Combining Radiotherapy With Pi3k Isoform-Specific Inhibitor Decreases Radioresistance And Suppresses Tumor Growth In Glioblastoma Cells

Abstract Glioblastoma (GBM) is the most malignant tumor that occurs within the brain and shows the dismal prognosis. The phosphoinositide 3-kinase (PI3K)-AKT signaling pathway plays a principal role in GBM. Also, Activated PI3K-AKT signaling by irradiation induces radioresistance. But, the pan-PI3K inhibitors cause side-effects in clinical trial. Different PI3K isoforms play non-redundant roles in brain tumor growth and regulating radioresistance. So it is expected that selective inhibition of PI3K isoforms decrease side effects. We demonstrated whether combining radiotherapy with the PI3K isoform inhibitor reduces radioresistance and tumor growth in GBM. Glioma261 expressed luciferase (GL261-luc) cell lines were used to investigate the synergistic effects of combining radiotherapy with the PI3K isoform inhibitors. GL261-luc were irradiated 1Gy with or without PI3K isoform inhibitors. GL261-luc irradiated by 1Gy was suppressed cell proliferation about 70% compared to control (p< 0.001). When irradiated with PI3K-isform inhibitor, each growth rate was about 18% (PI3K-pan, p< 0.00001), 25% (PI3K-alpha, p< 0.00001), 30% (PI3K-delta, p< 0.00001), 45% (PI3K-gamma/delta, p< 0.00001). Significant increase of DNA DSB and decrease of the migration ability were shown by combination radiotherapy with PI3K- isoform inhibitor. Especially, combining radiotherapy, PI3K-alpha inhibitor showed the effect similar to PI3K-pan inhibitor (In vitro). So, we analyzed combination therapy effects using PI3K-alphs inhibitor and radiotherapy in vivo. We demonstrated that combining radiotherapy with the PI3K-alpha isoform inhibitor markedly delayed tumor growth than radiotherapy only (p< 0.0001). Also, we confirmed that survival rate of intracranial GBM mouse was increased by combination therapy (p< 0.01). In addition, the expression of PD1, regulator of cancer immune system, in spleenocyte was increased by combination therapy (p< 0.001) (In vivo). Our results demonstrate that combining radiotherapy with the PI3K-alpha isoform improve radiosensitivity, which result in significant tumor growth delay and improved survival.