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The natural compound obtusaquinone targets pediatric high-grade gliomas through ROS-mediated ER stress
Jian Teng1,2, Ghazal Lashgari1,2, Elie I Tabet1,2
1Experimental Therapeutics and Molecular Imaging Unit, Department of Neurology, Neuro-Oncology Division, Massachusetts General Hospital, Boston, Massachusetts, USA.
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.
Insights
The natural compound obtusaquinone (OBT) effectively combats pediatric high-grade gliomas (pHGGs) by inducing endoplasmic reticulum (ER) stress. This research highlights OBT as a promising therapeutic candidate for these aggressive brain tumors.
Area of Science:
- Oncology
- Neuro-oncology
- Pharmacology
Background:
- Pediatric high-grade gliomas (pHGGs) are aggressive brain tumors with poor prognosis and limited treatment options.
- pHGGs exhibit resistance to chemotherapy and challenges in drug delivery to tumor sites.
- Cancer cell survival is linked to reactive oxygen species (ROS) production and endoplasmic reticulum (ER) stress.
Purpose of the Study:
- To evaluate the therapeutic potential of the natural compound obtusaquinone (OBT) against pediatric high-grade gliomas (pHGGs).
- To investigate the mechanism of action of OBT in pHGG cells and in vivo models.
Main Methods:
- Cytotoxicity of OBT was assessed using cell viability assays in patient-derived pHGG cultures.
- In vivo efficacy was evaluated in orthotopic mouse models of pHGG.
- Mechanism of action was explored using immunoblotting, immunostaining, flow cytometry, and biochemical assays.
Main Results:
- OBT significantly inhibited the survival of patient-derived pHGG cells in vitro.
- OBT demonstrated efficacy in reducing tumor growth and extending survival in orthotopic xenograft models.
- OBT was found to induce ER stress via the accumulation of ROS.
Conclusions:
- OBT exhibits significant anti-tumor activity against pHGGs.
- OBT represents a feasible and potentially effective therapeutic option for pHGG treatment.
- Targeting ER stress through OBT may offer a novel strategy for managing pediatric brain tumors.
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