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.
Highlights
Glioma is the most common primary brain tumor and among the most aggressive of human cancers [1, 2]
We show that tetraspanin 8 (Tspan8) can form a complex with Rictor, which is required for mTOR complex 2 (mTORC2) activation and glioma cell migration [15]
By measuring CellROX fluorescence [35, 36], we show that XL388 induced significant reactive oxygen species (ROS) production in A172 cells (Figure 4D)
Summary
Glioma is the most common primary brain tumor and among the most aggressive of human cancers [1, 2]. Over 10, 000 people are diagnosed with glioma each year in the United States, mostly with high-grade tumors [3]. The average survival of glioma patients is less than a year after initial diagnosis [1, 2]. Significant progress has been made in glioma treatments, including neurosurgical resection, radiation and chemotherapy [1, 2]. The five-year survival rate remains very disappointing [1, 2]. It is urgent to explore more efficient targeted therapies [4]
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