The natural compound obtusaquinone targets pediatric high-grade gliomas through ROS-mediated ER stress. Issue 1 (27th August 2020)

• Record Type: Journal Article
• Authors: Teng, Jian; Lashgari, Ghazal; Tabet, Elie I; Tannous, Bakhos A
• Is Part Of: Neuro-oncology advances. Volume 2:Issue 1(2020)
• Publication Date: 2020-08-27
• Subjects: cancer stem cells -- endoplasmic reticulum stress -- obtusaquinone -- pediatric high-grade gliomas -- reactive oxygen species; 616.99481
• DOI: 10.1093/noajnl/vdaa106
• Languages: English
• ISSNs: 2632-2498

Abstract

Abstract: Background: Pediatric high-grade gliomas (pHGGs) are aggressive primary brain tumors with local invasive growth and poor clinical prognosis. Treatment of pHGGs is particularly challenging given the intrinsic resistance to chemotherapy, an absence of novel therapeutics, and the difficulty of drugs to reach the tumor beds. Accumulating evidence suggests that production of reactive oxygen species (ROS) and misfolded proteins, which typically leads to endoplasmic reticulum (ER) stress, is an essential mechanism in cancer cell survival. Methods: Several cell viability assays were used in 6 patient-derived pHGG cultures to evaluate the effect of the natural compound obtusaquinone (OBT) on cytotoxicity. Orthotopic mouse models were used to determine OBT effects in vivo. Immunoblotting, immunostaining, flow cytometry, and biochemical assays were used to investigate the OBT mechanism of action. Results: OBT significantly inhibited cell survival of patient-derived pHGG cells in culture. OBT inhibited tumor growth and extended survival in 2 different orthotopic xenograft models. Mechanistically, OBT induced ER stress through abnormal ROS accumulation. Conclusion: Our data demonstrate the utility and feasibility of OBT as a potential therapeutic option for improving the clinical treatment of pHGGs.