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Published on: March 28, 2021
The therapeutic value of XL388 in human glioma cells
Shan Zhong1, Jun Xue1, Jiao-Jiao Cao2
1Department of Neurosurgery, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
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.
Insights
XL388, an oral PI3K-mTOR inhibitor, effectively reduced glioma cell growth, survival, and migration. It induced apoptosis via both Akt-mTOR-dependent and -independent pathways, showing promise in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Glioblastoma (GBM) remains a challenging brain tumor with limited treatment options.
- The phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway is frequently dysregulated in GBM, driving tumor growth and survival.
Purpose of the Study:
- To investigate the efficacy and mechanisms of XL388, an ATP-competitive PI3K-mTOR dual inhibitor, against human glioma cells.
- To evaluate the in vivo anti-glioma activity of XL388.
Main Methods:
- In vitro studies using established and primary human glioma cell lines (including Akt1-knockout cells).
- Assessment of cell viability, proliferation, migration, invasion, cell cycle, apoptosis, and signaling pathway activation (Akt-mTOR, Nrf2).
- In vivo studies using subcutaneous A172 xenografts in severe combined immunodeficient mice with oral administration of XL388.
Main Results:
- XL388 potently inhibited glioma cell survival, proliferation, migration, invasion, and cell cycle progression.
- XL388 induced apoptosis and inhibited Akt-mTORC1/2 signaling, with cytotoxicity observed even in Akt1-knockout cells.
- XL388 downregulated MAFG, inhibited Nrf2 signaling, and caused oxidative stress, which was partially reversed by antioxidants.
- Oral XL388 administration suppressed A172 xenograft growth in vivo, with evidence of target engagement.
Conclusions:
- XL388 demonstrates potent anti-glioma activity through both PI3K-mTOR-dependent and -independent mechanisms.
- XL388's ability to induce oxidative stress via MAFG/Nrf2 inhibition contributes to its cytotoxicity.
- XL388 shows therapeutic potential as an orally available agent for glioma treatment.
