glioma with LM, intrathecal cytarabine chemotherapy is not frequently used for first-line and relapse protocols. We encountered a clinical case demonstrating effective application of cytarabine in high-grade glioma with LM, prompting us to explore the effects of cytarabine on malignant glioma and molecular mechanisms of such effects through in vivo and in vitro experiments. The U87 cell line was selected to represent human glioma for studies. Cell viability was measured by MTT assay, plate colony formation assay, and trypan-blue dye exclusion test. Apoptosis was assessed by flow cytometry. Protein expression levels were detected by Western blot assay and immunohistochemistry. mRNA expression was examined by quantitative real-time reverse transcription polymerase chain reaction. Cytarabine inhibited tumor growth during the in vivo experiment. The present study confirmed that cytarabine inhibits proliferation and promotes apoptosis of U87 cells, and molecular analysis of this effect showed that cytarabine significantly reduces expression of phosphatidylinositol 3-kinase/serine/threonine kinase also known as the protein kinase B/mechanistic target of rapamycin (PI3K/Akt/mTOR) pathway, Ki-67, BCL2, and 4-1BB, and upregulates Bax and cleaved caspase-3. Our findings indicated that intrathecal administration of cytarabine manifests potential in prophylaxis and treatment of malignant glioma with LM. Effective medications for high-grade glioma with LM should contain cytarabine.

Keywords: leptomeningeal metastases, malignant glioma, cytarabine, PI3K/Akt/mTOR

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