Post-radiation treatment of 3,3'-diselenodipropionic acid augments cell kill by modulating DNA repair and cell migration pathways in A549 cells.

ABSTRACT

Aim of the present study was to test whether ionizing radiation (IR) treatment along with 3,3'-diselenodipropionic acid (DSePA), a redox active organodiselenide achieved better tumor control by suppressing the growth and migration of lung cancer cells. The results indicated that post-IR (2 Gy) treatment of DSePA (5 µM) led to a significantly higher cell death as compared to that of DSePA and IR treatments separately. Importantly, combinatorial treatment also showed reduction in the proportion of cancer stem cells and the clonogenic survival of A549 cells. The mechanistic studies indicated that combinatorial treatment although exhibited reductive environment (marked by decrease in ROS and increase of GSH/GSSG) at early time points (2-6 h postradiation), slowed DNA repair, inhibited epithelial-mesenchymal transition (EMT)/cell migration and induced significant level of apoptosis. DSePA mediated suppression of ATM/DNAPKs/p53 (DNA damage response signaling) and Akt/G-CSF (EMT) pathways appeared to be the major mechanism responsible for its radio-modulating activity. Finally, the combined treatment of IR (2 Gy × 4) and DSePA (0.1-0.25 mg/kg body weight daily through oral gavage) showed a significantly higher tumor suppression of the A549 xenograft as compared to that of DSePA and IR treatments separately in the mouse model. In conclusion, post-IR treatment of DSePA augmented cell kill by inhibiting DNA repair and cell migration in A549 cells.