Combined Strategy of Radioactive 125I Seeds and Salinomycin for Enhanced Glioma Chemo-radiotherapy: Evidences for ROS-Mediated Apoptosis and Signaling Crosstalk.

Abstract

Radioactive 125I seeds-based radiotherapy has achieved great success in treatment of human cancers. However, radioresistance and severe side effects badly limited its clinic application. Recently, chemoradiotherapy as a superior strategy has been rapidly developed and widely used in clinic. However, the underlying mechanism remains elusive. Herein, in the present study, a combined chemoradiation model of 125I seeds and salinomycin (SAL) in vitro and in vivo was designed, and the enhanced anticancer efficiency and mechanism were also evaluated in human glioma. The results showed that combined treatment of 125I seeds and SAL induced enhanced growth inhibition against human glioma cells through induction of cell apoptosis. Further investigation revealed that combined treatment of 125I seeds and SAL triggered enhanced DNA damage through inducing reactive oxide species (ROS) generation. Additionally, enhanced dysfunction of MAPKs and AKT pathways both contributed to combined treatment-induced growth inhibition against human glioma cells. Importantly, the U251 human glioma xenograft growth was effectively inhibited by combined treatment of 125I seeds and SAL by induction of cell apoptosis with involvement of inhibiting cell proliferation and angiogenesis. Taken together, our results indicated that combined treatment of 125I seeds and SAL achieved enhanced growth inhibition and apoptosis in human glioma in vitro and in vivo through triggering ROS-mediated DNA damage and regulation of MAPKs and AKT pathways, which validated that the combined strategy of using 125I seeds and SAL could be a highly efficient way to achieve enhanced glioma chemo-radiotherapy.