The natural compound obtusaquinone targets pediatric high-grade gliomas through ROS-mediated ER stress

Author:

Teng Jian12ORCID,Lashgari Ghazal12,Tabet Elie I12,Tannous Bakhos A12ORCID

Affiliation:

1. Experimental Therapeutics and Molecular Imaging Unit, Department of Neurology, Neuro-Oncology Division, Massachusetts General Hospital, Boston, Massachusetts, USA

2. Program in Neuroscience, Harvard Medical School, Boston, Massachusetts, USA

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.

Funder

National Institutes of Health

National Institute of Neurological Disorders and Stroke

Publisher

Oxford University Press (OUP)

Subject

Electrical and Electronic Engineering,Building and Construction

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