Synergistic effects by arsenite in radiosensitization

Glioblastoma is frequently (about 30%) occured and radioresistant brain tumor. Arsenite that penetrates blood-brain-barrier is known to show its synergistic effects with radiation in vitro and in vivo. However, its mechanism remains unclear. As the synergistic radiosensitization has been reported in p53 deficient cancer cells, its radiosensitivity may be related to p53 function. Therefore, we analyzed radiosensitization using p53 deficient cell lines, U87MG-E6 inactivated p53 and HCT116 (p53-/-). Synergistic effects by arsenite in radiosensitivity were observed in both cell lines. Using irradiation with heavy-ion, we also identified synergistic radiosensitization by arsenite in U87MG-E6 cell lines. Effects of arsenite on cells is known to involve generation of reactive oxygen species (ROS). To examine contribution of ROS to the cellular toxicity of arsenite in the radiosensitivity, we studied survival fraction analysis (SF) using N-Acetyl-L-Cysteine (NAC), a ROS scavenger. The radiosensitization by arsenite was disappeared by NAC. On the other hand, as DNA damage induced by arsenite is repaired by BRCA2-dependent homologous recombination, we performed SF analysis using knock-down of BRCA2 with BRCA2 siRNA. The results revealed that the increased radiosensitivity by arsenite is disappeared by the knock-down of BRCA2.Moreover, because it was also demonstrated that suppression of cell growth by arsenite is due to abnormal amplification of centrosomes, we analyze its contribution to the increased radiosensitivity by arsenite. As a result of that, the increased radiosensitization by arsenite was correlated to the abnormal amplification of centrosomes.These results will be discussed referring to relationship between radiosensitization and p53 functions.the 56th Annual Conference of the Particle Therapy Co-operative Group (PTCOG56