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

• DOI: 10.1038/srep13961
• Publication Date: 2015-09-10T09:13:19Z
• Authors: R. Alan Mitteer; Yanling Wang; Jennifer Shah; Sherika Gordon; Marcus Fager; Param-Puneet Butter; Hyun Jun Kim; Consuelo Guardiol...; Alejandro Carabe-...; Yi Fan
• Keywords: 0301 basic medicine; 2. Zero hunger; Photons; DNA Repair; Cell Cycle; Apoptosis; Glioma; Article; 3. Good health; G2 Phase Cell Cycle Checkpoints; Checkpoint Kinase 2; 03 medical and health sciences; 0302 clinical medicine; Cell Line, Tumor; Radiation, Ionizing; Checkpoint Kinase 1; Neoplastic Stem Cells; Humans; Phosphorylation; Protons; Reactive Oxygen Species; Protein Kinases; DNA Damage

AbstractGlioblastoma 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.