Novel Binary Targeting Molecule Enhances Radiation Response in Glioma Model by Induction of DNA Damage and Delay of DNA Repair

The most common and deadliest primary brain tumor derives from the cells that support neurons in the brain and is called glioblastoma multiforme (GBM). Although glioblastomas are known to be one of the most radioresistant types of tumor, development of new targeted drugs and their combination with radiotherapy have spawned renewed interest and enthusiasm for investigating new treatments possibilities. The aim of this study was to investigate the effect of ZRBA1, EGFR/DNA damage binary targeting molecule, in combination with radiation on proliferation of human glioma cells. The effect of ZRBA1 on the radiosensitivity of U87 and U373 cell lines was evaluated using clonogenic assays and spheroid migration assay whereas DNA damage and cell cycle progression were evaluated by FACS assays. Our data revealed that exposure of GBMs cells to ZRBA1 before irradiation resulted in an increase in radiosensitivity with dose enhancement factors at surviving fraction of 0.1 ranging from 1.3 to 1.7. Additionally, such combinational treatment caused strong cell cycle arrest in the G2/M phase (up to 72h post-treatment), which was accompanied by increased level of phosphorylated H2AX histone (gamma-H2AX). Importantly, in contrast to Temozolomide which enhances radiation response most effectively in MGMT-negative cells, radio-sensitizing proprieties of ZRBA1 does not depend on the MGMT methylation status. Overall, we demonstrated that ZRBA1 can enhance tumor cell radiosensitivity in vitro and suggest that this effect could be related to an inhibition of DNA repair. Therefore we postulate that ZRBA1 may be developed as a potent and innovative radio-sensitizing agent to treat malignant glioma tumors.