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Research Paper|Volume 12, Issue 22|pp 22550—22563

The therapeutic value of XL388 in human glioma cells

Shan Zhong1, Jun Xue1, Jiao-Jiao Cao2, Bomin Sun2, Qing-Fang Sun1, Liu-Guan Bian1, Liang-Yun Hu2, Si-Jian Pan1
  • 1Department of Neurosurgery, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
  • 2Department of Stereotactic and Functional Neurosurgery, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
* Equal contribution
Received: May 3, 2020Accepted: June 22, 2020Published: November 6, 2020
https://doi.org/10.18632/aging.103791

Copyright: © 2020 Zhong et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

XL388 is a highly efficient and orally-available ATP-competitive PI3K-mTOR dual inhibitor. Its activity against glioma cells was studied here. In established and primary human glioma cells, XL388 potently inhibited cell survival and proliferation as well as cell migration, invasion and cell cycle progression. The dual inhibitor induced significant apoptosis activation in glioma cells. In A172 cells and primary human glioma cells, XL388 inhibited Akt-mTORC1/2 activation by blocking phosphorylation of Akt and S6K1. XL388-induced glioma cell death was only partially attenuated by a constitutively-active mutant Akt1. Furthermore, it was cytotoxic against Akt1-knockout A172 glioma cells. XL388 downregulated MAF bZIP transcription factor G (MAFG) and inhibited Nrf2 signaling, causing oxidative injury in glioma cells. Conversely, antioxidants, n-acetylcysteine, pyrrolidine dithiocarbamate and AGI-106, alleviated XL388-induced cytotoxicity and apoptosis in glioma cells. Oral administration of XL388 inhibited subcutaneous A172 xenograft growth in severe combined immunodeficient mice. Akt-S6K1 inhibition and MAFG downregulation were detected in XL388-treated A172 xenograft tissues. Collectively, XL388 efficiently inhibits human glioma cell growth, through Akt-mTOR-dependent and -independent mechanisms.