Proton beam radiation induces DNA damage and cell apoptosis in glioma stem cells through reactive oxygen species.

R Alan Mitteer,Jennifer Shah,Yi Fan,Hyun Jun Kim,Alejandro Carabe-Fernandez,Sherika Gordon,Consuelo Guardiola-Salmeron,Param-Puneet Butter,Marcus Fager,Yanling Wang

doi:10.1038/srep13961

R Alan Mitteer, Jennifer Shah + Show 8 more

Open Access

https://doi.org/10.1038/srep13961

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Abstract

Glioblastoma multiforme (GBM) is among the most lethal of human malignancies. Most GBM tumors are refractory to cytotoxic therapies. Glioma stem cells (GSCs) significantly contribute to GBM progression and post-treatment tumor relapse, therefore serving as a key therapeutic target; however, GSCs are resistant to conventional radiation therapy. Proton therapy is one of the newer cancer treatment modalities and its effects on GSCs function remain unclear. Here, by utilizing patient-derived GSCs, we show that proton radiation generates greater cytotoxicity in GSCs than x-ray photon radiation. Compared with photon radiation, proton beam irradiation induces more single and double strand DNA breaks, less H2AX phosphorylation, increased Chk2 phosphorylation, and reduced cell cycle recovery from G2 arrest, leading to caspase-3 activation, PARP cleavage, and cell apoptosis. Furthermore, proton radiation generates a large quantity of reactive oxygen species (ROS), which is required for DNA damage, cell cycle redistribution, apoptosis, and cytotoxicity. Together, these findings indicate that proton radiation has a higher efficacy in treating GSCs than photon radiation. Our data reveal a ROS-dependent mechanism by which proton radiation induces DNA damage and cell apoptosis in GSCs. Thus, proton therapy may be more efficient than conventional x-ray photon therapy for eliminating GSCs in GBM patients.

Highlights

Glioblastoma multiforme (GBM), the grade IV glioma, is the most common primary brain tumor in humans
Proton radiation-induced apoptosis continually increased over time (3–6 days), while photon radiation-induced apoptosis was reduced over the same time period (Fig. 4B). These findings suggest that proton radiation-induced DNA damage and cytotoxicity are more irreparable and lead to further cell apoptosis in glioma stem cells (GSCs) when compared with photon therapy
Our study shows that proton radiation induces more robust DNA damage, cytotoxicity, and cell apoptosis than photon radiation, for the first time when using characterized cancer stem cells

Summary

Introduction

Glioblastoma multiforme (GBM), the grade IV glioma, is the most common primary brain tumor in humans. Proton therapy is one of the newer radiation treatment modalities and when compared with conventional x-ray photon radiation, proton beams can be deposited in small, precise areas with minimal lateral scattering in tissue, ensuring that little to no radiation is delivered to healthy tissue surrounding the tumor[5]. This makes proton therapy the preferred option for treating central nervous malignancies in order to minimize neurocognitive deficits in normal brain tissue[6,7,8]. Our data reveal that proton radiation induces greater DNA damage, cell cycle alteration, and cytotoxicity through reactive oxygen species (ROS)

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